2024-03-29T10:39:20Zhttp://openarchive.ki.se/oai/requestoai:openarchive.ki.se:10616/483122024-03-08T19:12:04Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Cedstrand, Emma
2022-12-22T09:10:44Z
2022-12-22T09:10:44Z
2022-12-22
978-91-8016-821-2
http://hdl.handle.net/10616/48312
Background: Poor mental health, e.g. stress, anxiety, and depression, in the workplace is a challenge worldwide due to the individual suffering and its impact on sickness absence and productivity loss, causing societal costs. The World Health Organisation classifies stress as the health epidemic of the 21st century. Psychosocial working conditions, i.e., how work is organised and the social interplay at work, are health determinants. Thus, psychosocial hazards are one explanation for work-related mental ill-health. Interventions aiming to improve the psychosocial work environment are recommended. Still, there is a scarcity of studies evaluating occupational health interventions targeting psychosocial working conditions to prevent mental ill health. Also, the existing evidence of the effectiveness of such interventions is inconclusive. Implementation failure is described as one main obstacle to succeeding with these interventions. To tackle the global challenges of work-related stress, we need a better understanding of what can be done in the workplace to prevent employees from becoming ill due to workplace stressors.
Aim: This thesis aims to contribute to knowledge on how stress-related ill health can be prevented in the workplace and develop our understanding of the design and implementation of occupational health interventions.
Methods: This thesis comprises three papers that evaluate two occupational health interventions to improve the psychosocial work environment and mental health. The interventions were conducted within the human services (I) and construction industry (II & III), respectively. In study I, we applied an embedded mixed methods design to evaluate a participatory intervention to improve the psychosocial work environment and mental health (burnout and quality of sleep) within a municipality in Sweden. We utilised a controlled trial and a process evaluation exploring fidelity and participants’ reactions to the intervention activities, learning experiences, and changes in behaviours and work routines. We collected data through documentation, interviews and three waves of questionnaires. Differences in outcome variables (questionnaires) over time were calculated using t-tests for partially overlapping samples to handle partly different study populations at each time point caused by employee turnover and drop-out. We analysed the interview data by applying a thematic analysis. The second and third studies were conducted in a large Swedish construction company. In study II, we investigated the participants’ satisfaction with engaging in the co-creation process, perceived knowledge, and skill development through interviews. In total, eight men and four women participated. We applied a thematic analysis to analyse the data. In study III, we used a controlled trial to evaluate the potential effects of the co-created intervention on the psychosocial work environment and self-reported stress. We collected data on the outcomes with online questionnaires at baseline, 12, and 24 months. We also assessed adherence to the intervention and dose delivered (i.e., fidelity). Marginal means models adjusting for missing data patterns were applied to estimate potential differences in outcomes between groups over time.
Findings: Neither of the interventions improved the long-term outcomes of burnout and stress, respectively. We found different effects of the municipality and construction industry interventions on the psychosocial working conditions. Within the municipality, we found detrimental effects of the intervention on social support from the manager, empowering leadership, control of work pacing, and role clarity. Within the construction industry, there was a noticeable improvement in role clarity for white-collar workers in the intervention group compared to the control group. The implementation fidelity, i.e., whether the intervention activities were delivered according to plan, was moderate in both projects. However, the process evaluation within the municipality project showed that the intervention activities led to few changes in attitudes, behaviours, and work routines. On the contrary, adherence to the construction industry intervention increased during the trial. The results of paper II showed that the co-creation participants reported increased learning about the psychosocial work environment and mental health. The respondents perceived the intervention and the implementation strategies as relevant and feasible. Thus, involving different stakeholders and allowing the organisation to decide the intervention activities and the implementation strategies seem to have enabled a good contextual fit.
Conclusions: The program theory, i.e., intervention developed within the construction company, can potentially improve role clarity for white-collar workers. Three design principles stand out regarding their positive effect on the implementation: organisational capability and incentive systems to promote health, aligning the intervention with existing organisational objectives and practices and conducting a needs assessment. The co-creation process in the construction industry seems to have positively affected the above-mentioned design principles. Thus, co-creating occupational health interventions seems promising to improve the implementation.
eng
info:eu-repo/semantics/openAccess
Evaluating occupational health interventions : design, implementation, and effects
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
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3.2 The Author shall, when granting the right to publish the Thesis 
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example as appendixes or through links or any other technical 
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3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
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3.5 The Author guarantees that the Thesis contains no material that 
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I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

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andra kopplingar till sådant material.

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Uppsägningstiden är tre (3) månader.

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vilket land dessa är etablerade. 

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Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

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kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
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9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/379952023-10-19T21:00:44Zcom_10616_1com_10616_201com_10616_46998col_10616_219col_10616_202col_10616_47000
Publications from KI
author
Hauksdóttir, Arna
2010-10-21T20:28:16Z
2010-10-21T20:28:16Z
2009-10-23
978-91-7409-702-3
20091113hauk
http://hdl.handle.net/10616/37995
Background: Grief can be seen as the mirror of love. However, some persons suffer beyond what can be viewed as normal grief, experiencing long-lasting decline of both mental and physical health - and even death. Investigating additional and avoidable risk factors connected to the loss may therefore be of vital importance for the development of preventive interventions.
Aims: To identify avoidable risk factors for the long-term psychological morbidity of widowers. We hypothesized that widowers, compared to married men, have a higher risk for psychological morbidity 4-5 years after their loss. We also postulated that this excess morbidity is determined by the degree of preparedness for the wife's death at the time of death. Moreover, we suggest that such preparedness can be facilitated by providing several kinds of health-care interventions.
Methods: Following a qualitative phase for study preparation, a study specific questionnaire (including questions on psychological morbidity and questions about the wife's disease period) was constructed and tested for face validity and for response rate and logistics in a pilot study on 76 widowers. The study base in the main study consisted of 907 men in Sweden who had lost a wife to cancer in the breast, ovary or colon in 2000 and 2001. Furthermore, we collected data from a control group of 330 married men who were frequency matched for age and residence. The questionnaires were sent out from November 2004 to November 2005.
Results: Participation rate was 76 percent for the widowers and 79 percent for the married men. Single widowers reported more psychological morbidity 4-5 years after the loss of a wife than widowers who were in a new romantic relationship at the time of follow-up. Highest relative risks obtained were for depression (RR 2.3), emotional numbness (RR 2.2) and waking up at night with anxiety (RR 2.3). Widowers in a new romantic relationship did not report more morbidity compared to married men.
Eighty-six percent of the widowers reported that the next-of-kin should be told immediately when the patient's cancer cannot be cured. Eighty percent of the widowers reported that they were told that the wife's cancer was incurable and a quarter of them were informed within one week before the patient's death.
Our data indicated that a low degree of preparedness at the time of wife's death increases a younger widower's (38 to 61 years old) risk for (among other symptoms): anxiety (RR 2.3), emotional numbness (RR 2.2) and having difficulty falling asleep (RR 2.2) 4-5 years after loss. For older widowers (62 to 80 years old), this pattern was not as evident. Several possible avoidable predictors for preparedness were identified: longer duration of the widower's intellectual awareness time before his wife's death (RR 4.1), if the widower could take in the information that his wife's disease could not be cured (RR 3.5), the couple had arranged their economic affairs (RR 1.5) and if the wife had stayed at a palliative care unit during the last months of her life (RR 1.2).
Findings: Widowers who remain single 4-5 years after their loss are at increased risk of psychological morbidity. Furthermore, the degree of preparedness before the wife's death may affect the long-term psychological well-being for widowers. Several care-related facilitators of preparedness were identified.
Implication: Improved care of men whose wives are dying of cancer may diminish the widowers risk of long-term morbidity. An intervention study, aiming at influencing preparedness before the death of a loved one, can be designed based on our findings. Such an intervention may entail significant public health effects by decreasing psychological and even physical morbidity of widowers.
eng
info:eu-repo/semantics/openAccess
Towards improved care and long-term well-being of men who lose a wife to cancer : a population based study
info:eu-repo/semantics/doctoralThesis
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oai:openarchive.ki.se:10616/418122022-10-24T13:13:46Zcom_10616_1com_10616_150com_10616_46998col_10616_219col_10616_151col_10616_47000
Publications from KI
author
Rebellato, Paola
2013-11-21T10:23:24Z
2013-11-21T10:23:24Z
2013-11-21
978-91-7549-359-6
http://hdl.handle.net/10616/41812
The calcium ion (Ca2+) is a highly versatile and ubiquitous signaling messenger in all cell types. Signal transduction occurs through changes in the cytosolic Ca2+ concentration after the opening of Ca2+ channels in the plasma membrane (PM) and endoplasmic reticulum (ER). The difference in Ca2+ concentration between the extracellular space and the cytosol is large, around 10,000 fold, creating a steep gradient that causes Ca2+ to rapidly flow into the cell. Signaling via Ca2+ is fundamental for triggering numerous vital processes in the cell, ranging from fertilization to cell death. Calcium signaling is also critical for regulating neurogenesis in various ways, some of which have been explored in this work.
Proliferation of neural progenitors is dependent on spontaneous Ca2+ activity that occurs in small-scale networks. Ca2+ activity is correlated with electrical activity both in vitro and in vivo and depends on connexin 43 gap junction and PM channels. Differentiation of neural progenitors is also regulated by Ca2+ signaling. We have found that T α1h voltage-dependent Ca2+ channels promote spontaneous Ca2+ activity and direct the differentiation of human neuroepithelial stem cells towards neurons, depending on caspase-3 enzymatic activity. These results were confirmed with T α1h knockout mice that showed a decreased number of neurons in the dorsal cortex. Neuronal migration also depends on Ca2+ signaling. We demonstrated that glial derived neurotrophic factor (GDNF) stimulates a Ca2+ response through the activation of the receptor tyrosine kinase (RET). The subsequent downstream signaling cascade includes phospholipase Cγ, which binds to RET Tyr1015. Mutating RET at Tyr1015 inhibits neuronal progenitor migration towards the cortical plate. We also showed that neurogenesis was altered by the addition of non-cytotoxic concentrations of polychlorinated biphenyls that disrupt spontaneous Ca2+ activity. Polychlorinated biphenyls are common food contaminants. In addition, methyl mercury, another food contaminant, disrupts neuronal differentiation in the opposite direction. Altogether, these data demonstrate the huge impact of Ca2+ signaling on the development of the embryonic brain.
To conclude, we have analyzed Ca2+ signaling during three critical steps of neurogenesis: proliferation, differentiation, and migration. All of these processes are known to be dependent on Ca2+. A deeper understanding of how Ca2+ regulates such different physiological processes is crucial for the field of regenerative medicine, in which control of the expansion and differentiation of neural stem cells can increase the production of neuronal cells in vitro for use in cell replacement therapies.
eng
info:eu-repo/semantics/openAccess
Calcium signaling in neurogenesis: regulation of proliferation, differentiation and migration of neural stem cells
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/41812/3/Thesis_Paola_Rebellato.pdf
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URL
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Thesis_Paola_Rebellato.pdf.txt
oai:openarchive.ki.se:10616/442522023-02-12T17:14:36Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Johansson, Maria H
2014-12-04T16:30:40Z
2014-12-04T16:30:40Z
1999-10-22
91-628-3849-0
19991112joha
http://hdl.handle.net/10616/44252
Development of self-tolerance in the immune system is characterized by somatic processes aiming at permanently eliminating, or silencing, potentially autoreactive lymphocytes. Such tolerance mechanisms are of outmost importance if autoimmunity is to be avoided. This thesis deals with tolerance development in natural killer (NK) cells, the third largest lymphocyte population. These cells are part of the innate immune system and participate in rejection of tumor cells and bone marrow transplants, clearance of viral and other infections, and in immunoregulation. NK cells were discovered in 1975, and were at that time considered to be a homogenous population of cells capable only of nonspecific effector mechanisms. As the role of the polymorphic MHC class I molecules in NK cell recognition has gradually emerged, there has been an increasing interest in exploring somatic processes for shaping of NK cell specificity and tolerance.
The NK cell pool is now known to contain a large number of subpopulations with different specificities. The specificity of each NK cell is determined by its composition of MHC-specific receptors, both inhibitory and activating. In the mouse, those are either Ly49 or CD941NKG2 receptors. Each Ly49 receptor is specific for a set of MHC class la molecules, while CD94/NKG2A, the only receptor in this family whose specificity is known, recognizes an MHC class lb molecule, Qa-1. NK cell specificity is a complex issue, since most NK cells express more than one, perhaps an average of three to four, different receptors, both activating and inhibitory ones. The studies included here describes attempts to dissect the complexity of NK cell specificity and tolerance, in particular how host MHC class I molecules influence NK cells. MHC class I transgenic mice have been central tools, including one line with a mosaic expression pattern of the introduced gene. Two different cellular phenotypes, sharing two MHC class I alleles but differing in expression of a third, coexist in these mice.
The studies have revealed that the peptide-binding part of host MHC class I molecules strongly influence development of NK cell specificity. However, not all MHC class I molecules of the host have a critical influence on NK cell education. With regard to self-tolerance, the studies with mice containing mixed MHC phenotypes have shown that autoreactive NK cells are not eliminated, at least not all of them: when tolerant NK cells were removed from their mosaic environment and cultured in vitro, tolerance was rapidly lost. This suggests that NK cell tolerance, in contrast to central T cell tolerance, may rely on mechanisms that need to operate continuously in vivo. Studies in mixed bone marrow chimeric mice indicated that the number of interactions between NK cells and potential targets with a given MHC phenotype may be important. The studies on Ly49A receptors in mosaic mice showed that the MHC class I molecules on surrounding cells as well as on the NK cell itself play distinct roles in regulating receptor expression. Further studies are required to determine how this relates to tolerance. Finally, liver and intestinal expression of an MHC class I transgene was sufficient to induce T-cell tolerance, but did not influence NK cell specificity.
In conclusion, although NK cell specificity is determined by the peptide presenting part of the MHC class I molecule, the processes leading to tolerance may be fundamentally different from those regulating the T-cell repertoire. Continuous regulation through interactions with surrounding cells is discussed as one possibly important factor in NK cell tolerance.
Natural killer cell tolerance : influence of the MHC class I expression in the host
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/378462022-10-13T23:47:06Zcom_10616_1com_10616_168com_10616_46998col_10616_219col_10616_169col_10616_47000
Publications from KI
author
Salonen Ros, Helena
2010-10-21T20:27:41Z
2010-10-21T20:27:41Z
2001-03-01
91-89428-09-9
20010322salo
http://hdl.handle.net/10616/37846
The aims of this thesis were to investigate and compare environmental effects on the liability of developing preeclampsia and gestational hypertension; to estimate the relative importance of genetic and environmental effects on the liability of developing preeclampsia and gestational hypertension; to assess the effect of childbearing on the risk of circulatory diseases; and to explore the effect of preeclampsia on the female offspring anthropometry in early adulthood.
We used the Swedish Birth Register to compare the effect of maternal diabetes, multiple birth, smoking, place of birth and obesity, on the liability of developing preeclampsia and gestational hypertension among 10,666 primiparous women. Maternal diabetes, multiple birth and obesity were all associated with increased risk of preeclampsia and gestational hypertension. Maternal smoking and non-Nordic maternal place of birth were associated with decreased risk of preeclampsia and gestational hypertension. The similarities in risk factor patterns may indicate similarities in the biological mechanisms underlying the two conditions.
To estimate the relative importance of genetic and environmental effects on the liability of developing preeclampsia and gestational hypertension, we used the Swedish Twin Register linked to the Medical Birth Register and used quantitative genetic analyses of pregnancies of 917 monozygotic and 1,199 dizygotic twin pairs. For preeclampsia, we found that genetic and environmental effects are of about equal importance. For gestational hypertension, the estimates of heritability and non-shared environmental effect were 0.24 and 0.76, respectively. When we considered both diseases together as pregnancy-induced hypertension with different degrees of severity, the estimates of heritability and non-shared environmental effect were 0.47 and 0.53, respectively.
We assessed the effect of childbearing on the risk of circulatory diseases by a cross-linkage of the Swedish Medical Birth Register and the Inpatient Register and analyzed 1,003,489 deliveries among 654,957 women. Compared with non-pregnant and early pregnant period, the risks of venous thromboembolic diseases were increased in third trimester, peaked during three days around delivery (relative risk 80) and declined during the puerperium. For arterial diseases (subarachnoid hemorrhage, intracerebral hemorrhage and cerebral infarction), there was, compared with non-pregnant and early pregnant period, a more than 30-fold increased risk during three days around delivery, which declined during the puerperium. We also studied the effects of maternal characteristics on the risk of stroke and pulmonary embolism during the third trimester of pregnancy, around, and after delivery. Although preeclampsia, multiple birth and Cesarean section were all associated with highly increased risk of both pulmonary embolism and stroke, these complications did not explain the increased risks related to pregnancy.
We explored the effect of intrauterine exposure to preeclampsia on the anthropometry in early adulthood among females. In all 230 young women exposed to preeclampsia in utero and 359 non-exposed women were included. In young adulthood there were no differences in height, body-mass index (BMI), waist to hip ratio or age at menarche between preeclampsia exposed female offspring as compared to non-exposed.
eng
info:eu-repo/semantics/openAccess
Preeclampsia and other circulatory diseases during pregnancy : etiological aspects and impact on female offspring
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/37846/1/thesis.pdf
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oai:openarchive.ki.se:10616/405372023-10-24T17:05:19Zcom_10616_1com_10616_207com_10616_46998col_10616_219col_10616_208col_10616_47000
Publications from KI
author
Khan, Mohsin Saeed
2011-05-23T09:09:49Z
2011-05-23T09:09:49Z
2011-05-23
978-91-7457-332-9
http://hdl.handle.net/10616/40537
Background: According to the UNAIDS’ estimates, the incidence of HIV infection has decreased by 19% over the last ten years. WHO estimated in 2005 that approximately 448 million cases of four major curable STIs occur in adults in the age group 15-49 years. Most at risk populations including women selling sex engage in behaviours that lead to HIV transmission. Health care providers are considered to play a pivotal role in the provision of preventive and curative services to individuals suffering from HIV/AIDS and STIs. The HIV
epidemic in Pakistan is concentrated among injecting drug users and Hijras
(transgenders).
Methods: The research involved both qualitative and quantitative research methods leading to Paper I – IV. In Paper I, individual interviews were conducted and then analyzed using the content analysis method. Respondent driven sampling was used to collect data for paper II and III, where in addition to administering a structured questionnaire, biological samples were collected to estimate the prevalence of HIV, T. pallidum, N. gonorrhoeae, C. trachomatis and T. vaginalis. Furthermore, structured questionnaire was administered to collect data for paper IV among health care providers.
Results: Limited opportunities, poverty, financial burdens, and the desire for more material assets have made girls and married women in Lahore enter and
become trapped in a “web” of selling sex. Whereas 91% of women selling
sex were married, 0.7% were infected with HIV, and an additional 18.5%
were suffering from different curable STIs. Only 19% and 83% of the
participants were aware of the terms HIV and AIDS, respectively, and only
37% had correct knowledge about transmission and prevention of AIDS. The
odds of being infected with C. trachomatis and N. gonorrhoeae were 2.1 (CI
95%; 1.1-3.8) and 1.9 (CI 95%; 1.1-3.5), respectively, if women reported “not
always” using condoms as compared to if they reported “always” using
condoms. There were varying knowledge levels and misconceptions regarding
STIs. Approximately two thirds of the women considered themselves to have
had STIs in the six months preceding the survey. Women selling sex who
reported consistent condom use were 1.5 times (CI 95%; 1.1-2.2) more likely
to seek treatment than women who did not consistently use condoms. The
treatment received did not follow any standard treatment guidelines,
influencing both effectiveness and compliance. Forty-five percent of the
healthcare providers had correct knowledge about the transmission and
prevention of HIV, and 82% were not aware of syndromic management of
STIs. Only 10% could cite the ‘correct treatment’ of gonorrhoea, syphilis
and vaginal discharge. The odds of having the ‘correct knowledge’ of
diagnosing gonorrhoea and syphilis were 2.1 (CI 95%; 1.2–3.8) if the
healthcare provider was a female medical doctor working in the public
sector.
Conclusions: Poverty, the drive for materialism, and the desire for money are the major driving forces for resorting to selling sex, depicting a social behavioural change. HIV infection and STIs among women selling sex were relatively low in this study, which is possibly due to a high condom use, relatively low numbers of sexual partners and availability of clinical services, including syndromic management. However, there exists a high risk for a concentrated HIV epidemic among women selling sex due to their low level of knowledge about HIV, attitudes, risk behaviour and sexual practices. The level of knowledge about STIs remains low among women selling sex in Lahore,
Pakistan. Furthermore, health-seeking behaviour for STI treatment is
influenced by ability to pay and ease of access, as well as availability in the
private sector. Even though health care providers in Lahore were providing
health care for both HIV/AIDS and STI patients, the low levels of
knowledge and practices and poor attitudes regarding the management of
HIV infection and STIs emphasize that further intensive training is needed to
improve their ability to correctly diagnose and subsequently treat patients
infected by STIs.
eng
info:eu-repo/semantics/openAccess
Poverty of opportunity for women selling sex in Lahore, Pakistan : knowledge, experiences and magnitude of HIV and STIs
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/40537/1/Thesis_Khan.pdf
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oai:openarchive.ki.se:10616/396382022-10-26T13:48:51Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Selg, Ewa
2010-10-21T20:32:27Z
2010-10-21T20:32:27Z
2008-02-01
978-91-7357-520-1
20080222selg
http://hdl.handle.net/10616/39638
Mast cells have a central role in the inflammatory response in airways of both atopic and non-atopic asthmatics. The mast cell-derived mediators such as histamine, leukotriene C4 and prostaglandin D2, released upon activation of the cell, produce acute bronchoconstriction that is characteristic of the early asthmatic response (EAR), and contribute to the development of airway inflammation and hyperresponsiveness following the initial reaction. There is a great need for relevant experimental in vitro models to study the airway effects of the mast cell-derived mediators. The overall aim of the experimental studies presented in this thesis was accordingly an evaluation of the relevance of the isolated perfused and ventilated guinea pig lung (IPL) as an experimental model to study the EAR.
The reactivity of the IPL to histamine, cysteinyl-leukotrienes (CysLTs: leukotriene (LT) C4, D4 and E4) and prostanoids, established by intravascular challenge of the normal lungs with these mediators, was closely similar to that of human airways. The cyclooxygenase (COX)-dependent modulation of the responses to bronchoconstrictive agonists in IPL followed two different patterns. The responses to histamine and LTD4 were amplified by agonist-induced secondary release of bronchoconstrictive COX products. Both COX isoenzymes, COX-1 and COX-2 participated in the LTD4-induced generation of COX products. In contrast, the response to PGD2 did not actively promote the agonist-induced release of COX products, but was down-modulated by relaxant COX products presumably tonically formed in airways.
Investigation of the pharmacology of the PGD2 response in IPL by the use of COX inhibitors gave rise to the hypothesis that diclofenac also was a thromboxane (TP) receptor antagonist. Further investigation of the effects of diclofenac and its structural analogue lumiracoxib on the TP-mediated responses in standard airway and vascular pharmacology in vitro models and in human platelets confirmed that these drugs, in addition to being COX unselective and highly COX-2 selective inhibitors, respectively, also were competitive TP receptor antagonists.
The IPL was demonstrated to provide a model where a specific, dose-dependent and reproducible bronchoconstriction was obtained in response to intravascular challenge with antigen (ovalbumin) in lungs actively sensitised to ovalbumin. The mediators of the antigen-induced bronchoconstriction were investigated by pharmacological interventions with an antihistamine, an antileukotriene or COX inhibitors as well as by measurements of the antigen-induced mediator release. It was established that similarly to the situation in human airways, histamine, CysLT and prostanoids mediated the antigen response in IPL. Furthermore, both COX-1 and COX-2 contributed to the immediate antigen-induced generation of prostanoids. The results of the inhibition of two classes of mediators at a time disclosed interactions among the mediators at several levels. The complete inhibition of the antigen response produced by inhibition of all the three mediator classes at a time demonstrated that the concerted actions of histamine, CysLTs and prostanoids could solely explain the immediate antigen-induced bronchoconstriction in this model. In conclusion, the IPL is considered a relevant experimental model for studies of the EAR, and it is proposed to test the concept of inhibition of the three mediator classes in subjects with asthma.
eng
info:eu-repo/semantics/openAccess
An experimental study of mediators in allergic bronchoconstriction with focus on eicosanoids
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39638/1/thesis.pdf
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oai:openarchive.ki.se:10616/441342022-10-20T15:19:49Zcom_10616_1com_10616_180com_10616_46998col_10616_219col_10616_181col_10616_47000
Publications from KI
author
Benach-Andreu, Jordi
2014-12-04T16:30:32Z
2014-12-04T16:30:32Z
1999-04-26
91-628-3498-3
19990517bena
http://hdl.handle.net/10616/44134
X-ray crystallography and site-directed mutagenesis were used to better understand the structure/function relationships in the family of short-chain dehydrogenases/reductases (SDR). This group of enzymes constitutes a protein family with at least 60 members with highly diverse functions in pro- and eukaryotes. Two enzymes of this family were studied in this work: Drosophila lebanonensis alcohol dehydrogenase (DADH; EC 1.1.1.1) and Comamonas testosteroni 3[beta]/17[beta]-hydroxysteroid dehydrogenase ([beta]/17[beta]-HSDH; EC 1.1.1.51).
Drosophila alcohol dehydrogenase is an NAD(H)-dependent oxidoreductase that catalyzes the oxidation of alcohols to aldehydes/ketones. The crystal structures of the apoform, the binary form (E·NAD+) and three ternary complexes (E·NAD+·acetone, E·NAD+·3-pentanone and E·NAD+·cyclohexanone) were solved at 1.9 Å, 2.4 Å, 2.2 Å, 1.4 Å and 1.6 Å resolution, respectively. DADH subunits show an [alpha]/[beta] single domain structure with a characteristic NAD(H) binding motif (Rossmann fold). The peptide chain of a subunit is folded into a central eight-stranded [beta]-sheet flanked on each side by three [alpha]-helices. DADH forms homodimers that have local twofold symmetry. Dimer association is dominated by a four-helix bundle motif as well as two C-terminal loops from each subunit. The structure of DADH undergoes a conformational change in order to bind the coenzyme. Furthermore, upon binding of the ketone, a region that was disordered in the apoform (186-191) gets stabilized and closes the active site cavity by creating either a small helix (E·NAD+·acetone, E·NAD+·3-pentanone) or an ordered loop (E·NAD+·cyclohexanone). The active site pocket comprises a hydrophobic and bifurcated cavity that explains why the enzyme is more efficient in oxidizing secondary aliphatic alcohols -preferably R enantiomers- than primary ones. Difference Fourier maps showed that the ketone inhibitor molecule has undergone a covalent reaction with the coenzyme in all three ternary complexes. Due to the presence of the positively charged ring of the coenzyme (NAD+) and the residue Lys155, the amino acid Tyrl51 is in its deprotonated state at physiological pH. Tyr151 can abstract a proton from the enolic form of the ketone and catalyze a nucleophilic attack of the C[alpha] atom to the C4 position of the coenzyme creating an NAD-ketone adduct. The binding of these NAD-ketone adducts to DADH accounts for the inactivation of the enzyme. The alcohol oxidation proceeds in a similar way, involving the same amino acids as in the formation of the NAD-ketone adduct. Tyr151 abstracts a proton from the alcohol and therefore facilitates hydride transfer to the coenzyme. Ser138 has been studied by site-directed mutagenesis and its role is to stabilize the substrate/reaction transition state. Molecular models for the three alloenzymes of D.melanogaster ADH (ADH-S, -F and -UF) were built using the available crystal structure of D.lebanonensis ADH as a template. A model based on the analysis of the electrostatic potential distribution is presented to explain their different biochemical behavior.
3[beta]/17[beta]-hydroxysteroid dehydrogenase is one of the inducible enzymes produced by the gram-negative bacterium Comamonas testosteroni expressed upon adaptive growth in testosterone-containing media. Crystallization, preliminary X-ray analysis, plausible crystal packing and initial refinement procedures are shown. Mutagenesis work has been carried out in order to understand the structural basis of hormone metabolism and to give insight into the structure/function relationship in short-chain dehydrogenases/reductases.
X-ray structure analysis of short-chain dehydrogenases/reductases
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/382672023-02-18T20:47:23Zcom_10616_1com_10616_201com_10616_46998col_10616_219col_10616_202col_10616_47000
Publications from KI
author
Ekholm-Reed, Susanna
2010-10-21T20:29:06Z
2010-10-21T20:29:06Z
2004-04-23
91-7349-894-7
20040514ekho
http://hdl.handle.net/10616/38267
Cyclin E, a positive regulatory subunit of Cdk2, normally accumulates periodically at the G1/S transition, where it promotes entry into S phase and other DNA replication-associated functions. However, in many types of human cancer, cyclin E is overexpressed and in some cases its expression becomes deregulated, a phenomenon generally associated with poor prognosis. Although it is not yet known how cyclin E deregulation promotes tumorigenesis, one possible mechanism may be through the generation of genomic instability, a common characteristic of tumor cells.
The restriction point (R) is a checkpoint in mid G1 phase, defined as the point after which cells can complete a division cycle independently of mitogenic signals. Regulation at this checkpoint is often lost in cancer cells. Passage through R has been shown to depend on the accumulation of a labile protein, suggested to be cyclin E. We carried out single cell analysis of cyclin E expression to determine the exact timing of cyclin E protein accumulation in relation to previous mitosis, passage through the restriction point (R) and subsequent S phase. By time-lapse video microscopy and immunofluorescence staining, we showed however, that passage through R is independent of the accumulation of cyclin E and does not require Cdk2 activity. These results rule out the hypothesis that passage through R is dependent on the accumulation of cyclin E but suggest that passage through R is a prerequisite for cyclin E accumulation.
Deregulation of cyclin E with respect to the cell cycle has been linked to a lengthening of S phase. We therefore investigated the effect of deregulated cyclin E on pre-replication complex (pre-RC) assembly in telophase cells. By immunofluorescence and biochemical analysis of chromatin bound pre-RC components in telophase cells, we show that loading of Mcm2, Mcm4 and Mcm7, believed to function in a complex with other Mcm proteins as a replicative DNA helicase, is severely impaired in these cells. We also show that DNA replication is impaired in cells constitutively expressing cyclin E. These results suggest that cyclin E interferes with proper pre-RC assembly, which may explain the observed replication defects that these cells exhibit. Cyclin E-mediated impairment of DNA replication constitutes a potential mechanism for the chromosome instability that has been observed in cells constitutively expressing cyclin E and might thereby represent the link between deregulation of cyclin E and tumorigenesis.
Recent studies demonstrate a link between cancer and mutations in hCdc4, the gene encoding the F-box protein that facilitates SCF-mediated degradation of cyclin E. However, in many of these tumors cyclin E is not overexpressed. We investigated whether deregulation of cyclin E expression rather than simple overexpression might be a more critical factor in tumorigenesis. We found a strong correlation between hCDC4 mutation and deregulation of cyclin E expression, suggesting that hCDC4 function is necessary for proper regulation of cyclin E expression. Thus, deregulation of cyclin E-Cdk2 activity and as a result, specific phosphorylation events, may be the critical factor in cyclin-E-mediated pathology.
eng
info:eu-repo/semantics/openAccess
The role of cyclin E in cell cycle regulation and genomic instability
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38267/1/thesis.pdf
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oai:openarchive.ki.se:10616/429612022-09-24T13:03:24Zcom_10616_1com_10616_46998col_10616_219col_10616_47000
Publications from KI
author
Pontén, Ingrid
2014-12-04T16:29:19Z
2014-12-04T16:29:19Z
1996-08-30
91-628-2153-9
19960920pont
http://hdl.handle.net/10616/42961
The widespread environmental pollutant benzo[a]pyrene (BP), is formed from incomplete combustion of fossil fuels and is mutagenic and carcinogenic after metabolic activation to bay-region diol epoxides and subsequent covalent binding to DNA. The metabolic activation pathway to diol epoxides is via BP-7,8-oxide and BP-7,8-dihydrodiol to yield preferentially 7R,8S-dihydroxy-9S,lOR-epoxy-7,8,9,10-tetrahydrobenzo[a]py- rene [(+)-anti-BPDE] and to lesser extents, 7R,8S-dihydroxy-9R,lOS-epoxy-BP [(-)-syn-BPDE], 7S,8R- dihydroxy-9S,lOR-epoxy-BP [(+)-syn-BPDE] and 7S,8R-dihydroxy-9R,lOS-epoxy-BP [(-)-anti-BPDE]. Although all stereoisomeric diol epoxides bind to DNA (via C-10), (+)-anti-BPDE is the most active form.
In order to better understand the mechanisms underlying the carcinogenic and mutagenic properties of DNA adducts derived from BPDE, studies of the physical relationship between adduct structure and base preference and recognition during replication, repair and transcription seems to be of great relevance. We have studied the spectroscopic properties and thermal stabilities of a 13-mer oligonucleotide site-specifically modified with anti- or syn-BPDE enantiomers. The oligonucleotide chosen. 5'-d(CCTATAGATATCC), contains only one target dG, the preferred binding site for covalent binding of BPDE diastereomers. An HPLC system for purifying the dG adducts was developed and the modified oligonucleotides were characterized by optical spectroscopy. One major N2-dG adduct was detected with the (+)-anti-BPDE, whereas (-)-anri-BPDE resulted in two N2-dG adducts, resulting from cis and trans additon of BPDE to'N2-dG. From syn-BPDE one major adduct was obtained from the (-)-enantiomer whereas the (+)-enantiomer resulted in two N2-dG adducts. It was concluded that the major adducts from (-)- and (+)-syn-BPDE were cis adducts. The minor adduct from (+)-syn-BPDE was identified as a dG adduct with trans configuration. The adduct environment is strongly influenced by duplex formation and interactions between the adduct and the base localized opposite the adduct as shown by the fluorescence behaviour. In view of thermal stability, the presence of a cis syn-BPDE adduct destabilizes the helix more than a (+)-anti-BPDE adduct.
In order to improve adduct yields various parameters relevant for the formation of dG adducts of BPDE stereoisomers with oligonucleotides were studied. The optimal experimental conditions found was different depending on the base sequence context employed, but in general low temperature to achieve long reaction time. near neutral Tris-HCI buffer or alkaline phosphate buffer, low concentration of organic solvent and high molar ratio of BPDE and oligonucleotide favour adduct formation.
Several studies have confirmed that the extent of binding of anti-BPDE to DNA is highly dependent on the sequence context, but very little is known about the selectivity of syn-BPDE. Therefore, using the same oligonucleotide as above and in addition, by exchanging the bases flanking the target dG, sequences containing all possible base combinations surrounding the central dG were reacted with (-)-syn-BPDE and, for comparison (+)-anti-BPDE. The adduct amounts were in the range 3-30% and 0-4% trans and cis (+)-anti- BPDE adducts respectively, whereas the range of cis and trans (-)-syn-BPDE adducts were 1-10% and 0-0.5% , respectively. The binding to dG of the stereoisomers studied differs in base selectivity. However, it is clear that the base sequence has a large impact on the amount of adducts formed from both diastereomers.
Extensive knowledge is available concerning the regulation, structure and function of the transcription factor. Activator Protein-l (AP-I, consisting of of homo- and heterodimers of Fos/Jun proteins), as well as its response to different stimuli. However, the effect of an alteration of the transcription binding site in DNA, for instance by the presence of covalently bound carcinogenic PAH intermediates has so far received little attention. We have specifically modified a 28-mer oligonucleotide containing the AP-I binding site, with (+)-anti- or (-)-syn-BPDE (yielding trans and cis adducts, respectively) and studied the effect on AP-I binding with HeLa cell nuclear extracts or truncated Fos/Jun proteins. The presence of a BPDE adduct extensively reduced the affinity for binding of proteins from HeLa cell nuclear extracts as compared to controls. No apparent differences in the response between the different adducts were obtained, suggesting that the binding geometry of the adduct is of little importance. From experiments with antibodies directed against c-Fos and c-Jun proteins it was clear that the binding to BPDE modified oligonucleotide seems to involve AP-I related proteins other than c-Fos and c-Jun. The data presented here clearly suggest that chemical modification of the AP- I transcription factor binding site with BPDE may seriously alter the extent and/or duration of expression of genes containing AP-l sites in their promoter regions.
Studies on oligonucleotide adducts formed from 7,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[A]pyrene stereoisomers
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/473112024-03-12T15:35:43Zcom_10616_1com_10616_168com_10616_46998col_10616_219col_10616_169col_10616_47000
Publications from KI
author
Ning, Zheng
2020-08-20T07:34:30Z
2020-08-20T07:34:30Z
2020-08-20
978-91-7831-887-2
http://hdl.handle.net/10616/47311
A general objective of genetic studies is to understand the genetic basis of complex traits such as height, body mass index (BMI), disease endpoints, etc. Such researches have been facilitated due to the completion of the human genome project and developments of high-throughput technologies. With the help of high-throughput genotyping and sequencing technologies, the information on millions of genetic markers can be measured for each individual.
The most widely used strategy to detect the associations between genetic variants and a complex trait is genome-wide association study (GWAS). Because the genetic architecture of most complex traits is highly polygenic, the signal to noise ratio is usually tiny. Thus, especially in human populations, GWAS often requires large samples to obtain sufficient power. Unfortunately, given the restrictions on sharing individual-level data, it is often not feasible to pool data from different cohorts. Despite that, in each cohort, it is possible to report and share GWAS summary statistics, such as sample sizes, allele frequencies, estimates of genetic effect sizes, and their standard errors for the genetic markers across the genome. Therefore one recent focus in statistical methodology development for genetic studies has been on meta-analysis techniques using summary-level data. The objective of this thesis is to develop novel statistical genetics methods based on GWAS summary statistics and to apply these methods to better understand the genetic architecture underlying complex traits.
In Study I, we developed a Selection Operator for JOint analyzing multiple SNPs (SOJO). We mathematically proved and empirically showed that the least absolute shrinkage and selection operator (LASSO) could be achieved using GWAS summary-level data. Compared to the stepwise selection procedures, SOJO performs better in variable selection. SOJO is useful for detecting additional variants with independent effects and assessing the magnitude of allelic heterogeneity within loci. In Study II, we developed a High-Definition Likelihood (HDL) method to improve the accuracy in genetic correlation estimation using GWAS summary statistics. Compared to the stateof-the-art method LD Score regression (LDSC), HDL achieves higher statistical power to detect genetic correlations between phenotypes by fully accounting for linkage disequilibrium (LD) information across the genome. In Study III, we introduced a four-level strategy for replication of loci detected by multi-trait GWAS methods. The four methods provide different degrees of replication strength, useful for providing additional evidence when a locus has been discovered and replicated by multivariate analysis of variance (MANOVA) or other multi-trait methods. The replication methods only require summary association statistics and are straightforward to be applied to multi-trait GWAS analyses. In Study IV, using GWAS summary statistics, we developed a method named Genetic Correlation Contrast for Causality (G3C) as a more robust test for the existence and direction of causal relationships between phenotypes. In contrast to Mendelian Randomization (MR), G3C does not rely on the assumption of no horizontal pleiotropy. G3C takes full advantage of genome-wide genetic association data and account for underlying genetic correlations between complex traits.
eng
info:eu-repo/semantics/openAccess
Novel statistical methods for genome-wide association summary statistics
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/47311/1/Thesis_Zheng_Ning.pdf
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Thesis_Zheng_Ning.pdf.txt
oai:openarchive.ki.se:10616/396652023-02-22T23:33:46Zcom_10616_1com_10616_156com_10616_210com_10616_46998col_10616_219col_10616_157col_10616_211col_10616_47000
Publications from KI
author
Andersson, Kerstin
2010-10-21T20:32:31Z
2010-10-21T20:32:31Z
2006-09-29
91-7140-816-9
20061020ande
http://hdl.handle.net/10616/39665
The general aim of this thesis was to investigate perceptions of oral health among elderly persons and among medical professionals working at primary health care centres. The study samples consisted of elderly persons and medical professionals in the County of Stockholm.
The thesis combines a quantitative and a qualitative perspective. The quantitative method was based on a questionnaire and clinical examination with defined variables carried out by a dental hygienist. Two different data collection methods were compared in Paper I. The qualitative methods comprised two types of in-depth interview. One interview study was phenomenological-hermeneutic inspired by Giorgi (Paper II) and the other was based on grounded theory inspired by Strauss & Corbin (Papers III & IV).
The results show that there are differences between the way the individuals who participated in the studies perceive their oral health and function and the way it is evaluated by professionals in clinical examinations (Paper I). Furthermore, the individuals' perceived oral health as a whole comprised of several aspects: functional, social and psychological. All the aspects were connected to well-being and quality of life (Paper II).
The studies of the medical professionals (Paper III) revealed that the general practitioners were unaware of the oral health of their elderly patients. They perceived cultural differences between medicine and dentistry. The district nurses (Paper IV) reported several obstacles that prevented them from taking responsibility for the whole nursing care around an individual. They perceived oral health and oral problems as belonging exclusively to dentistry.
The findings of all these studies emphasise the complexity of oral health and oral care when it comes to both the communication between the dental professionals and the patients and the cooperation between the medical and dental professionals. The research also points to the importance of finding ways to support and promote oral health among elderly individuals. As their general health deteriorates, their ability for self-care is reduced and they become less independent. Identifying this breaking point at which intervention becomes necessary is one of the major challenges to ensure good oral health in ageing.
In conclusion, improved understanding and co-operation between general practitioners and dental teams, as well as between district nurses and dental hygienists, is necessary to improve oral health and oral care which is important to enhance the well-being of the elderly.
eng
info:eu-repo/semantics/openAccess
Oral health in old age : perception among elderly persons and medical professionals
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39665/1/thesis.pdf
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MD5
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thesis.pdf
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File
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thesis.pdf.txt
oai:openarchive.ki.se:10616/454252019-09-29T21:01:15Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Bonnert, Marianne
2016-12-21T10:07:23Z
2016-12-21T10:07:23Z
2016-12-21
978-91-7676-525-8
http://hdl.handle.net/10616/45425
Background: Irritable bowel syndrome (IBS), functional abdominal pain (FAP), and functional dyspepsia (FD) belong to the functional abdominal pain disorders, and are common in adolescents all over the world. Adolescents with IBS, FAP or FD often report anxiety, depression, school absenteeism, and a quality of life as low as children with inflammatory bowel diseases. The treatment effects from pharmacological or dietary treatments are unsatisfactory for this age group, while cognitive behavioral therapies (CBT) have shown some promising effects. However, CBT is rarely available as there are very few CBT-therapists trained in functional abdominal pain disorders. For adult IBS, exposure-based internet-delivered CBT (Internet-CBT) has been very successful, but this kind of treatment has neither been evaluated for adolescent IBS, nor adapted to the age group.
Aims: The overall aim of this thesis was to develop an effective and easily accessible
treatment for adolescents with functional abdominal pain disorders. Specific aims were to
investigate:
° The feasibility and potential efficacy of exposure-based Internet-CBT for adolescents
with IBS, FAP or FD (Study I).
° The efficacy of exposure-based Internet-CBT for adolescents with IBS (Study II).
° Mechanisms of change in exposure-based Internet-CBT for adolescents with IBS
(Study III).
° The feasibility and potential efficacy of a tailored exposure-based Internet-CBT for
adolescents with FAP or FD (Study IV).
Methods: The feasibility and potential efficacy of the treatment were evaluated in an open
pilot including adolescents (age 13-17) with IBS, FAP or FD (Study I). The efficacy of the
treatment for adolescents with IBS was tested in a randomized controlled trial (RCT) with a
wait-list control (Study II). Treatment mechanisms were investigated on data from the RCT,
through analysis of change during treatment of two proposed mediators (perceived stress and
avoidant behavior), and primary outcome (global gastrointestinal symptoms) (Study III).
Lastly, the feasibility and potential efficacy of the treatment, when tailored specifically for
functional abdominal pain and functional dyspepsia, were evaluated in an open pilot (Study
IV). All trials had somatic symptoms as primary outcome, global gastrointestinal symptoms
in Study I-III, and pain intensity in Study IV. Assessments were made at pretreatment,
posttreatment, and at 6-month follow-up (Study I-II and IV). In the RCT weekly assessments
were included in the analyses (Study II). In Study IV, the follow-up assessments 6 months
after treatment are still ongoing, and will therefore not be presented in the thesis.
Results: In the first pilot treatment adherence was high, and the improvements were
significant and moderately sized, with a stable treatment effect after 6 months (Study I). The
RCT showed significant improvement on all relevant outcomes in favor of the treatment with
small to moderate effect sizes, which were stable or significantly improved 6 months after
treatment conclusion (Study II). The analysis of mediators showed that reduction in avoidant
behavior, but not reduction in perceived stress, predicted improvement in gastrointestinal
symptoms due to treatment (Study III). The open pilot for FAP and FD showed significant
improvement with strong effect sizes on all relevant outcomes, from pretreatment to
posttreatment (Study IV).
Conclusion: Exposure-based Internet-CBT is a feasible and effective treatment for
adolescent IBS. Feasibility and potential treatment effects may be increased with a tailored
treatment for FAP and FD. Our results suggest that, it is by reducing avoidant behavior that
gastrointestinal symptoms improve during exposure-based Internet-CBT, while a reduction in
stress is not a necessary target in treatment.
eng
info:eu-repo/semantics/openAccess
Internet-delivered exposure-based cognitive behavior therapy for adolescents with functional abdominal pain disorders
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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MD5
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Thesis_Marianne_Bonnert.pdf
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Thesis_Marianne_Bonnert.pdf.txt
oai:openarchive.ki.se:10616/426682022-10-14T14:06:49Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Larsson, Britt-Marie
2014-12-04T16:29:00Z
2014-12-04T16:29:00Z
2001-05-25
91-7045-603-8
20010615lars
http://hdl.handle.net/10616/42668
Swine farming is an occupation associated with high exposure levels to organic dust, but gases such as ammonia and hydrogen sulphide are also contributing to the potentially hazardous exposure. The prevalences for respiratory symptoms, chronic or work-related, are increased among swine farmers, compared to both the normal population as well as other farming categories.
Healthy subjects, previously unexposed to farming environment, developed an intense airway inflammation following three hours of exposure during weighing pigs or during cleaning procedure of an evacuated stable using a high-pressure cleaner. The inflammation was characterised by an increased bronchial responsiveness to methacholine between approximately 1 to 3 dose-doubling steps as well as an extensive migration of inflammatory cells, predominantly neutrophils, into the upper and lower airways. Elevated levels of the chemotactic factor IL-8 found in lavage fluid from the airways most likely achieve this accumulation of neutrophils. The significant correlation between changes in IL-8 levels and increased concentrations of neutrophils found in nasal lavage fluid supports such a theory. Other chemoattractants, could however, also contribute to the recruitment of neutrophils, since increased levels of LTB4 were demonstrated in the upper airways. Other signs of an induced inflammatory reaction were increased post-exposure levels of the inflammatory cytokine IL-6 in nasal lavage fluid and peripheral blood.
Involvement of cysteinyl-leukotrienes (cys-LTs) was also established. A local production of LTE4 was detected in the upper airways following exposure as well as an increased whole body formation of cys-LTs measured as increased levels of urinary LTE4. The cys-LTs were hypothesised to be contributing factors to the increased bronchial responsiveness. The intervention study with an inhibitor of leukotriene biosynthesis could not clarify this assumption due to an insufficient inhibitory effect on urinary LTE4 excretion.
Signs of mast cell activation were also demonstrated by increased levels of PGD2 , a mast cell mediator, measured as increased urinary levels of the PGD2 metabolite 9a, 11b-PGF2.
No relationship between measured inflammatory mediators and increased bronchial responsiveness could be detected, indicating that the airway response was not caused directly by mediator release. Instead, swelling of the airway mucosa and increased secretions due to the general inflammatory reaction could lead to an airway narrowing that would enhance the post-exposure response to methacholine.
Endotoxin has been postulated as the main factor behind respiratory illness in the farming environment. This hypothesis is not supported by our studies. Other agents, originating from Gram-positive bacteria are probably important contributors to the induction of the inflammatory reaction after swine house exposure. The perhaps most intriguing finding regarding exposure in this thesis, was the discovery that even if the healthy volunteers were equipped with a half mask with a particle filter during the exposure, they still responded with an increased bronchial responsiveness, although somewhat attenuated. However, the respiratory device showed better effect regarding reactions in the upper airways. This implicates a role for gases (e.g. ammonia) in the development of increased bronchial responsiveness in healthy, previously unexposed, subjects following an acute exposure in the swine farm environment. On the other hand, the particles seem to have a more prominent role for the reactions in the upper airways.
Induction of a non-allergic inflammation in the human respiratory tract by organic dust
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/419912023-10-31T21:20:56Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Andersson, Cecilia
2014-04-25T08:29:28Z
2014-04-25T08:29:28Z
2014-04-25
978-91-7549-533-0
http://hdl.handle.net/10616/41991
Crimean-Congo hemorrhagic fever (CCHF) is a severe acute human disease with potential lethal outcome caused by a virus, Crimean-Congo hemorrhagic fever virus (CCHFV). Not much is known regarding how CCHFV infects cells, replicates and why it cause vascular dysfunction. To better understand CCHFV- pathogenesis increased knowledge regarding these issues is needed.
Viruses have to enter a host cell in order to replicate its genome and here we show that CCHFV entry occur by clathrin-mediated endocytosis and is pH- dependent.
A new in situ detection technique was establihed to visualize individual CCHFV cRNA and vRNA transcripts. Potential colocalization with the viral nucleocapsid protein (NP) was also investigated. cRNA was found to be more concentrated to particular regions within the cytoplasm and co-localized with CCHFV NP. While vRNA was detected throughout the cytoplasma not colocalizating with CCHFV NP.
It is not known if the vascular leakage observed in CCHF is due to direct virus infection or is immune-mediated. A new in vitro model system was therefore established and it was found that CCHFV has a preference for basolateral entry. However and surprisingly, using CCHFV-infected monocyte-derived dendritic cells (moDCs) or their supernatant, a preference for apical entry was observed. This indicate that the change in entry site could be due to soluble factors from the moDCs. Neither direct infection nor addition of CCHFV-infected moDCs affected the cellular permeability of the human polarized epithelial cell layer, indicating that other factors are most likely are causing the vascular leakage.
Taken together, we established several new in vitro model systems to study CCHFV’s interaction with host cells. We also demonstrated the entry pathway for CCHFV into cells. These data and tools will hopefully facilitate and promote research on virus-host interactions which in turn may result in the development of new antivirals and/or vaccines against CCHFV.
eng
info:eu-repo/semantics/openAccess
Virus-host interactions : entry and replication of Crimean-Congo hemorrhagic fever virus
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/41991/1/Thesis_Cecilia_Andersson.pdf
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Thesis_Cecilia_Andersson.pdf.txt
oai:openarchive.ki.se:10616/484742024-02-06T12:56:39Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Mandolesi, Marco
2023-02-01T10:24:07Z
2023-02-01T10:24:07Z
2023-02-01
978-91-8016-923-3
http://hdl.handle.net/10616/48474
The cells of the adaptive immune system rely on somatic recombination of V, D and J genes to obtain a vast range of specificities. T cells use four chains encoded by three genomic loci, to produce alpha/beta or gamma/delta T cell receptors (TCRs). B cell receptors (BCRs) are encoded by three loci, a single heavy chain and two light chain loci, kappa and lambda. Because these genomic regions are highly polymorphic, the germline TCR and BCR repertoires are individual, shaping the elicited response against infections and vaccines in each person. In this thesis, I used a set of specialized tools and analysis pipelines to explore the adaptive immune receptors at the genomic and functional levels in both humans and non-human primates (NHP), highlighting the benefits of integrating individualized TCR/BCR repertoire analysis with functional studies to understand adaptive immune responses.
In paper I, we sequence expressed TCR repertoires of 45 individuals from four human populations: African, East Asian, South Asian, and European. Analysis of these repertoires with the germline gene inference tool, IgDiscover, identified 175 novel V and J alleles, most of which were characterized by codon changes or non-functional variants. The germline TCR repertoires were highly diverse between individuals, with some of the novel alleles identified only in specific populations. Furthermore, we report three introgressed regions inherited from Homo neanderthalensis. One of these regions includes a novel variant of TRGV4, frequent in Eurasians populations, which display altered reactivity to the ligand butyrophilin-like molecule 3 (BTNL3).
In papers II and III, we analyzed the humoral immune response in NHPs elicited by a series of immunizations with SARS-CoV-2 Spike-derived subunit proteins. In paper II, we observed detectable neutralization titers after priming with ancestral spike (S) protein with very high antibody titers obtained after boosting. The immunization regimen resulted in durable neutralization titers as well as S-specific memory B cells. In paper III, we used a heterotypic boosting strategy with beta-derived receptor binding domain (RBD) to broaden the response to circulating SARS-CoV-2 variants. The boost elicits potent and protective cross-neutralizing humoral immune responses.
In paper IV, we analyzed multi-compartmental longitudinal samples from two macaques used in paper II. We combined single cell and next generation sequencing (NGS) of BCR repertoires to characterize S-specific antibodies and S-specific B cell lineages elicited by immunizations with ancestral SARS-CoV-2 S proteins. Lineage tracing analysis identified persistent antibody lineages that were present after priming and were widely disseminated in blood, bone marrow (BM), spleen and different lymph nodes (LN), including a broadly neutralizing RBD-binding lineage. Through structural cryo-EM studies, we showed that this antibody achieved cross-neutralization by targeting conserved RBD residues with crucial interactions through its heavy chain CDR3 (HCDR3).
eng
info:eu-repo/semantics/openAccess
Genetic and functional analysis of the adaptive immune response
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/432102023-02-17T14:21:11Zcom_10616_1com_10616_201com_10616_46998col_10616_219col_10616_202col_10616_47000
Publications from KI
author
Stoltzfus, Patricia
2014-12-04T16:29:36Z
2014-12-04T16:29:36Z
2004-05-06
91-7349-888-2
20040527stol
http://hdl.handle.net/10616/43210
The early detection of neoplastic lesions is most critical in the successful treatment of malignant disease. This thesis investigates molecular targets for an improved detection and diagnosis of cancer by exploring the value of interphase fluorescence in situ hybridization (FISH) to detect specific chromosomal aneuploidies and gene amplifications, and laminin-5 gamma2 chain expression detected by immunohistochemistry as a marker for invasiveness. The aim of this thesis is to establish a better understanding of malignant transformation and tumor progression on the molecular level, and translate this knowledge to relevant diagnostic applications.
We collected fine needle aspirates from breast lesions and applied FISH to the cytological samples. Based on extensive comparative genomic hybridization (CGH) analysis, we designed three probe cocktails that target specific genetic aberrations known to be frequently involved in breast tumorigenesis. We have shown that benign lesions maintain a stable genome, however, carcinomas carry genetic aberrations that could readily be visualized with the probe cocktails. We have designed a translational assay that allows one to objectively diagnose breast cancer in cytological samples independent of any other markers. This test strengthens diagnostic precision and stratifies patients for specific rational treatments.
The value of the laminin-5 gamma2 chain as a marker of invasiveness was explored for the early diagnosis of invasive disease in cervical lesions. We designed a pilot study to investigate whether cytoplasmic laminin-5 gamma2 chain is expressed in cervical lesions that progress to carcinoma. We analyzed archival biopsies of matched preinvasive and invasive lesions. Our findings suggest that cytoplasmic laminin-5 gamma2 chain immunostaining is closely associated with the transition of preinvasive lesions into invasive disease. This study helps to establish the laminin-5 gamma2 chain as a molecular marker for invasiveness in cervical carcinomas, and is useful in the diagnostic interpretation of early invasive lesions.
Inspired by the laminin-5 gamma2 chain as a marker for invasiveness, we were interested in investigating whether laminin-5 gamma2 chain expression can be used as a marker to predict clinical outcome. We analyzed uniformly treated early stage (T1) carcinomas of the mobile tongue, in which the biological aggressiveness is variable. We found laminin-5 gamma2 chain expression was significantly higher in the tongue lesions that had recurred. We conclude that the laminin 5 gamma2 chain predicts aggressiveness in early stage carcinomas of the mobile tongue, and could be useful as a marker in stratifying those patients who would benefit from additional treatment, i e. radiation or neck dissection.
Vulvar carcinoma is an human papilloma virus (HPV) related tumor, and follows a similar pattern of progression as cervical carcinoma. We applied interphase FISH to vulvar carcinomas and pre-cancerous lesions with a multicolor probe for a telomerase gene mapping to chromosome 3q, a molecular target of cervical cancer. Included was laminin-5 gamma2 chain analysis. We found 3q amplified in all vulvar carcinomas and in the majority of precancerous lesions. Laminin-5 gamma2 chain expression was present only in the carcinomas. The results indicate that gain of chromosome 3q precedes the acquisition of invasive capacity in vulvar lesions, and thus is an early aberration in vulvar carcinogenesis. The detection of genomic amplification of 3q in diagnostic samples could be an independent test for the diagnosis of vulvar carcinomas and precursor lesions.
Molecular markers reflecting malignant transformation and tumor progression
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/434192023-02-18T21:45:23Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Vesali, Rokhsareh Farrah
2014-12-04T16:29:50Z
2014-12-04T16:29:50Z
2005-03-25
91-7140-285-3
20050415vesa
http://hdl.handle.net/10616/43419
Critically ill patients are characterised by a severe net protein catabolism. The rate of muscle protein loss is in the magnitude of 10% per week. A consequence of muscle wasting is increased weakness, which is associated with high rates of mortality and morbidity. Protein wasting is a result of either a decrease of protein synthesis or an increase of protein degradation or a combination of both.
To understand the underlying mechanisms determinations of both protein synthesis and degradation on the tissue level are necessary, since the regulation of protein turnover is different between tissues. Protein synthesis on the tissue level can be measured quantitatively, however protein degradation is more difficult to measure quantitatively and the methods to study muscle protein breakdown in humans are not fully validated.
One aim of this thesis was to descriptively study the amino acid and protein metabolism of skeletal muscle longitudinally in intensive care unit (ICU) patients. In a volunteer study endotoxin was used to obtain a human model of the initial phase of sepsis. To assess protein turnover in skeletal muscle, techniques to quantify synthesis as well as degradation in muscle tissue are required. Hence developing of new and accurate quantitative techniques to measure muscle protein breakdown are necessary. Another aim of the thesis was to develop and validate new and existing techniques to measure muscle protein breakdown rates which were validated in volunteers in the basal state and following endotoxin administration.
The temporal pattern of amino acid net balances across the leg and plasma concentrations, in particular glutamine and glutamate, in long-staying ICU patients were investigated. Neither glutamine concentration nor net release from the leg changed significantly during the initial two weeks of ICU stay, despite a net release of phenylalanine indicating a progressive net loss of skeletal muscle proteins. In addition, the net uptake of glutamate across the leg muscle was not altered during this period. Studying of amino acid metabolism in the initial phase of illnesses in ICU patients is not possible. Therefore endotoxin administration was used as a human model of the early phase of sepsis to obtain information of the initial pattern of amino acid metabolism in skeletal muscle. Concentrations of all amino acids in plasma and skeletal muscle decreased after endotoxin administration and in addition the efflux of most amino acid from the leg increased.
For studies of protein turnover at the tissue level, quantitatively accurate methods to measure protein kinetics are necessary. 3-Methylhistidine (3-MH) can be used as a marker of contractile protein degradation. Arterio-venous differences of 3-MH concentrations across limbs have been used to assess skeletal muscle protein degradation, but the methods to measure 3-MH net balances by HPLC techniques are not precise enough to measuring of the small arteriovenous concentration differences. The use of tracer techniques, employing 2H3-3-MH and 2 2H5-phenylalanine, enabled calculation of the rates of appearance for 3-MH and phenylalanine respectively. In the basal state these values were shown to be different from zero during the isotopic steady state. The effects of endotoxin on muscle protein metabolism were studied by three different models using tracer techniques.
Whole body phenylalanine rate of appearance increased indicating an increase in whole body protein degradation. From the leg there was an increased efflux of phenylalanine indicating a net protein loss, but no alteration in 3-MH net balance or rate of appearance. A 3-compartment model for phenylalanine turnover was used, which showed a decreased muscle protein synthesis but an unchanged degradation. So endotoxin administration cause altered muscle protein synthesis but does not influence protein degradation, although whole body protein degradation increases.
In summary alterations in amino acid metabolism in skeletal muscle are established early during the illnesses. During the initial two weeks of ICU stay no temporal changes in amino acid concentrations and net balances were seen, despite continuous protein loss from skeletal muscle. An endotoxin challenge decreased plasma and muscle amino acid concentrations and in addition the efflux of amino acids from the leg increased. Measurement of 3-MH rate of appearance from leg muscle using isotopically labelled 3-MH resulted in consistent and accurate values of contractile protein degradation rates. Endotoxin administration decreased human skeletal muscle synthesis rate while protein breakdown was not affected.
Amino acid and protein turnover in human skeletal muscle
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/378712023-02-23T15:45:26Zcom_10616_1com_10616_207com_10616_46998col_10616_219col_10616_208col_10616_47000
Publications from KI
author
Akhavan, Sharareh
2010-10-21T20:27:44Z
2010-10-21T20:27:44Z
2006-09-01
91-7140-849-5
20060922akha
http://hdl.handle.net/10616/37871
Sweden is one of the European countries that has gradually changed from a mainly ethnically homogeneous society into a multi-ethnic society. This change began in the late 1940s and has increased in pace, especially since the early 1960s. The overall aim of this thesis is to understand, describe and analyze the factors that contribute to poor health among female immigrants in Sweden, from the perspectives of class, gender and ethnicity.
This thesis is based on four different studies. The first study had a qualitative, longitudinal design. It was based on semi-structured interviews with ten (10) female Iranian immigrants aged 25-50 years old. The interviews were conducted on two occasions, in 1996 and 2002. The purpose was to identify and analyze the women's perception of various factors which had influenced their health over time. The second study had a cross-sectional design and consisted of 60 unemployed with immigrant or refugee backgrounds, 30 women and 30 men. The aim was to analyze the health of immigrants in relation to unemployment status and sick leave absences from a gender perspective. Both qualitative and quantitative methods were used for data collection. The third study was cross-sectional in design and consisted of 2,429 native and immigrant female employees in a municipality in the suburbs of Stockholm, in Sweden. The purpose was to study the work-related factors that influenced the health of female immigrants. The fourth study combined an explanatory approach with a cross-sectional design using qualitative data from semi-structured interviews. The studied group consisted of twenty (20) female immigrants who worked in different departments of a municipality in the suburbs of Stockholm. The aim of the study was to explore the work-related factors that affected the health of female immigrants.
The main findings in this thesis show that there is an interaction between health, work and migration. Adverse health was more evident among female immigrants who were either unemployed or on sick leave, than among male immigrants in a similar position. There was a strong association between the work-related health of female immigrants and social class. The three aspects based on class were wages, professional status and position in the hierarchical work organization. This thesis shows that the health of female immigrants cannot be attributed solely to "cultural differences", but that it must also be viewed within the contexts of class, gender and ethnicity. From the accounts of the interviewed women, two new insights on the factors that influence the health of female immigrants during the postmigration period can be put forward. Firstly, female immigrants may overcome some healthrelated factors such as domestic violence or experiences of traumatic events during the first decade of the post-migration period. However, the effects of other health determinants such as unemployment or experiences of discrimination and racism were observed even two decades after migration. Secondly, the impact of ethnic discrimination on health is not alleviated by the length of stay in the host country or by higher socioeconomic status. The only aspect that may have changed concerns the strategies used in coping with discrimination. The length of stay, entering the labor market and a more favorable socioeconomic status seem to result in better management and improved strategies for coping with ethnic discrimination. The thesis contributes new insights on the ethnic and gender discrimination that occurs regardless of a female immigrant's position in the organizational hierarchy. Nevertheless, the mechanism of discrimination can be different for those who are employed in low-status professions. This shows that class still matters and is a very important factor in public health research. As such, it should not be ignored in studies on health in relation to ethnicity.
The public health implications of the findings in this study suggest that public health policies aimed at female immigrants should provide a good introduction and access to health information to new arrivals. Specific measures are needed to recognize female immigrants' pre-migration work experience and academic qualifications in order to counteract the deskilling process, a process which results in unemployment, long-term social exclusion or employment in low-status professions with low incomes. Strategies for tackling ethnic discrimination/racism are needed, particularly on the labor market and in workplaces. Policies to stimulate an increase in the opportunities for mobility for female immigrants on the labor market are needed, especially for those who work in jobs with low status and low pay.
eng
info:eu-repo/semantics/openAccess
The health and working conditions of female immigrants in Sweden
info:eu-repo/semantics/doctoralThesis
URL
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oai:openarchive.ki.se:10616/405142023-10-23T16:17:56Zcom_10616_1com_10616_210com_10616_46998col_10616_219col_10616_211col_10616_47000
Publications from KI
author
Sjögren, Anders
2011-04-14T09:04:36Z
2011-04-14T09:04:36Z
2011-04-14
978-91-7457-286-5
http://hdl.handle.net/10616/40514
Interception of crowding, by extraction of deciduous and permanent teeth, to eliminate or at least facilitate orthodontic treatment has a long tradition. This treatment procedure, know as “guided eruption” or “serial extraction” was re-introduced by Robert Hotz and Birger Kjellgren in 1947-48. The sequential extraction procedure begins with the removal of the deciduous canines in the early mixed dentition and additional extractions of deciduous first molars and permanent bicuspids are considered after careful monitoring of dental arch development.
Few studies have evaluated the entire treatment procedure, especially the first phase including extraction of the deciduous canines. Dentists have therefore had to rely mainly on clinical experience and consequently this established procedure has become controversial.
The general aim of this work has been to evaluate the effects on incisor alignment and dental arch dimensions after interceptive deciduous canine extractions. Furthermore, patient’s reactions to these extractions regarding pain, discomfort and dental fear are described.
Paper I examined the reproducibility of and agreement between a conventional (using plaster casts) and a 3D virtual technique for recordings used in orthodontic study cast analysis.
Paper II and III were randomized controlled trials involving 73 and 71 children respectively, stratified for gender. Paper II evaluated the early effects on mandibular incisor irregularity and rotation together with changes in dental arch dimensions, overjet and overbite. Paper III evaluated the long-term effects on mandibular and maxillary incisor irregularity and rotation together with changes in dental arch dimensions, overjet and overbite. Paper IV explored procedural and postoperative pain and discomfort among child dental patients undergoing orthodontic extractions of four deciduous canines. Changes in dental fear ratings from pre- to post-treatment were also investigated.
The conclusions based on the results from the studies are that: The conventional method showed better reproducibility for angular variables, but no clear pattern was found for differences between the two methods in reproducibility of 8 linear variables. Reproducibility was considered clinically acceptable for both methods, although systematic errors indicated that the two methods should not be used interchangeably.
Extraction of deciduous canines can not be expected to improve maxillary or mandibular incisor alignment in a significant way and should therefore not be recommended for the relieve of incisor crowding. The congruent results between professional visual assessment and conventional measurements concerning alignment strengthen the validity of the treatment outcome results. No major effect was seen on arch dimensions, overjet or overbite.
The extraction of four deciduous canines was not found to trigger or increase dental fear and should not cause major post-operative inconvenience. A small number of individuals though had very high ratings of pain and discomfort at several occasions, revealing a need for updating clinical routines for pain management.
eng
info:eu-repo/semantics/openAccess
Influence of deciduous canine extractions on incisor alignment, dental arch dimensions and dental fear
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/426742022-10-14T15:18:22Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Englund, Katarina
2014-12-04T16:29:00Z
2014-12-04T16:29:00Z
2001-05-25
91-628-4706-6
20010615engla
http://hdl.handle.net/10616/42674
Uterine fibroids, or leiomyomas, are the most common benign tumors in the female genital tract.They represent a major cause of gynaecologic morbidity. The etiology of these tumors is largely unknown but the levels of estrogen (E) and progesterone (P) are considered to be the major determinants for fibroid growth. The aim of the present study was to clarify some aspects regarding the selective growth advantage of fibroids when compared with normal myometrium. Fibroids and/or myometrium were obtained at surgery. One group of women were preoperatively treated with a gonadotropin releasing hormone agonist (GnRHa). The women were carefully characterized concerning hormonal status. The ER and PR were determined with enzyme immunoassay (EIA), the mRNA expression was measured by solution hybridization and the IGF-I concentration in tissue by radioimmunoassay.
The ER and PR protein content was higher in fibroids than in myometrium in all groups, except postmenopausal and pregnant women. The ER content was high in all tissues when the P level was low, whereas low levels of ER were present in tissues obtained in P dominated conditions. The PR content was low in both tissues when serum E was low and a high level of PR was found in the E dominated proliferatory phase.The lowest levels were found in the pregnant group. There is a marked variation in the content of ER and PR, both between fibroids and myometrium and between tissues in different endocrine conditions. E seems to up-regulate PR and to down-regulate its own receptor, while P seems to down-regulate both ER and its own receptor. The exceptionally low levels observed during pregnancy are probably due to down-regulation caused by high hormone levels.
A lower level of c-fos and c-jun was observed in fibroids than in myometrium and the only sign of an influence by hormones was a significant increase in c-jun expression in myometrium from pregnant women. The low expression in fibroids may be part of the benign phenotype of the fibroids, although overexpresssion of protooncogenes in general are considered to be associated with tumorigenesis.
Both IGF-I and its mRNA were higher in fibroids than in myometrium in premenopausal, non treated patients but no differences were seen between the phases. Low levels of mRNA was found in the GnRHa treated and postmenopausal women and the highest levels of both IGF-I mRNA and IGF-I were seen in the pregnant group. IGF-I seems to be involved in sex steroid mediated growth regulation of uterine tissues and contribute to the growth advantage of fibroids. However, the bioavailability of the peptide is strongly regulated by the different binding proteins of which our knowledge is limited. The EG17R mRNA was lower in fibroids than in myometrium in the premenopausal groups but not in postmenopausal and pregnant women. The highest tissue levels were found in pregnant women and the lowest in the postmenopausal group. Despite the hormonal regulation of the EGFR the role of EG17 and its receptor in fibroid growth is presently unclear.
The selective gro wth advantage of fibroids is regulated in a complex way. These tumors maintain a high degree of differentiation and in most conditions they respond to hormonal stimulation in a simailar way as the myometrium. Altered signal transduction pathway(s) in fibroids might alter the cells normal response to hormones, such as E and P.
Hormonal regulation of sex steroid receptors and growth related genes in human myometrium and leiomyomas
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/481092022-06-01T07:50:58Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Winblad, Nerges
2022-05-30T10:57:26Z
2022-05-30T10:57:26Z
2022-05-30
978-91-8016-674-4
http://hdl.handle.net/10616/48109
With their intrinsic capacity to self-renew and their potential to differentiate to specialized tissues, human embryonic stem cells (hESCs) have many applications in the fields of cell therapy and developmental biology. By applying clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) genome engineering on selected genes in hESCs, we are able to create cells with desired characteristics.
In paper I, we wanted to explore the possibility of creating hypoimmunogenic stem cell lines for cell therapy. Therefore, the genes beta-2-microglobulin (B2M) and class II major histocompatibility complex transactivator (CIITA) were targeted to obtain hESCs that would not be able to present and express human leukocyte antigen (HLA) class I and class II, respectively. We derived three hESC lines, for which the expression of HLA class I, HLA class II or both were prevented. Whole genome sequencing (WGS) analysis identified few introduced off-target mutations, all of which were in non-coding regions and had not been attributed as pathogenic. These edited hESC lines were differentiated into retinal pigment epithelium (RPE) cells and tested in vitro against T cells and natural killer (NK) cells. Failure to present HLA class I and class II led to reduced CD8+ and CD4+ T cell responses, while NK cell degranulation increased and NK cell cytotoxicity remained unchanged. Finally, when the modified hESC-derived RPE cells were transplanted into a preclinical animal model, rejection was delayed regardless of the modification that had been introduced into the parental hESC lines.
In the following two studies, we used hESCs to model key molecular events during early human embryogenesis.
In paper II, we investigate lineage commitment during embryo development using naive and primed hESCs as models for the pre- and post-implantation epiblast, respectively. Inhibition of polycomb repressive complex 2 (PRC2) with pharmacologic inhibitors or through genetic ablation, led to the discovery that this protein complex maintains naive pluripotency and acts as a barrier, preventing naive hESCs from differentiating into trophectoderm or mesoderm lineages. New shared and naive-specific bivalent promoters were defined, identifying promoters of key trophectoderm and mesoderm genes as kept in a transcriptionally balanced state. Inhibition of PRC2 rendered naive hESCs in an activated state where both pluripotency and lineage-specific genes were expressed. Furthermore, transitioning through the activated state led to commitment to either trophectoderm or mesoderm lineages.
In paper III, the relationship between long non-coding RNA (lncRNA) X-inactive-specific transcript (XIST) and the transcriptional repressor spen family transcriptional repressor (SPEN) was studied. Previous studies using mouse embryonic stem cells had identified SPEN as an Xist-interacting protein. Specifically, SPEN was described to bind to Xist RNA during initiation of X chromosome inactivation (XCI), to facilitate Xist RNA stability and to inhibit the negative regulator of Xist, namely Tsix, by recruiting chromatin remodelers to its promoter. We hypothesized that naive hESCs could be used to study the effect of loss of SPEN on XIST RNA,
since XIST is induced during conversion and X chromosome expression becomes biallelic, similar to the preimplantation epiblast. Thus, we targeted the SPEN locus in primed hESCs and converted single-cell derived SPEN knockout clones to the naive stem cell state. Surprisingly, the impact of SPEN depletion on XIST was apparent already in the naive state and manifested as low detectable levels of XIST RNA at naive passage 8, which remained low at naive passage 13.
eng
info:eu-repo/semantics/openAccess
Exploring early development and regenerative medicine using CRISPR/Cas9
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/381782023-02-22T15:52:18Zcom_10616_1com_10616_180com_10616_46998col_10616_219col_10616_181col_10616_47000
Publications from KI
author
Ryk, Charlotta
2010-10-21T20:28:40Z
2010-10-21T20:28:40Z
2006-09-29
91-7140-940-8
20061020ryk
http://hdl.handle.net/10616/38178
Individuals have different susceptibility towards environmental exposures that may cause or contribute to disease. This inter-individual variation is partly due to genetic polymorphisms in genes involved in DNA repair and metabolism, which have potential to modulate the function of the encoded proteins.
This thesis is a contribution to the knowledge about the importance of polymorphisms, and how they might interfere with health. More specifically, the aims have been to investigate (1) if and how the mutational spectra of the tumour suppressor gene p53 in lung and bladder tumours is affected by genetic polymorphisms, (2) if polymorphisms can influence lung cancer risk in a study population with a high frequency of women and non-smokers, and (3) to develop a method to study the functionality of DNA repair polymorphisms in vitro.
Papers I-II are based on a lung cancer case-control study population, with approximately 50 % nonsmokers and 70 % women. Papers III-IV are based on a bladder cancer cohort that includes all bladder cancer cases in the Stockholm county between 1995-1996. In paper V, lymphocytes from healthy nonsmoking volunteers were collected to study the functionality of DNA repair polymorphisms, using the Comet assay. PCR-RFLP and Taq-Man allelic discrimination were used for genotyping, SSCP and sequencing for identification of p53 mutations in tumours.
The impact of genetic polymorphisms on the p53 gene was investigated in study I, III and IV. In study I we observed an association between the XPD 751G1n allele and an increased frequency of p53 transversion mutations in lung tumours, especially among smokers, suggesting that XPD 751G1n carriers have a reduced DNA repair proficiency. In study III we found that p53 transversion mutations were more common in bladder tumours of GSTM1 null individuals, and also the GSTP1 105Val allele was associated with a higher frequency of p53 transversion mutations than the wild type allele. GSTP1 105 Val was also associated with a higher frequency of p53 transitions at CpG sites. These results indicated that an impaired glutathione conjugation might affect the p53 mutational spectrum.
In study IV, the cyclin D1 variant allele homozygotes and the XRCC3 241 Met homozygotes were associated with an increased p53 mutation frequency, while the NQ01 187Ser and 139Trp alleles and the XPC 939GIn allele were associated with an increased frequency of p53 transversion mutations. Thus, in general, these polymorphisms seem to have an impact on the type of mutations in the p53 gene in lung- and bladdertumours, while their impact on the frequency of mutation is small. This increased risk for specific types of mutations probably reflects a higher susceptibility to environmental exposures following the impaired metabolism (glutathione conjugation), or less efficient DNA repair, among carriers of the susceptible alleles.
The influence of polymorphisms on lung cancer risk was investigated in study II, where the XRCC1 399GIn and the XRCC3 241 Met alleles were found to be associated with decreased risk for lung cancer among non-smoking- and smoking- women respectively. The NBS1 185GIn allele was associated with an increased risk among non-smoking and low-dose smoking women. The effects of the two HR-proteins, XRCC3 and NBS1 enhanced each other. Our results suggest that these polymorphisms influence the cancer risk through their effect on the repair capacity, which may alter the risk of having mutations fixed in the genome.
In study V, we used a modified comet assay to study the influence of DNA repair polymorphisms on repair of MMS-induced DNA damage in peripheral blood lymphocytes in vitro. The investigated APEX1 Asp 148Glu, XRCC3 Thr241Met and NBS1 Glu 185Gln polymorphisms were shown to have effect on the early stages of DNA repair, and were associated with the rate of transitions of cells from a more damaged to a less damaged state. This type of functional study of DNA repair enzyme polymorphisms will contribute to a better understanding of the significance of gene association studies in cancer research.
eng
info:eu-repo/semantics/openAccess
Influence of genetic polymorphisms on DNA repair, p53 mutations and cancer risk
info:eu-repo/semantics/doctoralThesis
URL
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oai:openarchive.ki.se:10616/420232023-11-01T00:12:14Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Chatzidionysiou, Katerina
2014-05-09T08:10:25Z
2014-05-09T08:10:25Z
2014-05-09
978-91-7549-561-3
http://hdl.handle.net/10616/42023
The landscape of RA treatment has unquestionably changed dramatically during the last decade. A deeper understanding of the pathophysiological and immunological mechanisms in RA, earlier and more aggressive treatment, and the development and introduction to daily clinical practice of a new class of antirheumatic drugs, the so-called biologic therapies, has contributed to this ‘revolution’.
To date, nine biologic agents have been approved for the treatment for RA and more molecules with distinct mechanisms of action are currently being tested in laboratories and in clinical trials. In all cases, very good clinical efficacy and safety were documented in large, randomized, controlled clinical trials that led to regulatory approval.
However, not all questions regarding the optimal use of these agents can be addressed in randomized trials. Observational studies based on registries can provide important information about the effectiveness and safety of biologics in real-life RA populations as well as better insight of different treatment strategies. Thus they are important ‘pieces of the puzzle’ and can help complete the picture of RA treatment.
This thesis comprises of two parts: part I is based on four studies about several aspects of rituximab use in RA which are based on a large international cohort. The second part is based on four studies about the use of TNF inhibitors in RA (cycling, switching and discontinuation) which are based on local and national registers and a pilot clinical trial.
eng
info:eu-repo/semantics/openAccess
Biological therapy in rheumatoid arthritis : epidemiological studies
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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Publications from KI
author
Dias, José
2011-10-06T10:30:53Z
2011-10-06T10:30:53Z
2011-10-06
978-91-7457-457-9
http://hdl.handle.net/10616/40704
The generation of neural cell diversity in the developing central nervous system relies on mechanisms that provide spatial and temporal information to neural progenitor cells. The deployment of morphogen gradients is an important strategy to impart spatial information to the field of responding cells. In this process, cells translate different concentrations of signal into the expression of distinct sets of cell fate-determining transcription factors, which determine cell fate as progenitors leave the cell cycle and differentiate into neurons. However, the mechanisms by which time regulates cell fate determination are poorly understood. The aim of this thesis is to better understand the mechanisms of spatial and temporal patterning in the specification of neural cell types.
In the ventral half of the neural tube, the graded activity of Sonic hedgehog (Shh) has been proposed to specify the patterned generation of distinct neuronal subtypes. It remains unclear, however, whether non-graded mechanisms of Shh signaling also contribute to this process. We show that Shh-induced Nkx2 proteins intrinsically amplify Shh responses and that this activity is important to specify floor plate (FP) and V3 fates in the ventral spinal cord. Conversely, Pax6 antagonizes Shh signaling and constrains its inductive activity over time. Furthermore, our data suggest that the spatial patterning of FP and V3 cells reflects a switch of neuronal potential in neural progenitors and not a requirement for different concentrations of Shh. Together, this study indicates that the output of graded Shh signaling depends on dynamic and non-graded changes of competence in responding cells.
At the hindbrain level, the progenitor domain dorsally abutting the FP generates visceral motor neurons (vMN) at early stages of development. To better understand the genetic program of vMN specification, we studied the role of proteins expressed in vMN progenitors during this process. We show that Nkx2.2 is sufficient to activate the expression of Phox2b, an important determinant of vMN fate. Moreover, the redundant activities of Nkx6.1 and Nkx6.2 proteins are not required for the generation of vMNs, but are important to prevent the parallel activation of dorsal cell fate differentiation programs and to ensure proper migration and axonal projection of vMNs. Thus, our data establish complementary roles for Nkx2.2 and Nkx6 proteins in the establishment of vMN identity.
In contrast to spatial patterning, the mechanisms that regulate the sequential generation of distinct cell types from a common pool of progenitors remain poorly resolved. To better understand these mechanisms we analyzed the sequential generation of vMN and serotonergic neurons (5HTN) from a common pool of Nkx2.2+ progenitors in the ventral hindbrain, and found that the temporal specification of these cell types depends on the integrated activities of Nkx and Hox proteins to regulate the temporal expression of Phox2b. In turn, Phox2b functions as a cell fate selector promoting vMN and repressing 5HTN fate. To further understand the vMN-to-5HTN switch, we screened for factors that could regulate this process, and identified Tgfβ2 as a signal that executes the switch through a temporal cross-repressive interaction with Phox2b. Moreover, we show that prolonged Shh activity establishes the initial period of vMN fate and induces Tgfβ2 expression with a temporal delay. Together, our studies reveal that a Shh-Tgfβ signaling relay mechanism regulates the sequential generation of vMNs and 5HTNs in a dynamic process that can be modulated by determinants controlling spatial patterning.
eng
info:eu-repo/semantics/openAccess
Spatial and temporal mechanisms of cell fate determination in the developing CNS
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/381132023-02-21T09:08:38Zcom_10616_1com_10616_159com_10616_46998col_10616_219col_10616_160col_10616_47000
Publications from KI
author
Ruas, Jorge Lira
2010-10-21T20:28:32Z
2010-10-21T20:28:32Z
2005-05-20
91-7140-329-9
20050613ruas
http://hdl.handle.net/10616/38113
Under limited oxygen availability (hypoxia) cells undergo rapid reprogramming in order to survive in the new environment until normoxic conditions are re-established. The observation that hypoxia can induce the expression of genes involved in erythropoiesis, angiogenesis and glucose metabolism among others, led to the identification of the hypoxia-inducible factor-1 (HIF-1) as a master regulator of the hypoxia-response pathway. HIF-1 is a heterodimeric transcriptional activator composed of two subunits (HIF-1alpha and ARNT) that belong to the bHLH/PAS family of transcription factors. At normoxia, HIF-1 activity is inhibited by rapid degradation of the alpha subunit, targeted to the 26S proteasome by interaction with the E3 ubiquitin-ligase pVHL. Under hypoxia, HIF-1alpha is stabilized and translocates to the nucleus where it dimerizes with ARNT and activates target gene expression by recruiting coactivator proteins.
The aim of this study was to investigate the structure/function relationship of HIF-1alpha N- and Cterminal activation domains (N- and C-TAD) and to analyze the mechanisms of conditional recruitment of coregulator proteins. Furthermore, we were interested in analyzing the coordinated subcellular and intranuclear redistribution of proteins involved in the hypoxic response. The information and reagents obtained in initial studies were used in the identification of new HIF-1- interacting proteins.
In the study of HIF-1alpha N-TAD, we identified several amino acid residues critical for the transactivation and degradation functions of this bifunctional domain. Although we observed a significant structural overlap between both functions, we demonstrated by mutation analysis that the transactivation activity is mediated by a longer peptide when compared to the minimal degradation box, which is circumscribed to the core of the domain. We concluded that HIF-1alpha NTAD functions as an independent transactivation domain in a CBP-dependent manner.
In silico analysis of the secondary structure of HIF-1alpha C-TAD revealed two putative alpha-helices in the initial and terminal regions of this domain. The function of these putative structures was analyzed by alanine-scanning mutagenesis and revealed two subdomains with disparate contributions to the overall activity of the C-TAD. The C-terminal helix (helix-2) proved to be critical for transactivation and for interaction with the CH1 domain of CBP. In this study we observed that colocalization of CFP-HIF-1alpha and YFP-CBP in intranuclear colocalization foci was dependent of the integrity of both HIF-1alpha transactivation domains.
We have shown that, although SRC-1 is an important coactivator of HIF-1 function, the interaction between the two proteins needs to be mediated by CBP. In vivo colocalization studies showed that CBP plays a dominant role in the intranuclear redistribution of the HIF- 1alpha/ARNT/CBP/SRC-1 complex into foci of colocalization that partially overlapped the distribution of RNA Pol IIo.
We have characterized a novel interaction interface between HIF-1alpha and CBP, that is mediated by direct binding of the N-TAD to the CH3 domain of CBP. In this study we provide evidence that, under hypoxic conditions, the high affinity of HIF-1á for limiting amounts of CBP, may interfere with other CBP-dependent pathways.
Finally, we have identified the enzyme C1-tetrahydrofolate synthase as a novel protein that participates in the regulation of HIF-1alpha activity. Overexpression of C1-tetrahydrofolate synthase dramatically increased HIF-1-mediated transactivation due to stabilization of the alpha subunit. We show that C1-tetrahydrofolate synthase stabilizes HIF-1alpha by interfering with PHD-mediated hydroxylation of Pro563 of the N-TAD and inhibiting pVHL-recruitment and protein degradation. The results from these studies have contributed to a better understanding of the mechanisms that control HIF-1 activation and provide evidence for novel levels of regulation of HIF activity.
eng
info:eu-repo/semantics/openAccess
Oxygen-dependent regulation of transcription by the hypoxia-inducible factor-1
info:eu-repo/semantics/doctoralThesis
URL
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oai:openarchive.ki.se:10616/463672023-10-18T17:09:12Zcom_10616_1com_10616_183com_10616_46998col_10616_219col_10616_184col_10616_47000
Publications from KI
author
Nematollahi Mahani, Amir
2018-05-30T13:35:45Z
2018-05-30T13:35:45Z
2018-05-30
978-91-7831-123-1
http://hdl.handle.net/10616/46367
The Myc proto-oncogene, is a highly disordered (lack of structure formation) transcription factor (TF), which can bind to its partner proteins and regulate different biological functions of the cells including proliferation, cell cycle, differentiation and apoptosis. In general, Myc deregulation is a major prime force in human tumors, which contributes to their uncontrolled cell proliferation, metastasis and tumor cell immortalizations. In particular, Myc expression influences the transcriptional profile of cells by promoting RNA Polymerase II gene transcription to produce mRNA, as well as the transcription of the rRNA and tRNA genes transcribed by RNA Polymerase I and III, respectively. Thus, controlling expression of ribosome components, required for protein synthesis, appears to be an important role of Myc in normal and cancer cells.
In this thesis, I have studied phylogenetic and molecular evolution of the Myc family proteins, for the first time exploiting their protein order/disorder properties and the extent of their conservation through the Metazoan and beyond. We systematically analyzed the predicted protein disorder profile of Myc family proteins using a range of different algorithms. Therefore, we showed that all Myc proteins are structurally disordered TFs and most of the interaction domains of c-Myc are within disordered regions. Moreover, Using Intrinsically Disorder Protein (IDP) profiles we established a new way to evaluate the evolution of TFs based on their disorder profile. Use of IDR predictions instead of protein sequences produced a better-supported phylogenetic tree of Myc proteins, including large clades containing c-Myc, MycN, MycL and dMyc proteins. In addition, we analyzed the effect of Burkitt’s lymphoma (BL) mutations on the disorder profile and suggested that these adaptive BL-Associated Mutations (BL-AM) could change the local conformation of c-Myc and thereby its functions.
Next, we studied Myc in the nucleolus, an adaptive context that has scarcely been studied, and its involvement in spatial chromatin domain organization of the rRNA genes. Accordingly, we found that Myc activation caused altered spatial organization of the mammalian rDNA by tethering the rDNA to the nucleolar scaffold/matrix via non-transcribed intergenic spacer sequences of the rDNA. In addition, in rat fibroblast cell lines we found that matrix associated rRNA genes are hypo-methylated on DNA sites in their upstream core promoter regions (CpG site at position -145).
Finally, I characterized lymphoma-associated gene expression induced by wild type Myc and how it is adapted in response to BL-AM (T58A and T58I). For this purpose, I established a cell system, consisting of low passage primary B-cells transduced with lentivirus expression constructs, in which wild type or BL-AM Myc could be induced to varying degrees by doxycycline in order to progressively promote a lymphoma-like phenotype. The transduced cells also constitutively over-expressed the BMI1 and BCLXL proteins to inhibit apoptosis. Progressive increase in Myc expression was associated with a progressive increase in cell proliferation, size and proportion of cells in S-phase for both wild type Myc and BL-AM, albeit with some differences between the different Myc proteins. RNA-Seq was used to measure cellular transcripts at seven different doxycycline concentrations for cells expressing wild type and BL-AM Myc. Generalized linear models (as implemented in the MaSigPro package (v3.3)) were then used to identify differentially regulated genes (DEG) with regard to Myc level and/ or mutant status. Thus, we found 4443 DEG common to all three-cell system as well as 543 DEG deregulated only in T58A and T58I cells. On the other hand, the results show DEG common between wild type and T58A (n=553) as well as between wild type and T58I (n=1062). Further analysis, identified 15 gene clusters with different patterns of differential gene expression and these genes were enriched in generally distinct sets of gene ontology terms, indicating little functional overlap between clusters. The data identify gene sets induced by Myc as the cells convert to lymphoma-like cells as well as gene sets where one or both BL-AM augment changes induced by wild type Myc.
eng
info:eu-repo/semantics/openAccess
Functional adaptation of c-Myc and its role in lymphoma-associated gene regulation
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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Thesis_Amir_Mahani.pdf.txt
oai:openarchive.ki.se:10616/423282019-09-30T03:31:31Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Kruspig, Björn
2014-12-17T12:31:52Z
2014-12-17T12:31:52Z
2014-12-17
978-91-7549-766-2
http://hdl.handle.net/10616/42328
Mitochondria possess a central role in several cellular metabolic pathways, maintenance of calcium homeostasis, production of reactive oxygen species (ROS) and in the regulation of various cell death modalities. A majority of cancers demonstrate aberrations in mitochondrial functions, which were shown to contribute to tumourigenesis. In addition, many mechanisms
of chemotherapy-resistance are located upstream of the mitochondria in cell death pathways. Thus, destabilization of mitochondria and permeabilization of the outer mitochondrial membrane (OMM), a point of no return in apoptosis induction, represent promising strategies for anticancer therapy.
One major aim of this thesis was to identify therapeutic approaches to overcome resistance of cancer cells to conventional chemotherapeutic drugs. We could show in Paper I that chemotherapy resistance mechanisms in cancers, mediated by various oncogenic signalling/mutations, could be overcome by targeting Complex II of the mitochondrial respiratory chain. Treatment of Neuroblastoma (NB) cells with α-tocopheryl succinate (α-TOS), a redox-silent analogue of vitamin-E, which was shown to target Complex II, mediate ROS-production and an increase of cytosolic calcium levels, could induce apoptosis in cancers cells irrespective of their MycN or p53 status. We propose that this is based on the ability of α-TOS to induce both mechanisms of OMM permeabilization, in a Bax/Bak-dependent manner, as well as calcium-dependent induction of mitochondrial permeability transition (MPT).
In Paper II and III we investigated the possibility of sensitizing cancer cells to conventional anticancer drugs in a co-treatment setting with compounds targeting Complex II. In case of α-TOS (Paper II), the obtained results revealed contrasting effects for the chemotherapeutic
drugs etoposide and cisplatin. In case of etoposide, α-TOS was able to sensitize cancer cells in a dose-dependent manner. Whereas strikingly, in case of cisplatin, low concentration of α-TOS protected cells from cisplatin-induced toxicity. We demonstrated that the succinate moiety of α-TOS is mediating this protective effect via stimulation of Complex II activity. However, when Complex II was inhibited using thenoyltrifluoroacetone (TTFA) (Paper III), a specific inhibitor of the ubiquinone binding site of Complex II, cells could be sensitized to both, etoposide- and cisplatin- induced cytotoxicity. This chemosensitizing effect was shown
to rely on Complex II-mediated ROS-production.
For the study that was concluded in Paper IV, a different approach was utilized. Citrate, a substrate of the tricarboxylic acid cycle, was shown to induce cytotoxicity in cells. The underlying mechanism was speculated to be based on citrate’s inhibitory effect on several crucial glycolytic enzymes and its ability to chelate calcium. We could demonstrate that although these features contribute, the main cause of cell death induced by citrate is the activation of initiator caspases. The underlying mechanism was proposed to be the kosmotropic property of citrate.
In summary, the findings of this PhD thesis clearly underline the potency of exploiting
mitochondria for anticancer therapy. Particularly Complex II plays an intriguing role in the sensitivity towards chemotherapy and represents an attractive target that should be further explored in future projects. In addition, new roles of well-known mitochondrial substrates were revealed.
eng
info:eu-repo/semantics/openAccess
Mitochondria : a target for anticancer therapy
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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Thesis_Björn_Kruspig.pdf.txt
oai:openarchive.ki.se:10616/422692019-09-30T03:32:18Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Ljungblad, Cecilia
2015-02-13T10:32:54Z
2015-02-13T10:32:54Z
2015-02-13
978-91-7549-832-4
http://hdl.handle.net/10616/42269
Background: People working in social care constitute the largest occupational group in Sweden and they have the highest prevalence of sickness absence. Since sickness absence results in great human and societal costs, there is incentive to develop initiatives to promote health for this group. Previous research about both what measures are effective and how soon effects occur are limited and more knowledge about this is needed.
Aim: The overall aim of the thesis was to gain more knowledge about associations between workplace health promotion and employee health, sickness absence, and sickness presence in municipal social care organizations.
Method: Four studies were conducted concerning social care organizations and their employees in 60 Swedish municipalities, based on data from registers as well as from surveys to employees, top managers, and policy makers, respectively. A randomized sample of 60 of the 290 municipalities in Sweden and a randomized sample of 15,871 people employed at least half time throughout 2006 within the social care sector in these 60 municipalities was used. A questionnaire was sent to the employees selected (9270) and 58% replied (study I-IV). Another questionnaire was sent to top managers who represented the employer in the same 60 municipalities (n=60) (study II). A third questionnaire was sent to policymakers in the 60 municipalities (study III). Register data was obtained on sickness absence (>14 days) in 2006 for the 9270 employees and on long-term sickness absence (>90 days) in 2007–2012 for all social service workers in the 60 municipalities. Both cross-sectional (study I–II and IV) and prospective (study III) study designs were used, using individual level data (study IV) and organizational level data (study I-III). Descriptive statistics, bivariate and multiple linear and logistic regression analyses, and structural equation modelling analyses were performed.
Results: Organizations that had more favorable employee ratings of individual- and organizational-directed (psychosocial work conditions) workplace health promotion measures had better health and lower sickness absence levels among their employees (study I). Organizational- and individual-directed workplace health promotion measures and employee satisfaction with workplace health promotion measures were associated with better employee health (study II). There was an association between provision of organizational-directed workplace health promotion measures (prevention program) and future lower levels of long-term sickness absence (study III). There were associations present between the use of health profile assessment and fitness activities and a lower odds ratio of being sickness present (study IV).
Conclusions: There were low or moderate associations between provision/use of workplace health promotion for individual and/or organizational approaches and lower levels of poor self-rated health, lower future incidence of long-term sickness absence, and lower odds ratio for sickness presence.
eng
info:eu-repo/semantics/openAccess
Workplace health promotion and employee health in municipal social care organizations
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/42269/3/Thesis_Cecilia_Ljungblad.pdf
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Thesis_Cecilia_Ljungblad.pdf.txt
oai:openarchive.ki.se:10616/482292024-03-09T09:17:04Zcom_10616_1com_10616_192com_10616_46998col_10616_219col_10616_193col_10616_47000
Publications from KI
author
Dismorr, Michael
2022-09-27T11:35:19Z
2022-09-27T11:35:19Z
2022-09-27
978-91-8016-738-3
http://hdl.handle.net/10616/48229
Background: The use of bioprosthetic valves is common and offers a prosthetic option that does not require anti-coagulant therapy, but with shorter valve longevity compared to mechanical prostheses. Valve model selection might influence the long-term performance of the prosthesis. The research questions in the four studies were 1) Does blood type A-like antigens on porcine valves lead to decreased long-term performance of the valve in blood type B/0 patients, 2) Is there a difference in long-term performance between bovine and porcine valves, 3) Does some aortic valve models perform better or worse compared to other aortic valve models, 4) Does prosthesis-patient mismatch (PPM) impact long-term survival, valve reintervention and heart failure hospitalization.
Methods and results: Study I. Patients who received a porcine valve between 1995 and 2012 were identified from the Swedish cardiac surgery register and categorized according to blood type B/0 (1693, 49.5%) and A/AB (1724, 50.5%). The groups had similar baseline characteristics. The cumulative incidence of valve reintervention at 15 years was 3.4% (95% CI: 2.5 to 4.4%) and 3.6% (95% CI: 2.6 to 4.6%) in the B/0 and A/AB groups, respectively. After multivariable adjustment, there was no difference in valve reintervention (HR 0.95, 95% CI: 0.62 to 1.45), heart failure hospitalization (HR 0.92, 95% CI: 0.77 to 1.08) and all-cause mortality (HR 0.95, 95% CI: 0.87 to 1.05) rates in patients with blood type B/0 compared to patients with blood type A/AB. Study II. Patients who received a porcine (4194, 33%) or bovine (8647, 67%) aortic valve between 1995 and 2012 were identified from the Swedish cardiac surgery register. Inverse probability of treatment weighting was used to adjust for inter-group differences. Porcine valves were associated with improved survival (HR 0.90, 95% CI: 0.85 to 0.96) and an increased risk for valve reintervention (HR 1.48, 95% CI: 1.11 to 1.98). There was no difference in heart failure hospitalization between porcine and bovine valves. Study III. All patients who underwent primary surgical bioprosthetic aortic valve replacement in Sweden 2003 to 2018 were identified from the Swedish cardiac surgery register. Patients were categorized according to valve model; Perimount, Mosaic/Hancock, Biocor/Epic, Mitroflow/Crown, Soprano and Trifecta. Regression standardization was used to account for differences in baseline characteristics. Perimount had the lowest, and Mitroflow/Crown had the highest cumulative incidence of reintervention (3.6%, 95% CI: 3.1 to 4.2% and 12%, 95% CI: 9.8 to 15%), all-cause mortality (44%, 95% CI: 43 to 45% and 54%, 95% CI: 52 to 57%) and heart failure hospitalization (13%, 95% CI: 12 to 14% and 20%, 95% CI: 18 to 23%) at ten years, respectively. Study IV. All patients who underwent primary surgical bioprosthetic aortic valve replacement in Sweden 2003 to 2018 were identified from the Swedish cardiac surgery register. Patients were categorized according to no (7377, 45%), moderate (8502, 52%) and severe (544, 3%) PPM, estimated by valve model, valve size and the patient’s body surface area. The survival difference at ten years was 4.6% (95% CI: 0.7 to 8.5%) and 1.7% (95% CI: 0.1 to 3.3%) between no versus severe and moderate PPM, respectively. Severe PPM was also associated with a significant increase in heart failure hospitalization, with a ten-year difference of 6.0% (95% CI: 2.2 to 9.7%) compared to no PPM. There was no difference in valve reintervention between different grades of PPM.
Conclusions: 1) It is safe to use porcine valves irrespective of blood type, 2) Porcine valves increases the risk for subsequent valve interventions, 3) The widespread use of the Perimount valve is supported by excellent long-term clinical performance, and an increased clinical vigilance is warranted in patients with a Mitroflow/Crown or Soprano valve, 4) Steps should be taken to avoid severe PPM, but the clinical effect of moderate PPM might be negligible.
eng
info:eu-repo/semantics/openAccess
Epidemiological studies of bioprosthetic aortic valves
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/441512022-10-18T00:37:55Zcom_10616_1com_10616_180com_10616_46998col_10616_219col_10616_181col_10616_47000
Publications from KI
author
Ellis, Matthew James
2014-12-04T16:30:33Z
2014-12-04T16:30:33Z
1999-05-07
91-628-3549-1
19990528elli
http://hdl.handle.net/10616/44151
Protein structures at moderate to high resolution can now be readily solved using an electron microscope and image processing techniques. The averaging conditions required to overcome the low signal to noise ratio of electron microscope images are particularly well satisfied by two-dimensional crystals. However, a major limiting step in such a study is production of suitable protein arrays.
The work presented describes a study of the two-dimensional crystallization and structural characterisation of several biologically significant soluble proteins. An interfacial crystallization technique was employed where proteins congregate at the interface between an aqueous subphase and a phospholipid layer due to interaction with the phospholipids. The inherent fluidity of the layer allows orientation and aggregation into a two-dimensional lattice.
A Langmuir trough investigation of the surface activity of the 33 kDa Staphylococcus aureus pore forming [alpha]-toxin and its interaction with phospholipid layers at the air/water interface showed the protein to have a detergent like behaviour and a strong affinity for the negatively charged phospholipid dimyristoylphosphatidylserine. Optimising the parameters of this interaction led to successful twodimensional crystallization of the toxin into a tetragonal lattice with two-sided plane group symmetry p4212. Tilt series data collected from such crystalline areas were used to reconstruct a three-dimensional structure of the toxin oligomer at ~17 Å resolution (Paper I).
A similar interfacial approach to the two-dimensional crystallization of native Chaperonin TF55 from Sulfolobus solfataricus, hyperthermophilic archaea, yielded two crystal forms of this large (1 MDa) hetero-oligomeric double ring complex. A phospholipid dependent orientation of the oligomer was observed. Side-view para-crystalline areas arose from interaction with dimyristoylphosphatidylcholine whereas interaction with dioleoylphosphatidylglycerol produced trigonal arrays of the complex in an endon orientation.
The two-dimensional projection structure calculated from the trigonal arrays exhibited the symmetries of two-sided plane group p312 allowing us to suggest a three-dimensional arrangement of the two subunit types (Paper II). This model was later confirmed and enlarged upon via tilt-series data collection, and reconstruction into a three-dimensional volume at ~18 Å resolution (Paper IV). A projection map from the fortuitous two-dimensional crystallization of reconstituted [beta]-rings of the chaperonin TF55 from the closely related Sulfolobus shibatae also showed p312 symmetry even though the [beta] subunit oligomers possessed, as expected, a non-crystallographic nine-fold symmetry axis (Paper III).
Application of these Langmuir trough interfacial techniques to the two-dimensional crystallization of two steroid-hormone receptor constructs (Estrogen receptor (alpha) ligand binding domain and a Protein-A glucocorticoid receptor DNA binding domain fusion protein), resulted in successful crystallization of one of the proteins. The approach's relevance as a screening method for two-dimensional crystallization was demonstrated (Paper V).
Electron crystallography of soluble proteins
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/409772023-10-17T10:54:44Zcom_10616_1com_10616_177com_10616_46998col_10616_219col_10616_178col_10616_47000
Publications from KI
author
Lindberg, Olof
2012-05-08T09:47:38Z
2012-05-08T09:47:38Z
2012-05-08
978-91-7457-695-5
http://hdl.handle.net/10616/40977
Cortical and subcortical regions of the brain decrease in volume in normal as well as pathological aging. Previous studies indicate that certain parts of the brain, like the prefrontal cortex, may be particularly vulnerable to age-related processes which are manifested by significant volume loss in this region. Cortical volume loss may be further enhanced by different kinds of pathology in the brain.
The purpose of this study was to further investigate regional volumetric changes of the frontal lobe in normal aging and in aging patients with dementia.
In study I-III patients with frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and healthy controls are investigated. Cortical atrophy is related to clinical symptoms (study I), discussed in relation to gross morphology and cytoarchitecture (study II), and compared with the atrophy in the hippocampus (study III).
In study IV a large number of normal elderly participants are investigated. Age-related volume loss in the limbic system (the dorsal anterior cingulate cortex and the hippocampus) is compared with atrophy of a region of the prefrontal cortex (the orbitofrontal cortex). Volumetric data of frontal and temporal cortical regions and the hippocampus was acquired by manual delineation on structural magnetic resonance images.
Results of study I and III reveal that the clinical symptoms displayed by the subtypes of FTLD are commonly reflected in a specific pattern of atrophy in frontotemporal cortices as well as in the hippocampus. Study II suggests that the surface morphology of sulci and gyri may be unreliable landmarks for cyto-architectonic regions of the frontal cortex. Study IV finally indicates that a common characteristic of limbic regions may be that age-related volume loss is delayed in comparison to regions of the prefrontal cortex. Results also suggest that the dorsal anterior cingulate is more resistant to age-related volume loss than hippocampus, which implies that age-related volume loss occurs at different rates for different regions also within the limbic system.
eng
info:eu-repo/semantics/openAccess
The aging frontal lobe in health and disease : a structural magnetic resonance imaging study
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


AGREEMENT ON ELECTRONIC PUBLICATION OF THESES

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. Grant of rights

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. The Library's obligations

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. The Author's obligations

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. Paper printouts, etc.

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. Assignment of the agreement, etc.

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. Termination of the agreement

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. Processing of personal data

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. Liability

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. Full regulation

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. Upplåtelse

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. Bibliotekets åtaganden

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. Författarens åtaganden

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. Pappersutskrifter m.m.

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. Överlåtelse av avtalet m. m.

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. Avtalets upphörande

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. Behandling av personuppgifter

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. Ansvar

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. Fullständig reglering

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/402712023-10-22T18:39:34Zcom_10616_1com_10616_168com_10616_46998col_10616_219col_10616_169col_10616_47000
Publications from KI
author
Li, Jingmei
2011-01-19T14:00:36Z
2011-01-19T14:00:36Z
2011-01-19
978-91-7457-179-0
http://hdl.handle.net/10616/40271
The main purpose of this thesis was to identify genetic risk factors using both hypothesis-based and hypothesis-free approaches.
In an attempt to identify common disease susceptibility alleles for breast cancer, we started off with a hypothesis-free approach, and performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls.
As GWAS has been said to underperform for studying complex diseases such as breast cancer, we investigated to see if the variance explained by common variants could be increased by studying specific disease subtypes. Breast cancer may be characterized on the basis of whether estrogen receptors (ER) are expressed in the tumour cells. The two breast cancer tumour subtypes (ER-positive and ER- negative) are generally considered as biologically distinct diseases and have been associated with remarkably different gene expression profiles. ER status is important clinically, and is used both as a prognosticator and treatment predictor since it determines if a patient may benefit from anti-estrogen therapy. We thus performed an independent GWAS using a subset of ER-negative breast cancer cases and all of the controls from the initial genome-wide study, and, in addition, also evaluated whether the two cancer subtypes are fundamentally different on a germline level.
Besides hypothesis-free GWAS, we also conducted hypothesis-based analyses based on candidate pathways to identify common variants associated with breast cancer. Several studies have examined the effect of genetic variants in genes involved in the estrogen metabolic pathway on mammographic density, but the number of loci studied and the sample sizes evaluated have been small and pathways have not been evaluated comprehensively. We evaluated a total of 239 SNPs in 34 genes in the estrogen metabolic pathway in 1,731 Swedish women who participated in a breast cancer case-control study.
Slightly venturing outside the genetic scope of this thesis, we looked at a breast cancer risk factor - body size - that is associated with very different postmenopausal breast cancer risks at different time points in a woman’s lifetime, namely, birth, childhood, and postmenopausal adult.
The significance of these studies will be apparent when, using the new genetic and epidemiological knowledge found, we are able to classify women according to high or low risk of breast cancer on the basis of genetic disposition or other breast cancer risk factors, so that appropriate interventions and disease management decisions may be made, to ultimately reduce incidence and mortality of breast cancer.
eng
info:eu-repo/semantics/openAccess
Genetic determinants of breast cancer risk
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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Thesis.pdf.txt
oai:openarchive.ki.se:10616/405102023-10-23T14:36:11Zcom_10616_1com_10616_207com_10616_46998col_10616_219col_10616_208col_10616_47000
Publications from KI
author
Bergman, Peter N
2011-04-08T09:06:53Z
2011-04-08T09:06:53Z
2011-04-08
978-91-7457-306-0
http://hdl.handle.net/10616/40510
The overall aim of this thesis was to investigate working conditions and organizational strategies providing conditions for job resources with potential for development, positive well-being and health. The aim was formed on the assumption that the organization affects working conditions, working conditions affects employees‟ development, well-being, health and sickness absence. Both a qualitative case study design and a longitudinal epidemiologic design were used in this thesis. These two different approaches are complementary in enhancing scientific knowledge as well as providing implementable tools for development and reduced absenteeism.
Study I was a qualitative study aiming at identifying manageable organizational factors affecting working conditions and sickness absence. Interviews primarily with managers were analyzed with a qualitative thematic approach. This was made to distinguish organizational features characterizing companies with low compared to average levels of sickness absence. The results revealed strategies and procedures in leadership, employee development, communication, employee participation and involvement, corporate values and visions and strategies for employee health, as characterizing companies with low levels of sickness absence.
In study II the organizational conditions and strategies for creating job resources in companies with low levels of sickness absence was explored and described by using the same qualitative method as in study I. Organizational conditions for following job resources were found: Authority, Autonomy, Support, Skill utilization, Feedback, Role clarity, Predictability, and Learning possibilities. A main finding was that strategies and conditions for job resources were found to be provided for both leaders and employees through the active use of teams. Another main finding was that the companies were providing different kinds of learning opportunities, regulated by personal development plans.
The third study, a study of the active learning hypothesis conducted with a longitudinal and population based design, scrutinizes demands and control as antecedents for learning according to the Job Demand Control model. Logistic regression analyses were used to estimate the associations. Results showed positive main effects of skill discretion, task authority, and control, as well as a positive effect of active and low strain working conditions on developing problem-solving skills, indicating that working conditions including high levels of control may positively affect coping skills and behavior also in the non-work domain.
However, levels of non-participation were high in this study. Therefore, an extensive analysis of non-participation was made in study IV. Multivariate logistic regressions revealed that the rates of non-response were higher among males, younger persons, singles, those with lower income, lower education and those born outside the Nordic countries. This led to an overrepresenta-tion of Nordic, older, married women with high education and income, in the sample used in study III. The overall conclusion of this thesis is that working conditions and organizational strategies to provide job resources have effect on levels of sickness absence and development.
eng
info:eu-repo/semantics/openAccess
Developing working conditions
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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Thesis.pdf
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Spikblad.pdf
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Thesis.pdf.txt
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oai:openarchive.ki.se:10616/378992023-02-17T20:00:20Zcom_10616_1com_10616_177com_10616_46998col_10616_219col_10616_178col_10616_47000
Publications from KI
author
Ramfelt, Ethel
2010-10-21T20:28:02Z
2010-10-21T20:28:02Z
2004-05-20
91-7349-925-0
20040610ramf
http://hdl.handle.net/10616/37899
The main aim of this thesis was to investigate preferences for
participating in treatment decision-making in patients with colorectal
cancer before treatment and at a one-year followup and to compare the
relationship between these preferences and coping factors. An additional
aim was to explore the patients' meaning of illness and their experiences
of decision-making concerning treatment and care.
The aim of study I was to examine preferences about the degree of
participation in treatment decisions among a group of patients with
colorectal cancer and to relate the results to the patients' sense of
coherence and the meaning they attributed to the disease. The results
show that 62 % of the patients preferred a collaborative role in
treatment decisions. There were no statistically significant differences
between the preferred roles with respect to the patients' sense of
coherence and the meaning they attributed to the disease.
The aim of study II was to compare preferences for participation in
treatment decisions before and one-year after surgery with the patients'
sense of coherence. The results show that before surgery 71 % of the
patients and at the one-year follow-up 75 % of the patients' preferred
collaborative roles in decision-making. Sixty-four percent maintained
their preferred roles from before surgery to the one-year follow-up.
There were no statistically significant differences between the preferred
roles with respect to the patients' sense of coherence either before
surgery or at follow-up.
The aim of study III was to explore emotional and interactional
perspectives of the meaning of illness, for a one-year illness period
from the time of receiving the cancer diagnosis. The constant comparative
method was used to analyse data. The meaning of the illness was expressed
in the main theme, 'Attempting to find meaning in illness in order to
achieve emotional coherence'. The theme consists of two dimensions;
unified and dichotomised embodiment. The sub-themes of unified embodiment
dimension were: gratefulness, confidence in oneself and others, looking
forward, and creating a new future. The sub-themes of the dichotomised
dimension embodiment were; altered self-worth, loss of temporality,
infringement, and loss of integrity.
The aim of study IV was to explore and conceptualise the experiences of
participating in decisions. The constant comparative method was used. The
concept of participation was formulated into the main theme as 'Compliant
participation in serious decisions'. The theme comprised two variations:
complying with participation and complying without participation.
Complying with participating was characterised by a high level of
selfconfidence and selfcompetence and was associated refers to open
dialogues between the participant, physician and nurse. Complying without
participating was characterised by the participants' uncertainty and
being urged to submit to decisions with a minimum delay without having
time to consider the information provided or influence the treatment and
care process.
Conclusion: A patient's preference in participation in treatment and care
decision-making seems to be preconditioned by many factors, above all
their understanding of the situation, information attained, the meaning
they ascribe to the illness as well as interpersonal factors. To
participate (or choosing not to participate) builds on open and affirming
dialogues, information and knowledge about the illness. This helps the
patient to experience a sense of coherence and selfcontrol. The findings
suggest that support of a patient's participation in treatment and care
decision-making should aim to minimise or prevent distress and
uncertainty. Increased patient participation in treatment and care
decision making is interpreted as a health promoting way to cope with
their illness. Further research is required to illuminate social and
interpersonal aspects of patient participation in decision-making in
order to develop appropriate ways of providing emotional support to this
group of patients.
eng
info:eu-repo/semantics/openAccess
Patient with cancer : their preferences and experiences of participation in treatment and care decisions
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/37899/1/thesis.pdf
File
MD5
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201338
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thesis.pdf
URL
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thesis.pdf.txt
oai:openarchive.ki.se:10616/483102024-03-08T19:58:46Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Rönningås, Ulrika
2022-11-15T10:01:41Z
2022-11-15T10:01:41Z
2022-11-15
978-91-8016-855-7
http://hdl.handle.net/10616/48310
Background: In the past decade, thanks to improved treatment options, many men with metastatic prostate cancer now survive longer than they would have before. The PSA value is often followed during the entire disease trajectory as a sign, but in late phases, symptom burden, quality of life (QoL), and/or psycho-social factors are assigned more importance in treatment decisions and evaluations. From the men´s perspective the change of the clinical importance of the PSA value in assessment of treatment effect and as a sign of disease progression may not be obvious and they may therefore experience distress about values with little clinical relevance. When having a life-limiting disease, symptom management also plays a vital role in the balance between prolonging life and QoL but there are few studies describing symptom burden in a real-world situation in these men. In order to support these men, it is important to gain an understanding from the men‘s perspective of their experiences and interpretations of signs and symptoms.
Aim: The overall aim of this thesis project was to study signs and symptoms in relation to progression of the disease in men with advanced prostate cancer. The underlying hypothesis was that signs and symptoms may be experienced as distressing as markers of potential progression influencing QoL in advanced prostate cancer.
Methods: Both quantitative and qualitative research approaches were used. The thesis is based on data from two different overall projects: a survey sent to all members of the Swedish Prostate Cancer Federation (SPCF) and the PROstate Cancer-Experiences and Expectations During treatment (PROCEED) project. In study I descriptive statistics and logistic regression analysis were used to analyze self-reported questionnaires regarding distress and PSA values. In study II content analysis was used to analyze longitudinal interview data. In study III, descriptive- and linear regression analysis were used to describe symptoms, symptom dimensions and symptom burden, and to investigate associations between QoL and symptom burden. In study IV, descriptive statistics regarding symptoms, symptom dimensions and symptom burden were described at five timepoints. To analyze changes over time for symptom burden, linear mixed modeling was applied.
Results: Men with advanced prostate cancer experience an uncertain illness situation when living with a life-limiting disease. They used signs and symptoms to make sense of their situation. Many of the men were preoccupied with the PSA values as the sign that they described as most important. Over time, as some men experienced more and more symptoms, the importance of the PSA values decreased, and the symptoms and consequences of the symptoms became more important to the men. Some men had a lot of symptoms when starting treatment, mostly physical and not so often psychological symptoms. Except for distress in relation to increased levels of PSA, many men did not report feelings such as worry or fear, even if most of them knew that they had a limited time to live. The different symptoms varied in dimensions of frequency, severity and distress, and sexual problems were most reported, followed by pain and lack of energy. The physical symptoms worsened significantly over time while psychological symptoms and number of symptoms did not.
Conclusion: When living with progressing advanced prostate cancer, an uncertain illness situation was described. In this uncertainty, signs and symptoms were used to make sense of their situation. To understand the men’s interpretations of signs and symptoms is important since misunderstandings or misinterpretations may cause unnecessary distress and reduced QoL in this late phase of the disease. The men experienced mostly physical symptoms, which also worsened over time. Sexual problems were common and may need to be acknowledged more, even if the underlying causes is difficult to resolve, support in handling the problem could be beneficial. Pain and fatigue were also common and were experienced as distressing, and some symptoms may have been insufficiently managed. These findings may help health care professionals to understand the disease from the men’s perspective. Enhancing QoL is also the main goal for palliative care and a palliative approach early in the disease trajectory in the oncology outpatient setting could benefit these men.
eng
info:eu-repo/semantics/openAccess
Experiences of signs and symptoms among men with advanced prostate cancer
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/48310/3/Thesis_Ulrika_R%c3%b6nning%c3%a5s.pdf
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MD5
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application/pdf
Thesis_Ulrika_Rönningås.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/48310/4/Thesis_Ulrika_R%c3%b6nning%c3%a5s.pdf.txt
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MD5
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Thesis_Ulrika_Rönningås.pdf.txt
oai:openarchive.ki.se:10616/381912022-10-30T00:49:09Zcom_10616_1com_10616_183com_10616_46998col_10616_219col_10616_184col_10616_47000
Publications from KI
author
Christensson, Marta
2010-10-21T20:28:49Z
2010-10-21T20:28:49Z
2009-10-16
978-91-7409-621-7
20091106chri
http://hdl.handle.net/10616/38191
This thesis focuses on the role of T cells in ANCA-associated vasculitis. We initially investigated activation markers on T cells in patients with Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and renal limited disease (RLD) and found increased expression indicating continuous activation despite clinical remission. As apoptosis maintains homeostatic control of lymphocyte populations we examined its role in WG, MPA and RLD in comparison with patients with rheumatoid arthritis, lupus erythematosus and Sjögren´s syndrome. We found that patients with ANCApositive vasculitis have high serum levels of soluble Fas (sFas) that remain elevated even in clinical remission.
In our third paper we studied the influence of chemokines on the cell surface expression of thrombospondin-1 (TSP-1) in T cells. The results demonstrate a chemokine-dependent CD26-controlled regulation of T cell polarity and migration through endogenous TSP-1. Based on the results in the third paper we then studied patients with ANCA positive vasculitis with respect to serum levels of chemokines, T cell mRNA expression of chemokine receptors, and possible influence of CD26 on TSP-1 expression. We found altered chemokine levels and evidence for impaired CD26 suppression of chemokine-dependent TSP-1 expression in vasculitis patients in comparison with patients with asthma suggesting that a mechanism for negative regulation of T cell migration is suppressed in these patients.
These findings suggest that T cells play an important role in ANCA associated vasculitis and may be useful targets in the development of therapeutic strategies.
eng
info:eu-repo/semantics/openAccess
Immunological studies on anca-associated vasculitis with special reference to T cell activation
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38191/1/thesis.pdf
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MD5
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thesis.pdf
URL
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File
MD5
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thesis.pdf.txt
oai:openarchive.ki.se:10616/396972024-01-03T22:28:19Zcom_10616_1com_10616_177com_10616_46998col_10616_219col_10616_178col_10616_47000
Publications from KI
author
Famer, Daniel
2010-10-21T20:32:37Z
2010-10-21T20:32:37Z
2007-08-06
978-91-7357-260-6
20070827fame
http://hdl.handle.net/10616/39697
BACKGROUND: Alzheimer's disease (AD) is a severe neurodegenerative disease that mainly afflicts elderly persons, with a characteristic progressive decline of cognitive functions and dementia. It is believed that the majority of all AD patients are affected by the sporadic form, thus caused by the combined effects of several risk factors, such as elevated cholesterol levels in midlife and deficiencies in the lipoprotein transporters apolipoprotein E (ApoE). Cholesterol play an essential role in the central nervous system (CNS) were it maintains normal physiological conditions, and is a requirement for the ability of neurons to communicate. It has previously been demonstrated that the cholesterol homeostasis in the CNS is maintained by a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol, with a net flux of 27-hydroxycholesterol from the circulation into the brain. The importance of a preserved cholesterol homeostasis has been supported by the observation that dietary cholesterol may induce an inflammation in the CNS, and increase the levels of pro-inflammatory mediators. It has, in direct association with these observations, been demonstrated that plasma levels of pro-inflammatory proteins, such as interleukin-6, are increased before the clinical onset of AD, after which a chronic state of inflammation often is found. Accordingly, it has been suggested that memory and cognitive functions could benefit from a cholesterol-lowering therapy.
STUDIES: The research presented in this thesis has examined the effect of cholesterol and cholesterol-lowering therapy with rosuvastatin, on key factors associated with AD. The experimental setup consisted of in vitro-models with human neuroblastoma SH-SY5Y cells (paper I II), and in vivo-models with wild type (WT) and ApoE knockout (ApoE-/-) mice, provided with high levels of dietary cholesterol for 18 weeks (paper III IV). The hydrophilic compound rosuvastatin is an effective inhibitor of cholesterol synthesis and has been demonstrated to be an effective treatment for hypercholesterolemia, with an indirect effect on microglial activation and inflammation through isoprenoid depletion.
RESULTS: Paper I describes the selective non-amyloidogenic processing (alpha-secretase activity) of the amyloid precursor protein (APP), induced by 24(S)-hydroxycholesterol, with a subsequent increased ratio of alpha-/beta-secretase activity, and increased levels of soluble APPalpha and total soluble sAPP; effects significantly decreased by the presence of 27-hydroxycholesterol. Paper II describes the effect of pre-treating in vitro-cultures with rosuvastatin prior exposure to Abeta oligomers. The treatment was found to decrease caspase-3 activity and promote cell survival, with a selective non-amyloidogenic processing of APP. However, no influence was observed on cell viability, with a potential explanation in a downregulated metabolism. Paper III IV describes the effect of high levels of dietary cholesterol in vivo, with increased microglial activation in WT mice, increased gliosis in ApoE-/- mice and subsequent increased plasma IL-6 levels in WT and ApoE-/- mice. The elevated levels of total cholesterol (TC) were found to be caused by increased levels of HDL and LDL in WT mice, whereas only LDL where increased in ApoE-/- mice. Plasma TC levels were correlated with body weight gain in WT and ApoE-/- mice. Furthermore, the selective and ApoE-associated influence induced by the rosuvastatin therapy, on the effects of dietary cholesterol, is described. We observed a decreased microglial activation and gliosis in WT and ApoE-/- mice, with plasma IL-6 levels decreased by 45% in WT mice, without reaching significance. The elevated levels of TC and LDL were decreased in WT mice, whereas no effect was observed on the levels of TC, HDL or LDL in ApoE-/- mice. Body weight gain was decreased in WT mice, with a previously unpublished age- and ApoE-associated declining response to the therapy observed in ApoE-/- mice.
SUMMARY: The presented thesis has examined the connection between Alzheimer's disease and cholesterol, and demonstrated a selection of detrimental effects which may be induced by high levels of dietary cholesterol. Furthermore, the thesis has demonstrated the potential for a cholesterol-lowering therapy with rosuvastatin to exercise a preventive influence, with an age- and ApoE-associated response. The latter is an important observation, which indicates that rosuvastatin may be an effective therapy up to a certain point in the progression of the disease, after which the effects decline. In conclusion, the results discussed in this thesis offer a hypothetical explanation, at least in part, for the discrepancies observed in clinical trials on statins. In addition, this thesis have been able to support the theoretical connection between AD and plasma cholesterol levels with the observation that 27-hydroxycholesterol may exhibit an inhibitory influence on 24(S)-hydroxycholesterol and non-AD processes. It is suggested that persons with high risk of developing AD may benefit from a rosuvastatin therapy, in combination with lifestyle precautions taken in early midlife. The approach could be an effective lifestyle-preventive strategy, with preserved cognitive functions and quality of life at high age.
eng
info:eu-repo/semantics/openAccess
Implications of cholesterol and cholesterol-lowering therapy in Alzheimer's disease
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39697/1/thesis.pdf
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oai:openarchive.ki.se:10616/386472023-02-23T16:43:28Zcom_10616_1com_10616_159com_10616_46998col_10616_219col_10616_160col_10616_47000
Publications from KI
author
Menéndez Benito, Victoria
2010-10-21T20:30:03Z
2010-10-21T20:30:03Z
2006-03-31
91-7140-706-5
20060421mene
http://hdl.handle.net/10616/38647
The dual function of the ubiquitin-proteasome system in protein quality control and as a master regulator of vital cellular processes places the system in a delicate position. This might be particularly relevant under patho-physiological conditions such as endoplasmic reticulum stress, which provoke the accumulation of aberrant proteins. This scenario, also referred to as proteotoxic stress, is associated with numerous devastating disorders, including a large number of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and polyglutamine diseases. The question is whether the ubiquitin-proteasome system is able to promptly and adequately respond to these challenging conditions without compromising its other functions.
One of the difficulties approaching these questions is the lack of systems for monitoring the functionality of the ubiquitin-proteasome activity in vivo. We have generated fluorescent reporter substrates for monitoring the functionality of the ubiquitin-proteasome system in cell lines. In addition, we have developed a transgenic mouse model constitutively expressing one of these reporters. Finally, we have designed and characterized a novel fluorescent activity probe that permits specific labeling of proteasomes in vitro and in vivo.
We have subsequently used these models to gain insight into the mechanisms contributing to the long term accumulation of deleterious proteins during proteotoxic stress. These studies revealed that proteotoxic stress conditions compromises the functionality of the ubiquitin-proteasome system. In these circumstances, ubiquitin-proteasomal degradation is still taking place but it is suboptimal. Detailed analysis of the dynamics of ubiquitylation in living cells suggests that ubiquitin is a rate limiting factor during stress conditions. Importantly, we found that whereas the ubiquitin-proteasome was able to remove the majority of the accumulated substrates once the cells have recovered from the stress condition, the cells were unable to clear accumulated aggregation-prone substrates. This observation might explain the preferential accumulation of such substrates in conformational diseases.
eng
info:eu-repo/semantics/openAccess
The ubiquitin-proteasome system during proteotoxic stress
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38647/1/thesis.pdf
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oai:openarchive.ki.se:10616/477132024-03-10T03:21:07Zcom_10616_1com_10616_180com_10616_46998col_10616_219col_10616_181col_10616_47000
Publications from KI
author
Chen, Xue
2021-10-01T08:49:15Z
2021-10-01T08:49:15Z
2021-10-01
978-91-8016-355-2
http://hdl.handle.net/10616/47713
Hutchinson-Gilford progeria syndrome (HGPS) is a rare childhood disease characterized by failure to thrive, bone abnormalities, hair loss, and a shortened life span due to cardiovascular disease, and nuclear shape abnormalities in cultured cells. HGPS is caused by de-novo mutations in LMNA, the gene encoding prelamin A. Lamin A is produced from prelamin A following three modifications at a carboxyl-terminal CAAX motif: farnesylation of the cysteine by farnesyltransferase (FTase); release of the –AAX by RAS-converting enzyme 1 (RCE1); and methylation of the farnesylcysteine residue by isoprenylcysteine carboxyl methyltransferase (ICMT); mature lamin A is subsequently produced by proteolytic removal of the last 15 amino acids (including the farnesylcysteine residue) by Zinc metalloproteinase Ste24 homologue (ZMPSTE24). The HGPS mutation produces a truncated prelamin A—progerin—which lacks the ZMPSTE24 cleavage site; thus, farnesylated and methylated progerin accumulates at the nuclear lamina in HGPS patient’s cells and causes all disease phenotypes. Other rare forms of progeria result from inactivating mutations in ZMPSTE24 which leads to accumulation of full-length prelamin A.
Targeting FTase with small-molecule drugs prevents prelamin A and progerin farnesylation and corrects the nuclear shape abnormalities observed in cultured progeria cells and reduces symptoms in progeria mouse models. Today, FTase inhibitors (FTIs) constitute the only approved therapy for HGPS. However, FTIs have anti-proliferative properties and their effects in HGPS patients including the survival benefit are modest. Thus, new therapeutic strategies are needed. In this thesis, I have explored the biochemical and medical consequences of targeting ICMT and RCE1 on the function of prelamin A and progerin and the therapeutic benefits of these interventions.
In paper I, we followed up on our group’s earlier genetic studies showing that targeting Icmt overcomes senescence of Zmpste24-deficient cells and human HGPS cells and increases survival of Zmpste24-deficient mice with progeria. We found that knockout of Icmt improves survival of progerin knock-in mice—a more relevant model of HGPS. Moreover, we synthesized a small-molecule ICMT inhibitor, C75, and showed that it inhibits ICMT, stimulates AKT signaling, reduces senescence, and increases proliferation of cultured progeria cells but has no effect on cells lacking the Icmt gene, indicating drug specificity.
In paper II, we tested the hypothesis that targeting RCE1-mediated cleavage of prelamin A would reduce its toxicity and be useful for therapeutic purposes. It was already known that in the absence of RCE1, ZMPSTE24 can perform the same –AAX cleavage; thus, this strategy would only work on progeria caused by ZMPSTE24 deficiency. We found that knockout of Rce1 in Zmpste24-deficient mice prevented –AAX proteolysis, reduced progeria phenotypes, and improved survival, but to a lesser extent than targeting Icmt. Inhibiting RCE1 expression in cells from a ZMPSTE24-deficient patient stimulated AKT signaling, reduced senescence, and improved proliferation.
We conclude that targeting RCE1 and ICMT reduces the toxicity of prelamin A and progerin and that an ICMT inhibitor can overcome senescence and stimulate proliferation of HGPS cells. The results suggest RCE1 could be a potential drug target in future therapy of ZMPSTE24 deficiency and that ICMT inhibitors should be further developed for in-depth preclinical evaluation in HGPS therapy.
eng
info:eu-repo/semantics/openAccess
Defining the role of CAAX protein proteolysis and methylation in the pathogenesis and treatment of progeria
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/462302019-09-30T00:56:28Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Larssen, Pia
2018-03-28T12:59:05Z
2018-03-28T12:59:05Z
2018-03-28
978-91-7676-931-7
http://hdl.handle.net/10616/46230
Exosomes are small vesicles with immune-stimulatory capacity, which can activate T cell responses in a B cell dependent manner, and therefore may serve as immune therapeutic tools. Peptide-loaded dendritic cell (DC)-derived exosomes are proven safe in clinical trials, although with limited ability to induce cytotoxic T lymphocyte (CTL) responses or prolong patient survival. Therefore, we aimed to investigate the role of exosomal MHC/peptide complexes in immune activation and explore how to enhance exosome induced immunotherapies by applying additional stimuli to the exosomes. Bone marrow-derived dendritic cell (BMDC) exosomes loaded with ovalbumin (OVA) and α-galactosylceramide (αGC) were used for this purpose. Exosomes lacking major histocompatibility complex (MHC) class I or those that were MHC mismatched were thoroughly studied in vivo for their ability to stimulate effector T cells and humoral responses. In addition, we applied a novel strategy, lyophilization, for exosomal loading of antigen and adjuvants. Here, OVA, CpG-ODN and αGC were added to RAW 264.7-derived exosomes and assessed for their immune-stimulatory capacity. We demonstrated that exosomal MHC/peptide complexes were redundant for T cell stimulation in vivo in the presence of whole OVA, as MHCI-/- and allogeneic exosomes could successfully induce CD8+ T cell responses and inhibit tumor progression (study I). Importantly, allogeneic exosomes served as an adjuvant by the upregulation of T follicular helper (Tfh) cells and increased antigen-specific antibody production (study II). We also discovered that lyophilization was feasible for loading exosomes without markedly altering exosome characteristics. Notably, additional use of the TLR9 ligand CpG-ODN improved their immune-stimulatory properties and achieved tumor regression (study III).
Selective loading and accumulation of certain tissue-specific proteins and RNA into exosomes provides a platform for potential biomarker analysis, the advantages of which include the accessibility of vesicles in body fluids (“liquid biopsies”), and the ability to trace cellular origin. However, limited material often restricts exosome proteomic analyses. Therefore, we aimed at applying the highly sensitive proximity extension assay (PEA) on cell line- and body fluid-derived exosomes to investigate the potential of using PEA for exosome protein evaluation. We confirmed that PEA can be applied on exosomes to trace their cellular source and to identify accumulated vesicle proteins. Also, the protein content of the body fluid-derived exosomes from breast milk and seminal fluid displayed diverse protein profiles (study IV), suggesting the cell/tissue traceability of exosomes by PEA and motivating their future use as biomarkers.
In conclusion, this thesis provides increased understanding of the mechanisms underlying exosome-based immunotherapies and suggests the use of impersonalized exosomes and allogenicity as a possible means of enhancing their immune-stimulatory effects in a clinical setting. In addition, this thesis offers insight into novel technologies for improved exosomal loading and the use of PEA for exosome proteomic research.
eng
info:eu-repo/semantics/openAccess
Advances in exosome-mediated immunotherapy and diagnostics
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46230/3/Thesis_Pia_Larssen.pdf
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8ede74cda876d996ca2b2279519340ee
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Thesis_Pia_Larssen.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46230/4/Thesis_Pia_Larssen.pdf.txt
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Thesis_Pia_Larssen.pdf.txt
oai:openarchive.ki.se:10616/389072022-10-27T17:57:47Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Guerreiro Cacais, Andre Ortlieb
2010-10-21T20:30:38Z
2010-10-21T20:30:38Z
2008-04-04
978-91-7357-581-2
20080425guer
http://hdl.handle.net/10616/38907
Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus involved in
the pathogenesis of a wide spectrum of malignant and non-malignant
diseases. In healthy EBV carriers, the virus is believed to infect two
major cellular targets - B lymphocytes and epithelial cells. While EBV
latency is established predominantly, if not exclusively, in
B-lymphocytes, virus replication can take place both in B cells and
epithelial cells. Lytic replication ensures virus transmission to new
carriers and replenishes the cellular reservoirs of virus persistence.
The generally asymptomatic and harmless persistence of EBV relies on a
tightly controlled immune response and distinct modes of virus/cell
interactions observed at different stages of EBV life cycle. The aim of
this thesis was to characterize the mutual influence of the host immune
system and EBV at the replicative stage of virus infection.
We showed that EBV enters monocytes and inhibits their differentiation
into dendritic cells (DCs) without the need of viral gene expression. The
sensitivity of the cells to virus-induced apoptosis progressively
decreases along the process of DC maturation and is strongly dependent on
the cell type in which the virus replicated before infecting DC
precursors, since epithelial-cells derived viruses exhibited a
significantly stronger pro-apoptotic activity than their B cell-derived
counterparts. The capacity of the virus to suppress DC development might
help in delaying the establishment of EBV specific immunity before the
pool of infected B cells reaches the size sufficient for long-term virus
persistence.
During virus replication, both B cells and epithelial cells may escape
recognition by cytotoxic CD8+ T cells through downregulation of MHC class
I molecules. Our work demonstrated that MHC class I heavy-chain and
beta2m mRNA and protein synthesis are inhibited during EBV replication.
Several other characteristic changes observed in the MHC class I
processing and presentation pathway during the lytic cycle were
recapitulated by chemical inhibition of protein synthesis. These results
were recently confirmed by others and the viral protein responsible for
host-cell global protein synthesis shutdown was shown to be encoded by
the BGLF5 open reading frame of the EBV genome.
Triggering of receptors of the tumor necrosis factor (TNF) superfamily
participates both in determining the fate of B-lymphocytes during the
process of their differentiation and in immunologic clearance of virus
infected targets. Initiation of EBV lytic cycle counteracted
sensitization to death induced by TNF-related apoptosis-inducing ligand
(TRAIL) that resulted from B-cell receptor (BCR) triggering in Burkitt s
lymphoma cells. Differential modulation of death-transmitting and decoy
TRAIL receptors was associated with sensitization to TRAIL in response to
BCR-triggering or protection from TRAIL by EBV lytic cycle. Interference
with TRAIL-mediated checkpoints in B-cell differentiation may account for
the involvement of EBV in autoimmune diseases. Decreased sensitivity to
TRAIL may also protect EBV infected cells from recognition by CTL and
NK-cells.
B-cell homeostasis is severely perturbed during malaria infection. We
showed that the CIDR1á domain of P. falciparum erythrocyte membrane
protein 1 (PfEMP1), a multiadhesive protein expressed during the
erythrocytic phase of the parasite life cycle, binds to B cells and
induces EBV replication. This might partly explain the increased EBV
viral load during malaria infection and the increased risk of B cell
immortalization in the ontogenesis of endemic Burkitt s lymphoma.
Results presented in this thesis strengthen the notion that EBV
replication actively modulates the functioning of the immune system at
different levels through complex interactions of viral products with
several types of cells and contributes to immune suppression,
autoimmunity and tumorogenesis through a number of mechanisms whose
details require further characterization. Research lines defined by this
work may lead to new approaches towards management of EBV associated
diseases.
eng
info:eu-repo/semantics/openAccess
Immunological consequences of Epstein-Barr virus replication
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38907/1/thesis.pdf
File
MD5
8cc164e8be26f82c7613c747c289a7af
383183
application/pdf
thesis.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38907/2/thesis.pdf.txt
File
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152053
text/plain
thesis.pdf.txt
oai:openarchive.ki.se:10616/433652022-09-16T21:49:06Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Weiland, Malin
2014-12-04T16:29:46Z
2014-12-04T16:29:46Z
2004-11-19
91-7140-158-X
20041210weil
http://hdl.handle.net/10616/43365
The protozoan parasite Giardia lamblia is a major cause of diarrhoea in
humans and other mammals. Infection starts by ingestion of infectious
cysts that excyst in the upper part of the small intestine and attach to
intestinal epithelial cells. In the intestine the trophozoites multiply
by binary fission and trigger a form of diarrhoea called giardiasis.
Humoral immunity has been shown to be important for clearance of the
infection, but only a few antigens have been identified and
characterized.
In this thesis we have identified several immunoreactive proteins by
performing the first large-scale proteomics study performed in G. lamblia.
Sixteen immunoreactive proteins were identified using serum samples from
93 patients with acute giardiasis, infected during a waterborne outbreak
in Sweden. Several of the identified proteins (i. e. alpha-1-, alpha-2-,
alpha-7.1-giardin, OCT and ADI) were produced in recombinant form, mixed
and used successfully as a diagnostic tool to screen sera from infected
patients. The anti-Giardia IgG titers in serum from patients with acute
giardiasis could be correlated to recombinant alpha-giardin
immunoreactivity. The immunoreactive region of alpha-1 giardin was mapped
to amino acids 160-200. In similarity to other annexins, alpha-1 giardin
was shown to be plasma membrane associated. In addition, immunoelectron
and immunofluorescence microscopy revealed that some alpha-1 giardin is
displayed on the surface of excyzoites (recently excysted cells).
Recombinant alpha-1 giardin displayed a Ca2+-dependent binding to
glycosaminoglycans and bound specifically to thin sections of human small
intestine.
By a genome survey and phylogenetic analyses 14 additional (21 in total)
genes coding for proteins related to alpha-giardins were identified.
Several alpha-giardin genes localized to the same chromosomal fragment,
indicating a molecular evolution through gene duplication and subsequent
functional divergence. RT-PCR analysis, during the G. lamblia life cycle,
revealed large differences in the mRNA expression levels among the
alpha-giardins. The alpha-giardin proteins localized to different
cytoskeletal components such as flagella, adhesive disc and plasma
membrane, thus pointing toward a function in cell motility, attachment
and membrane stability. The cytoskeleton is crucial for parasite survival
and virulence. In this respect, the ?-giardins are excellent targets for
the development of a G. lamblia-specific drug.
Additionally, the influcence of differentiation on antigenic variation of
the immunodominant variant specific surface proteins (VSPs) was studied.
The results showed that there are two independent switch events during in
vitro differentiation of isolates from the two major human Giardia
genotypes, one during encystation and one during excystation. During
encystation, the dominantly expressed VSP transcript within the
trophozoite population is down regulated, whereupon a new
encystation/cyst specific VSP is expressed late in enycstation. In
addition, results obtained by analysing single cell parasites during
vegetative growth and excystation support the idea that one major VSP is
expressed per trophozoite at any given time. Also, the switching during
excystation appears to take place after the excysted parasite has
undergone its first cell division step. Notably, the switch events during
differentiation occur at about the same time as nuclear division and DNA
replication. In this respect, we hypothesize that differentiation driven
antigenic variation is influenced by nuclear division and/or DNA
replication events.
Immunodominant proteins in Giardia lamblia
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/405852023-10-24T16:34:47Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Hedman, Erik
2011-05-18T08:11:11Z
2011-05-18T08:11:11Z
2011-05-18
978-91-7457-340-4
http://hdl.handle.net/10616/40585
Background: Cognitive behaviour therapy (CBT) is an effective, well-established, but not widely available treatment for social anxiety disorder (SAD). Internet-based cognitive behavior therapy (ICBT) has the potential to increase availability and facilitate dissemination of therapeutic services for SAD. However, research is needed to establish efficacy, effectiveness, long-term effects, cost-effectiveness and potential determinants of treatment outcome.
Aims: The present thesis aimed at investigating the following: a) The efficacy of ICBT for SAD in a university setting (Study I), b) the effectiveness of ICBT for SAD in a psychiatric setting (Study II), c) The effects of ICBT for SAD over 5 years (Study III), d) The cost-effectiveness of ICBT for SAD compared to conventional CBT (Study IV), and e) Clinical and genetic determinants of ICBT for SAD in relation to conventional CBT (Study V).
Methods: Two large scale randomised controlled trials (RCTs) were conducted. In the first RCT (Study I), ICBT (n=40) was compared to CBT bibliotherapy (n=40) and a waiting list control (n=40). The second RCT (Study II) was a non-inferiority trial comparing ICBT (n=64) to cognitive behavioural group therapy (CBGT; n=62) in a clinical setting. In Study III, a 5-year follow-up assessment was conducted of participants of Study I. In Study IV, a prospective cost-effectiveness and cost-utility analysis of ICBT compared to CBGT was conducted using a societal perspective. Based on clinical and genetic data collected in Study II, predictors and moderators of treatment outcome of ICBT in relation to CBGT were investigated in Study V.
Results: Study I: ICBT for SAD yielded large effect sizes on measures of social anxiety and demonstrated superiority to waiting list controls and a trend towards superiority of CBT bibliotherapy. Study II: ICBT for SAD was well within the non- inferiority margin compared to CBGT on the primary outcome measure. Study III: Participants receiving ICBT for SAD made further improvements from post-assessment to 1-year follow-up. These improvements were maintained at 5-year follow-up. Study IV: The incremental cost-effectiveness ratio was -7042 USD, suggesting that ICBT compared to CBGT leads to incremental gains to a lower cost. Study V: Demographic, clinical and therapy related factors predicted outcome of CBT. A few clinical factors moderated treatment outcome of ICBT in relation to CBGT. None of the investigated candidate genes had an impact on treatment outcome.
Conclusions: ICBT for SAD is efficacious, effective in a clinical setting, long-term effective and, compared to conventional CBT, cost-effective regardless of willingness to pay. In addition, treatment outcome can be predicted. ICBT for SAD is ready for implementation and dissemination.
eng
info:eu-repo/semantics/openAccess
Internet-based cognitive behaviour therapy for social anxiety disorder : from efficacy to effectiveness
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/410642023-10-28T18:07:32Zcom_10616_1com_10616_165com_10616_46998col_10616_219col_10616_166col_10616_47000
Publications from KI
author
Edelbring, Samuel
2012-05-22T15:15:24Z
2012-05-22T15:15:24Z
2012-05-22
978-91-7457-795-2
http://hdl.handle.net/10616/41064
With the rapid technological development and the broadening access to computers over recent decades, several technological innovations have emerged in medical education, including virtual patients. Students’ use of virtual patients is proposed to fill gaps in clinical exposure, and train clinical reasoning. However, higher education faculties have been slow to adopt new technology as a regular part of curricula. Virtual patients and similar technologies have either been implemented by enthusiastic teachers or by university policy directives. A possible reason for the low uptake of virtual patients in curricula is a lack of a clear understanding of how their use contributes to student learning.
The four studies described in this thesis address learning with virtual patients from three perspectives: the student perspective on learning with virtual patients; the course integration perspective; and the individual study strategy perspective. A mixed methods approach was used given the overarching interest to seek understanding and clarification of student learning with virtual patients.
Data were gathered by research interviews with medical students during clerkship, and by questionnaires in clerkship preparatory courses. Interview data was analysed by a phenomenological approach, and scales were formed from questionnaire responses which were analysed cross-sectionally for the four teaching hospitals affiliated with the medical programme at Karolinska Institutet. Use frequency, students’ perceived benefit of virtual patients, their wish for more guidance on using virtual patients and, wish for more assessment and feedback on virtual patient work were targeted in the questionnaires. Furthermore, the students’ preferences of study strategies were analysed in relation to the virtual patient activity using regulation strategy scales from the Inventory of Learning Styles devised by Jan Vermunt.
The findings suggested that virtual patient learning activities offer possibilities of applying biomedical knowledge to clinical cases in a way that was engaging and supported decision-making. Furthermore, the virtual patient learning activities were perceived as having an intermediate function between textbook learning and learning with actual patients. The consequences of integration strategies in the course context were influential for how students perceived the benefit of learning with virtual patients.
Intensity of processing of virtual patient cases, and presenting cases for other students were associated with high perceived benefit of virtual patient learning activities. Students’ self-regulation abilities were also associated with perceived benefit of the virtual patient learning activities, although to a lesser extent than the influence of the course context.
The technology of virtual patients provides possibilities that enhance student learning, and should thus be a necessary part of education. However, this research show that an educational integration strategy is needed that supports students’ active processing of virtual patient cases.
eng
info:eu-repo/semantics/openAccess
Technology in education, necessary but not sufficient : understanding learning with virtual patients
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


AGREEMENT ON ELECTRONIC PUBLICATION OF THESES

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. Grant of rights

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. The Library's obligations

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. The Author's obligations

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. Paper printouts, etc.

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. Assignment of the agreement, etc.

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. Termination of the agreement

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. Processing of personal data

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. Liability

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. Full regulation

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. Upplåtelse

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. Bibliotekets åtaganden

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. Författarens åtaganden

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. Pappersutskrifter m.m.

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. Överlåtelse av avtalet m. m.

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. Avtalets upphörande

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. Behandling av personuppgifter

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. Ansvar

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. Fullständig reglering

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/453812024-01-03T21:31:49Zcom_10616_1com_10616_177com_10616_46998col_10616_219col_10616_178col_10616_47000
Publications from KI
author
Cermakova, Pavla
2016-12-08T09:16:23Z
2016-12-08T09:16:23Z
2016-12-08
978-91-7676-547-0
http://hdl.handle.net/10616/45381
The objective of this thesis was to characterize the burden of cardiovascular diseases in patients with dementia, their treatment and association with survival. Further, we aimed to explore whether cardiac structure in young adults can affect the aging brain. We performed 5 observational cohort studies, based on patients registered in the Swedish Dementia Registry (Papers I-IV) and participants in a population-based study Coronary Artery Risk Development in Young Adults (Paper V). The results can be summarized as follows:
(I) Seventy per cent of patients with dementia are prescribed cardiovascular drugs. Their use is highest in patients with vascular dementia and lowest in patients with Parkinson´s disease dementia.
(II) Patients with heart failure and dementia constitute an old and under-diagnosed population. Heart failure with preserved ejection fraction is the most common type of heart failure and vascular dementia the most frequent dementia disorder.
(III) The most common chronic cardiovascular disease in patients with dementia is ischemic heart disease (23% of patients are affected), followed by cerebrovascular diseases (20% of patients) and atrial fibrillation (19% of patients). The occurrence and prognostic significant of chronic cardiovascular diseases differs in specific dementia disorders.
(IV) Twenty one per cent of patients with dementia are managed invasively for acute myocardial infarction. The use of invasive procedures is associated with lower age and higher cognitive status. This study suggests that the invasive management of myocardial infarction has a benefit for survival of patients with dementia.
(V) Higher left atrial volume in young adulthood is associated with lower white matter integrity in mid-life. This study suggests that improvement of cardiac function in young adults may benefit the aging brain.
eng
info:eu-repo/semantics/openAccess
Cardiovascular disease in dementia
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/45381/1/Thesis_Pavla_Cermakova.pdf
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oai:openarchive.ki.se:10616/394462022-10-31T22:18:19Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Strandberg, Karin
2010-10-21T20:31:59Z
2010-10-21T20:31:59Z
2009-05-22
978-91-7409-525-8
20090612stra
http://hdl.handle.net/10616/39446
Acute exposure of healthy subjects in a swine barn induces an intense airway inflammation and increased bronchial responsiveness. Dust collected in swine houses is a potent stimulus for release of pro-inflammatory cytokines from cells in vitro. The main aim of this thesis was to elucidate the effects of long-acting ß2-agonists and glucocorticosteroids on inflammatory mechanisms in vivo and in vitro using organic dust as pro-inflammatory stimulus.
In the first study, formoterol and salmeterol were shown to induce enhancement of IL-6 and IL-8 release from non-stimulated primary bronchial epithelial cells (PBEC) and A549 cells in vitro. The beta2-agonists also added to the effect of organic dust. This enhanced release was blocked by a beta-blocker in PBEC, but not in A549 cells. The results indicate different mechanisms of beta2-agonists action in bronchial and alveolar epithelial cells, and that A549 cells do not possess functional beta2-adrenoceptors.
In the second study formoterol was shown to add to the dust-induced IL-6, but not IL-8 release from PBEC. Budesonide attenuated the release of both cytokines in a dose-response manner. This inhibiting effect was sustained but not reinforced by formoterol. No synergistic effect between formoterol and budesonide was found.
In the third study the effect of formoterol and budesonide on chemokine/cytokine release, chemokine receptor expression and chemotaxis in isolated human neutrophils in vitro was evaluated. Formoterol enhanced and budesonide inhibited IL-6, IL-8, and GRO-alpha release from LPS-stimulated neutrophils. Formoterol upregulated both CXCR1 and CXCR2 expression, whereas budesonide upregulated the expression of CXCR2 only. Despite the effects on chemokine release and drug-induced up-regulation of chemokine receptors, no influence on neutrophil chemotaxis could be demonstrated by the beta2-agonist or the glucocorticosteroid.
In the fourth study, 12 healthy subjects were exposed to organic dust in a swine barn. In this cross-over designed study, we found that one single dose of salmeterol partially protected against the increased responsiveness to methacholine. Salmeterol did not influence the inflammatory response to dust exposure. One week pre-treatment with fluticasone or ibuprofen had no effect on the airway responses and did not alter the effect of salmeterol. In addition, a retrospective analysis of pooled data from four previous studies was performed. We concluded that exposure leads to an enhancement of bronchial responsiveness to a certain maximal level which is similar in all subjects, and almost totally unrelated to pre-exposure level of bronchial responsiveness.
In conclusion, although beta2-agonists and glucocorticosteroids influence the release of pro-inflammatory cytokines/chemokines and up-regulate chemokine receptors in vitro, these drugs did not influence the investigated inflammatory parameters in vivo. As the increase in bronchial responsiveness following organic dust exposure is strongly related to pre-exposure bronchial responsiveness, interventions altering bronchial responsiveness have to be compared between groups with similar pre-challenge bronchial responsiveness or in a cross-over design. No additive/synergistic effects between beta2-agonists and steroids were found.
eng
info:eu-repo/semantics/openAccess
The effect of beta2-adrenoceptor agonists and steroids on induced airway inflammation and bronchial responsiveness
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39446/1/thesis.pdf
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oai:openarchive.ki.se:10616/397402022-11-06T02:03:16Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Bulhak, Aliaksandr
2010-10-21T20:32:44Z
2010-10-21T20:32:44Z
2007-05-25
978-91-7357-226-2
20070615bulh
http://hdl.handle.net/10616/39740
Acute myocardial ischaemia causes metabolic changes and results in a rapid decrease in the energy available to the cell. This leads to cell injury that, depending on the length of the ischaemic time, is reversible or irreversible. Restoration of coronary flow to the jeopardized myocardial tissue, referred to as reperfusion, is generally a prerequisite for tissue survival, but may also per se contribute to the injury.
Endothelial dysfunction, characterized by an impairment of endothelium-dependent relaxation, due to reduced bioavailability of endothelial nitric oxide (NO), is an early event in the pathophysiology of myocardial ischaemia-reperfusion injury. Endothelial dysfunction is also important in other cardiovascular disorders such as atherosclerosis, hypertension, and diabetes. It has been suggested that drugs used in the treatment of these disorders also exert cardioprotective effects. Inhibitors of 3 hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) and agonists of peroxisome proliferatoractivated receptor (PPAR) -alpha and -gamma may protect the myocardiurn against ischaemia reperfusion injury in addition to their respective lipid-lowering and insulin-sensitizing effects.
The aim of the present thesis was to investigate the cardioprotective mechanisms of drugs used for treatment of hyperlipidaemia and insulin resistance. Of particular interest was to study the mechanisms related to NO bioavailability.
1. Oral pretreatment with the HMG-CoA reductase inhibitors rosuvastatin and pravastatin for 5 days, without affecting serum cholesterol, reduced infarct size (IS) in pigs subjected to 45 min of ischaemia followed by 4 h of reperfusion. Myeloperoxidase (MPO) activity, an index of neutrophil infiltration, was attenuated in the ischaemic/reperfased myocardiurn by pretreatment with rosuvastatin. The rosuvastatin-induced cardio protection and attenuation of MPO activity in the ischaemic/reperfused myocardium were abolished by NO synthase (NOS) inhibition. The expression of endothelial NOS (eNOS) and inducible (iNOS) proteins in the myocardiurn were not altered by rosuvastatin.
2. Intraperitoneal (i.p.) administration of rosuvastatin for 48 h reduced IS in rats subjected to 30 min of ischae mia followed by 120 min of reperfusion. Rosuvastatin also increased the cytosol/membrane ratio of RhoA protein in the myocardiurn from rats not subjected to ischaemia-reperfusion. Addition of the isoprenoid geranylgeranyl pyrophosphate (GGPP) abolished both the rosuvastatin-induced cardioprotection and the inhibition of RhoA translocation.
3. Intravenous (i.v.) administration of the PPAR-alpha agonist WY-14643 (WY) 3 0 min before the onset of ischaemia reduced IS in rats subjected to 30 min of ischaemia followed by 120 min of reperfusion. WY also in creased eNOS, but not iNOS, protein expression and decreased endothelin-I mRNA levels in the ischaemic myocardium. Co-administration of WY with the NOS-inhibitor L-NNA abolished the cardioprotective effect of WY, but did not alter the PPAR-alpha-agonist-induced changes in eNOS protein or endothelin-1 mRNA in the ischaemic myocardium.
4. The PPAR-gamma agonist rosiglitazone increased the recovery of the left ventricular function and the coronary flow following global ischaemia in the isolated hearts from wild-type mice, but suppressed the recovery of myocardial function in eNOS knockout mice. Addition of the NOS inhibitor L-NNA significantly blunted the improvement in the recovery of the left ventricular function induced by rosiglitazone in the wild-type mice. Rosiglitazone induced eNOS phosphorylation at Ser1177 and Thr495 without affecting total eNOS expression. There was no effect of L-NNA on the expression of phosphorylated eNOS.
In conclusion, endothelial dysfunction characterized by decreased NO bioavailability, is an important component in the pathophysiology of myocardial ischaemia-reperfusion injury. Cardioprotection induced by inhibition of HMGCoA reductase and PPAR-alpha and -gamma stimulation is mediated via a mechanism involving maintenance of NO bioavailability. Thus, maintained bioavailability of NO is a key cardioprotective mechanism of the lipid-lowering statins and fibrates, and the insulin sensitizing thiazolidinediones.
eng
info:eu-repo/semantics/openAccess
Cardioprotective mechanisms by inhibition of the HMG-CoA reductase pathway and stimulation of peroxisome proliferator-activated receptors in myocardial ischaemia-reperfusion
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39740/1/thesis.pdf
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oai:openarchive.ki.se:10616/437362022-10-04T17:47:59Zcom_10616_1com_10616_46998col_10616_219col_10616_47000
Publications from KI
author
Ohlsson, Åke
2014-12-04T16:30:09Z
2014-12-04T16:30:09Z
1997-09-05
91-628-2602-6
19970926ohls
http://hdl.handle.net/10616/43736
Patients with chronic heart failure constitute an increasingly large group. Despite recent therapeutic improvements, these patients have a poor prognosis. The diagnosis and the often complex pharmacological treatment are commonly evaluated and guided by physical examinations and non-invasive measurements, although the relationship between clinical signs and central hemodynamics is less obvious during the chronic phase of the disease. Access to invasive hemodynamic information should be of importance, but traditional catheterisations only give a snapshot of a supine patient. Long-term monitoring should be useful but is difficult to achieve with the conventional catheterisation techniques. The present study was performed to evaluate an implantable hemodynamic monitoring system, capable of long-term measurements and storage of recorded data. Development of the system was based on available pacemaker technology and the external design was similar to an ordinary pacing system. Sensors for continuous measurements of oxygen saturation and pressure were incorporated in leads that were connected to a monitor and memory unit contained within an ordinary pacemaker can. The sensor-carrying leads were positioned in the right ventricle, where mixed venous oxygen saturation could accurately be measured compared to values obtained from the pulmonary artery. Diastolic pulmonary arterial pressure could be adequately estimated from the right ventricular pressure at the time of maximum dP/dt. These findings showed that important hemodynamic parameters could be obtained from a right ventricular lead position avoiding the pulmonary artery, which may impose a risk of dislodgement during long-term monitoring.
A monitoring system with one oxygen sensor and one sensor for relative pressure values was implanted in five patients with severe cardio-pulmonary disease during seven to 16 months. Another system in which the absolute pressures could be recorded was implanted in 21 patients with severe heart failure. Acceptable recordings were obtained for at least 12 months from 18 of these 26 systems without any serious monitor-related complications. The patients accepted the implanted monitors without concern.
Recordings from the pressure sensors for absolute values were strongly correlated to pressure obtained from a Swan Ganz catheter during repeated catheterisations. Directional and magnitudinal changes in pressure were adequately expressed by the sensor for relative values. The oxygen sensor failure rate was unacceptably high although the accuracy and long-term stability of the non-failing sensors were adequate compared with oxygen saturation in blood, sampled from the pulmonary artery. The monitoring system was capable of recording and storing hemodynamic parameters with variable resolution, from low to high. During long-term recordings during daily life the recorded parameters adequately reflected hemodynamic changes related to everyday activities. Based on oxygen saturation values from the implantable monitor, cardiac output could be "semi-invasively" obtained with a strong correlation with cardiac output determined during conventional catheterisations. Long-term ambulatory hemodynamic monitoring was feasible and recorded data may be of value in the clinical management of heart failure.
Continuous ambulatory hemodynamic monitoring with an implantable system : the feasibility of a new technique
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/453592019-09-29T22:26:21Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Sekiziyivu, Proscovia Naluyima
2016-11-17T11:31:21Z
2016-11-17T11:31:21Z
2016-11-17
978-91-7676-453-4
http://hdl.handle.net/10616/45359
The global epidemic of HIV has resulted in more than 34 million deaths and currently 36.9 million HIV-infected people worldwide. Uganda has an HIV prevalence of 7.3%, equating to about 1.6 million people. This has placed enormous pressure on the social, economic and medical structure of society. HIV is phylogenetically diverse, with HIV-1 subtypes A, B and C accounting for ≥70% of infections globally. While HIV-1 subtype C confers the worst prognosis for a patient, it is closely followed by subtype D which, together with subtype A, accounts for ≥90% of HIV infections in Uganda. HIV infection is associated with rapid viral replication, concomitant inflammation and immune activation, and massive CD4 T cell loss, which all together contribute to morbidity and eventual death. Although antiretroviral therapy lowers viral load and improves CD4 T cell recovery in chronic infection, it does not fully eliminate chronic immune activation nor restore immune function, resulting in non-AIDS related morbidity. Additionally, despite great effort, a preventive or therapeutic vaccine is yet to be developed.
Studies in chronic untreated HIV-1 infection may shed more light on correlates of immune protection that may be utilized to develop effective preventive or therapeutic vaccines or drugs. The innate immune system, as the first to encounter the HIV virus upon exposure and infection may be critical in directing immune responses that can prevent, attenuate or cure infection. In this thesis I aimed to study the role of the innate cellular immunity in the immunopathogenesis of HIV-1 subtype A and D infection in Uganda. In Paper I, using whole blood from healthy blood bank donors, we established normal lymphocyte reference ranges for Ugandans and showed demographic differences that may influence immune responses to disease and vaccination. Additionally, utilizing cryopreserved peripheral mononuclear blood cells from chronic untreated HIV-1 infected persons we studied the phenotypes and function of natural killer cells, unconventional T cells and regulatory T cells plus their roles in HIV-1 infection (Papers II-IV). Here we found both HIV-associated immune dysregulation of multiple cellular subsets and expansion of a previously little described innate-like terminally differentiated CD8 T cell subset. Furthermore, in Paper V we describe demographic differences in biomarkers of inflammation that not only associate with disease progression, but also expand our knowledge of HIV-related gut dysbiosis. Thus, the data presented here provides more insight into HIV-driven immune dysfunction, subtyperelated immunopathogenesis, and demographic differences that add to the body of knowledge concerning HIV infection.
eng
info:eu-repo/semantics/openAccess
Role of innate cellular immunity in the immunopathogenesis of HIV-1 infection in Uganda
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/45359/4/Thesis_Proscovia_Naluyima_Sekiziyivu.pdf
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Thesis_Proscovia_Naluyima_Sekiziyivu.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/45359/5/Thesis_Proscovia_Naluyima_Sekiziyivu.pdf.txt
File
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Thesis_Proscovia_Naluyima_Sekiziyivu.pdf.txt
oai:openarchive.ki.se:10616/467652019-09-30T00:31:14Zcom_10616_1com_10616_213com_10616_46998col_10616_219col_10616_214col_10616_47000
Publications from KI
author
Úlfsdóttir, Hanna
2019-05-23T07:05:04Z
2019-05-23T07:05:04Z
2019-05-23
978-91-7831-451-5
http://hdl.handle.net/10616/46765
The aim of this thesis was to study waterbirth in a Swedish context and to bring focus on clinical
outcomes and women’s experiences associated with waterbirth. The literature describes advantages
for women giving birth in water like relaxation and a positive birth experience. Still, waterbirth is
controversial in Sweden and has not been offered at hospitals until recently.
Study I compared birth characteristics and outcomes of waterbirths with conventional uncomplicated
births at the two clinics in Sweden providing waterbirth, from March 2014 to November 2015
(n=306+306). We found an association with fewer perineal tears of second degree among women
giving birth in water and that these women were exposed to significantly less interventions such as
amniotomy and oxytocin infusion intrapartum. There were no differences in Apgar scores or
admissions to the neonatal intensive care unit, but three cases of umbilical cord rupture occurred
among the waterbirths. Women having a waterbirth ranked their experience of childbirth higher in a
numeric rating scale indicating a more positive birth experience.
Study II was a qualitative study based on 20 in-depth interviews describing women’s experience of
giving birth in water. The interviews, which took place 3-5 months postpartum were analyzed with
qualitative content analysis. The overall theme emerging from the analysis was “Like an empowering
microhome” describing the effect of being strengthened, enabled and authorized in the birth process.
The limited space of a bathtub was described to give a relaxed and homelike feeling of privacy. Three
categories were identified: “Synergy between body and mind”, “Privacy and discretion” and “Natural
and pleasant”.
In Study III we explored the experience, knowledge and attitudes regarding waterbirth among
midwives, obstetricians/gynecologists and neonatologists in a cross-sectional study. Using a web-
via The Swedish Association of Midwives and the Heads of department of all Swedish maternity wards between April and June 2016, yieleded 1609 responses. The questionnaire contained a Likert Scale and open-ended questions which were analyzed with descriptive statistics and quantitative content analysis. We found that midwives had amore positive attitude to waterbirth as well as towards providing and implementing waterbirth, compared to physicians. Strong opinions wereheld about waterbirth, which to some extent were based on subjective attitudes secondary to knowledge, experience and evidence.
In Study IV we compared childbirth experience between women having a waterbirth (n=111) and women having an uncomplicated conventional birth (n=104) using the validated Childbirth Experience Questionnaire (CEQ). The 22-item questionnaire assessed four domains: Own capacity, Professional support, Perceived safety and Participation. Further, supplementary questions about the second stage of labour were added to the web-questionnaire. The total CEQ score did not differ between the groups, while women having a waterbirth scored significantly higher in the domain, “Own capacity” and lower in the domain, “Professional support”. Women having a waterbirth rated significantly less pain and higher scores of being in control in the second stage of labour.
eng
info:eu-repo/semantics/openAccess
To give birth in water
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/378602022-09-16T15:00:31Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Muhr, Per
2010-10-21T20:27:43Z
2010-10-21T20:27:43Z
2010-05-06
978-91-7409-878-5
20100527muhr
http://hdl.handle.net/10616/37860
During compulsory military service, the hearing capacity of the
conscripts is at risk, because of exposure to continuous and impulse
noise that exceeds the threshold levels of the European Union and the
Swedish Work Environment Authority. In young adult life, a multitude of
other risk factors also might result in auditory symptoms and hearing
impairment. A Military Hearing Conservation Program is of the utmost
importance to prevent auditory complications caused by the military
exposure.
Aims: a. to assess the prevalence values of hearing impairment in young
men at conscription in the period 1971-1995; b. to analyse relations
between causative factors and hearing symptoms/hearing impairment before
military service; c. to estimate the incidence and relative risk of
hearing decline during military service (the efficacy of the Hearing
Conservation Program).
Methods: In Paper I we obtained cross-sectional data on prevalence values
of hearing impairment at conscription, at age 18, from six complete age
cohorts born in 1953-1977, in all 337 986 men. Of these, 89.3% were
tested with screening audiometry. A group of 839 men from three different
military units were included in Paper II and IV. They all performed
mandatory screening audiometry and filled in a questionnaire at reporting
to training in 2002- 2004. The same procedure was repeated at discharge.
In Paper III a group of 747 conscripts from three regiments were
included. They performed mandatory screening audiometry at reporting to
training in 1999 and at discharge in 2000. In study II, III, and IV the
cross sectional data were evaluated as prevalence values and the
longitudinal data as incidence values. The comparison groups with no
military noise exposure made the first audiometric test at the Centre of
Conscription and the second at the army unit at reporting for training.
Results: The prevalence values of hearing impairment decreased in the
period 1971-1981 from 15.7% to 8.3 and increased in 1986-1995 from 9.8%
to 16.3%. This pattern was caused by changes of mild high frequency
elevations. The threshold elevations of 45 dB HL or more decreased over
the entire study period. Most often only one ear was affected. High
frequency hearing impairment was more common in the left ear. Before
military service 6.8% of the conscripts reported one or more auditory
symptoms often or always. They had been exposed to a multitude of
excessive noise levels, the most common being rock concerts or
discotheques. TTS after noise exposure was related to elevated prevalence
values of hearing impairment and auditory symptoms. The conscripts who
often played loud music had an elevated risk for tinnitus but not for
hearing impairment. At discharge from military service we observed a
relative risk of hearing decline compared to the contrast group of 2.7 in
2000 and of 1.8 in 2003-05. In 2000 we observed an elevated risk of
hearing decline during military service for those of the conscripts who
had a mild hearing impairment already at reporting to training. This
effect was not observed in the more strictly screened group in 2003-2005.
Conclusions: TTS after noise exposure was related to elevated hearing
thresholds and auditory symptoms. To perform loud music was related to
increase in tinnitus but not in hearing thresholds. Prevalence values of
hearing impairment, tinnitus and sensitivity to noise were elevated at
discharge compared to at reporting to service. Incidence values of
hearing decline were elevated during military service compared to before.
eng
info:eu-repo/semantics/openAccess
Hearing in young men : the influence of military noise and epidemiological aspects
info:eu-repo/semantics/doctoralThesis
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http://openarchive.ki.se/xmlui/bitstream/10616/37860/1/thesis.pdf
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oai:openarchive.ki.se:10616/422902019-09-29T22:05:49Zcom_10616_1com_10616_183com_10616_46998col_10616_219col_10616_184col_10616_47000
Publications from KI
author
Chang, Ming
2014-11-13T15:03:19Z
2014-11-13T15:03:19Z
2014-11-13
978-91-7549-679-5
http://hdl.handle.net/10616/42290
Individuals vary widely in their response to drug treatment. After receiving doses of a drug that are recommended based on a population average, some patients could have an insufficient response, whereas others may experience adverse effects. Of the many factors causing variability in drug response across individuals, genetic polymorphism of drug-metabolizing enzymes is deemed to be one of the valuable independent predictors of this variability. CYP2C19 is an important polymorphically expressed enzyme known to catalyze the metabolism of several widely prescribed drugs, including omeprazole, warfarin (R-enantiomer), and citalopram/escitalopram. The impact of CYP2C19 polymorphisms on the pharmacokinetics (PK) of its substrates and corresponding clinical relevance are of great interest.
The aim of this thesis is to investigate the influence of CYP2C19 polymorphisms on PK and pharmacodynamics (PD) of clinically important CYP2C19 substrates (e.g., omeprazole, citalopram, and warfarin), and to advance the understanding of their inter-individual variability in drug therapy. We quantified the effect of functional CYP2C19 allele variants, including the gain-of- function allele (CYP2C19*17), on drug exposure and response in order to facilitate personalized dose selection.
In Paper I, we studied the disposition of omeprazole and its effect on plasma gastrin levels following single and multiple doses in the three phenotype groups (extensive metabolisers [EMs], intermediate metabolisers [IMs], and poor metabolisers [PMs]) of S- mephenytoin hydroxylation. When 20 mg of omeprazole was given orally for 8 days on a once-daily (QD) regimen, the relative AUC ratios in EMs, IMs, and PMs were 1:5.3:13.1. Differences in the plasma gastrin levels (used as a PD marker) were also significant between the three groups and the increase was in an omeprazole-concentration-dependent fashion. Suitability of omeprazole as a probe for CYP2C19 was also explored. The metabolic ratio (MR) of omeprazole was correlated significantly with S/R ratio of mephenytoin.
Paper II further studied the use of omeprazole as a probe for CYP2C19 activity in a population of 160 unrelated Swedish subjects. There was a close correlation between MRs of omeprazole and S/R ratios of mephenytoin. A good agreement was also demonstrated between the CYP2C19 phenotypes (both by omeprazole and mephenytoin) and the genotype with respect to CYP2C19*2, indicating that genotype is a valid predictor of CYP2C19 activity. Since omeprazole is a substrate for both CYP2C19 and CYP3A4, the potential advantage also includes using it as a dual-substrate probe.
In Paper III, we used omeprazole as a dual substrate probe to assess the potential for PK interactions between carbamazepine (CBZ) and omeprazole and, particularly, the inducibility of CYP3A4 and CYP2C19 by CBZ. Both omeprazole and hydroxyomeprazole decreased by approximately 40% in mean AUC after coadministration of omeprazole with CBZ, while the sulphone metabolite increased by 44%. None of the AUC changes were statistically significant due to the large variation and small sample size. A significant decrease in the AUC ratio between hydroxyomeprazole and sulphone metabolite was observed, suggesting induction was more pronounced for CYP3A4 than for CYP2C19.
The potential contribution of the CYP2C19 genotypes on R-warfarin clearance with special focus on the gain-of-function allele (CYP2C19*17) was the primary objective for Paper IV. Compared to CYP2C19*2 carriers, the mean R-warfarin clearance increased by 32% in CYP2C19*17 carriers, 26% in the CYP2C19*2/*17 genotype, and 11% in CYP2C19*1/*1 genotype. CYP2C19 genotypes also contributed to the variability of INR/daily dose where VKORC1 (Vitamin K epoxide reductase subcomplex 1) and CYP2C9 genotypes are the major determinants in warfarin treatment. About 52% of variance can be explained by the combinations of VKORC1, CYP2C9, CYP2C19, age, gender, and bodyweight, of which CYP2C19 genotypes accounted for 7%.
Paper V pooled data from16 published studies to quantify the effect of functional CYP2C19 allele variants on citalopram/escitalopram exposure by means of meta-analysis. Compared to subjects with EM/EM (*1/*1) genotype, the exposure to (es)citalopram increased by 95% in the PM/PM (*2/*2, *2/*3, or *3/*3), 30% in the EM/PM (*1/*2 or *1/*3), and 25% in the UM (ultrarapid metaboliser)/PM (*17/*2 or *17/*3) groups. In contrast, the exposure to (es)citalopram decreased by 36% in the UM/UM (*17/*17) and by 14% in the UM/EM (*17/*1) groups. All functional CYP2C19 genotypes showed significant effects on citalopram/escitalopram exposure compared to the CYP2C19*1/*1 genotype.
In conclusion, there are significant effects of CYP2C19 polymorphisms on PK and PD of drugs that are metabolized by the CYP2C19 enzyme. The results of this thesis demonstrate that CYP2C19 genotype is an important independent predictor of the exposure to omeprazole, R-warfarin, and citalopram/escitalopram. Increased knowledge and understanding of inter-individual variability, genotype-phenotype correlation, and the impact of CYP2C19 polymorphisms on clinical practice are helpful in optimizing personalized drug therapy.
eng
info:eu-repo/semantics/openAccess
CYP2C19 polymorphisms in drug metabolism and response
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/469922024-03-15T14:02:12Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Wijk, Hanna
2020-02-07T12:26:30Z
2020-02-07T12:26:30Z
2020-02-07
978-91-7831-678-6
http://hdl.handle.net/10616/46992
Competent physicians working in teams with other health professionals are a prerequisite for excellent patient care. The context for this thesis is physicians’ specialist training, which consists of workplace learning in an environment primarily designed for other purposes than education, with sometimes contradictory objectives. Educational leaders have been singled out as important for the educational quality. Their tasks are complex and their influence on education may be challenging. Notwithstanding, factors that are influencing effectiveness in completing the tasks remain unexplored. The overall aim of this thesis is to explore educational leadership in physicians’ specialist training. The central research question is, ‘Which factors influence the role of the programme directors in Sweden?’ The four empirical studies are positioned within a cultural conceptual perspective on leadership, recognizing context as an influential factor in facilitating and limiting leadership. The studies are guided by a constructivist approach, three using qualitative methods and one a quantitative method.
Study I explored programme directors’ perceptions of their work tasks, interpreted within Bolman and Deal’s theoretical framework. The structural (structuring the education) and human resource function (supporting individuals and handling relations) were emphasized. Less described were the political (negotiating and mediating) and the symbolic function (influencing the educational culture). Study II explored factors perceived to influence programme directors’ effectiveness. Individual factors, such as the programme director’s own competence, were mainly facilitating, while structural factors, such as conditions for the role, were mainly hindering. Whether relational (such as communication and support) and attitudinal factors (such as values and attitudes) were perceived to be hindering or facilitating differed between the participants. Study III investigated factors related to the role of the programme directors that are associated with high educational quality. The findings showed that factors at both individual, relational, attitudinal and structural level were associated with high quality. Factors related to communication, support and attitude seemed to be of particular importance. Most high-quality education was found for the programme directors at a single unit that experienced sufficient impact on education. Study IV explored the process of successful change implementation. Similarities shown included experiencing the change to be meaningful, working in coalition with others and employing a long-term perspective on change, where involvement and anchoring were essential. Experiencing mandate was central, which was dependent on the next level of leadership.
The findings show that the programme director role is influenced by contextual factors such as organisatorial characteristics and values, factors related to the leadership role such as conditions fore the role and competence, and factors related to the specialist training organisation and climate, such as communicationn and attitudes. Power and mandate are central concepts, and since the role mainly relies on personal power sources, relational factors may be of particular importance. In line with a diminished focus on leadership traits, the main message in this thesis argues that in order to strengthen the role of programme directors, a differentiated strategy with an aim to increase programme directors’ influence on specialist training should be used.
eng
info:eu-repo/semantics/openAccess
Educational leadership in physicians' specialist training : programme directors' experiences
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/446772021-11-15T12:37:20Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Shchetynsky, Klementy
2015-08-20T10:06:38Z
2015-08-20T10:06:38Z
2015-08-20
978-91-7549-956-7
http://hdl.handle.net/10616/44677
Complex disease is characterized by the interplay of multiple genetic and environmental
factors. Rheumatoid arthritis (RA) is a complex autoimmune disease with a pronounced
genetic component, mainly due to HLA-DRB1 gene, but also a multitude of loci outside the
HLA region. In this work we strive to contribute to the understanding of the functional
involvement of these susceptibility loci in the pathogenesis of RA.
This study is based on a large material of whole blood samples and peripheral blood
mononuclear cells (PBMCs) from RA patients and matched healthy controls from Sweden.
The main methods used in this work included probe-based genotyping and gene-expression
assays, cell cultures, RNA-sequencing, gene-gene interaction and pathway analysis, as well
as a plethora of common molecular genetics and bioinformatics methods.
We investigated the role of expression of known genetic risk factors PTPN22 and PTPN2 in
RA, with a special attention to the splicing profile of these genes. Our data indicates
significant differences in the expression ratio of splice variants for PTPN22 in whole blood
samples from RA patients and healthy controls. For PTPN2 we demonstrate a significant
difference in the relative mRNA expression of' transcript TC48 in PBMCs of healthy controls
and RA patients. Additionally, we identified new susceptibility SNPs in the PTPN2 locus:
rs657555 and rs11080606, by addressing the interaction of PTPN2 variants with HLA-DRB1
shared-epitope (SE) alleles in autoantibody positive RA patients in two independent cohorts.
In this work, we also address the functional genetic role of the members of the MAP
signaling pathway upstream of p38 and JNK – crucial enzymes in RA – with a regard to
splicing profile and their connection to HLA-DRB1. We found a significant statistical
interaction for rs10468473 from MAP2K4 locus with SE alleles in autoantibody-positive RA.
Importantly, individuals heterozygous for rs10468473 demonstrated higher expression of
total MAP2K4 mRNA in blood, compared to A-allele homozygous. We also describe a
novel, putatively translated RNA splice form of MAP2K4, that is differentially expressed in
peripheral blood mononuclear cells from 88 RA cases and controls, and is modulated in
response to TNF in Jurkat cell line.
Finally, we performed an expression analysis of multiple validated RA risk loci, and pathway
analysis to assess functional relationship between RA susceptibility genes and predict new
potential study candidates. New candidate molecules suggested by the pathway analysis,
genes ERBB2 and HSPB1, as well as HLA-DRB1, were differentially expressed between RA
patients and healthy individuals in RNA-seq data. ERBB2 expression profile was similar in
whole blood of both treated and untreated patients compared to healthy individuals. A similar
expression profile was replicated for ERBB2 in PBMCs in an independent material.
In this work, we approached the task of elucidating the functional aspects of genetic
susceptibility of RA, by integrating genetic epidemiology, transcriptomics, proteomics, cellmodels,
and bioinformatics. We maintain, that such integrative approach provides the
rationale to prioritize genes and genetic events for further functional studies. Our findings
also outline the need to consider potential clinical significance of alternative splicing in gene
expression studies.
eng
info:eu-repo/semantics/openAccess
Genomic profiling and gene-gene interaction in rheumatoid arthritis
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/44677/7/Thesis_Klementy_Shchetynsky.pdf
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Thesis_Klementy_Shchetynsky.pdf.txt
oai:openarchive.ki.se:10616/476612024-03-10T05:31:00Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Ivert, Lina
2021-06-01T09:34:29Z
2021-06-01T09:34:29Z
2021-06-01
978-91-8016-256-2
http://hdl.handle.net/10616/47661
Background: Atopic dermatitis (AD) is one of the most common chronic skin disorders globally. It is an itchy inflammatory skin disease that can have a detrimental impact on health-related quality of life. In recent years, AD has been associated with non-atopic conditions, though this requires further exploration. Novel understanding of AD pathogenesis has recently led to development of the first biological treatment. The overall aims of the thesis were to assess cardiovascular disease (CVD), autoimmune disease and depression among adults with AD, and to investigate the response to, and some adverse events from, systemic treatment that includes the first biological for AD.
Methods: Register-based, case-control studies were conducted to assess CVD and autoimmune comorbidity among patients with AD. The source population comprised the entire Swedish population aged ≥ 15 years. Cases, including all those with an inpatient diagnosis of AD (from 1968) and/or a specialist outpatient diagnosis of AD (from 2001) through 2016, were matched by sex and age to healthy controls (104,832 cases of AD, 1,022,435 controls). Patients were classified as having severe AD if they had received systemic pharmacotherapy for AD or had been treated in a dermatological ward with AD as the main diagnosis. Otherwise, AD was classified as non-severe. The clinical cohort studies and the case-series used data from a register containing prospectively collected data from adult patients with AD on systemic treatment at the Karolinska University Hospital from 2017. The register was launched for national use in 2019.
Result: Studies I–II: After multivariable adjustments for comorbidities and socioeconomic status, AD was associated with angina pectoris (adjusted odds ratio (aOR) 1.13, 95% confidence interval (CI) 1.08–1.19). Non-severe AD was associated with myocardial infarction (aOR 1.15, 95% CI 1.07–1.23) among men. Severe AD was associated with ischaemic stroke, with similar estimates in men and women (aOR 1.19, 95% CI 1.07–1.33). Diabetes mellitus, hyperlipidaemia, and hypertension were more prevalent in patients with severe AD than in controls, and hyperlipidaemia and hypertension were also more prevalent in patients with non-severe AD than in controls. Having AD was significantly associated with having one or more autoimmune diseases as compared with controls: (aOR 1.97, 95% CI 1.93–2.01), and this association was significantly stronger for having multiple autoimmune diseases than for having only one. The association was strongest for autoimmune disorders involving the skin, the gastrointestinal tract or the connective tissue. Studies III–V: In a caseseries of 10 patients with severe, long-lasting AD and most often also previous eye disease, 9/10 developed eye complications during dupilumab treatment, most commonly conjunctivitis (7/10). In a cohort study of patients treated with dupilumab (n = 12), weight gain (mean 6.1 kg, range 0.1–18.0 kg, p = 0.002) was seen after 1 year on treatment. In spite of these adverse events, dupilumab was very effective and safe. More than half of patients with moderate-to-severe AD eligible for systemic treatment (n = 60) had depressive symptoms, 25% of whom presented with moderate-to-severe depression and 5% of whom had pronounced suicidal ideation. Systemic treatment for AD significantly reduced depressive symptoms, in addition to relieving symptoms of AD.
Conclusion: AD was associated with CVD and several autoimmune disorders. More than half of the patients with moderate-to-severe AD in routine dermatological care had depressive symptoms. Dupilumab was very effective and safe overall, but was associated with ocular adverse events and weight gain in these small studies. Systemic treatment for AD significantly reduced depressive symptoms in parallel with reducing AD symptoms.
eng
info:eu-repo/semantics/openAccess
Atopic dermatitis in adults : epidemiological studies of comorbidity and studies of patients on systemic treatment
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/47661/3/Thesis_Lina_Ivert.pdf
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MD5
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oai:openarchive.ki.se:10616/411842023-10-29T17:46:27Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Eng, Kai
2012-09-24T09:51:22Z
2012-09-24T09:51:22Z
2012-09-24
978-91-7457-891-1
http://hdl.handle.net/10616/41184
Semliki Forest virus (SFV) infection causes dramatic changes to the infected cell. For example, synthesis of most cellular proteins shuts off within 4 hours. The cell launches an antiviral response, forms stress granules and, as we found in the work leading up to this thesis, accumulates autophagosomes. Studies on various host responses to viral infections are relevant for understanding both viral pathogenesis and innate immunity against viruses.
In the past decade autophagy has gained prominence as a protein degradation system, and the autophagy field is only just beginning to understand how this cellular mechanism is modulated during viral infection, and what role it plays either in host cell defence, or in supporting viral replication. To be better equipped for studying autophagy, we developed a flow cytometry-based method for quantifying autophagosomes, in Paper I. The method was quicker and less subjective than most pre-existing methods. Then, in Paper II we investigated autophagy during SFV infection, and found that autophagosomes accumulated during infection not due to increased synthesis of new autophagosomes, but due to a decreased rate of degradation of autophagosomes. We also found that expression of the SFV glycoproteins was necessary for the accumulation of autophagosomes.
Our work on autophagy led us to investigate the status of mTOR, a regulator of autophagy, during SFV infection. mTOR is normally active under nutrient rich conditions, and inactive under nutrient starvation conditions. In Paper III, we showed that SFV infection caused mTOR to remain active during nutrient starvation. Unlike the effect on autophagosome accumulation, this effect on mTOR did not depend on expression of the SFV glycoproteins. Despite the maintenance of mTOR activity in SFV infected cells, inhibition of mTOR activity with rapamycin had no effect on SFV growth rate.
Collectively, the results presented in this thesis provide a novel, practical tool for measuring autophagy, as well as insight on how autophagy and its regulator mTOR are modulated during SFV infection.
eng
info:eu-repo/semantics/openAccess
Regulation of autophagy and mTOR during Semliki Forest virus infection
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


AGREEMENT ON ELECTRONIC PUBLICATION OF THESES

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. Grant of rights

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. The Library's obligations

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. The Author's obligations

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. Paper printouts, etc.

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. Assignment of the agreement, etc.

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. Termination of the agreement

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. Processing of personal data

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. Liability

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. Full regulation

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. Upplåtelse

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. Bibliotekets åtaganden

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. Författarens åtaganden

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. Pappersutskrifter m.m.

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. Överlåtelse av avtalet m. m.

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. Avtalets upphörande

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. Behandling av personuppgifter

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. Ansvar

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. Fullständig reglering

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/428892023-02-26T19:31:25Zcom_10616_1com_10616_192com_10616_46998col_10616_219col_10616_193col_10616_47000
Publications from KI
author
Jiao, Hong
2014-12-04T16:29:14Z
2014-12-04T16:29:14Z
2002-08-26
91-7349-287-6
20020916jiao
http://hdl.handle.net/10616/42889
Type 2 diabetes (T2D) is characterized by two apparently distinct pathophysiologic defects - insulin resistance and a failure of the pancreatic Beta-cells to compensate for this resistance by appropriately increasing insulin secretion. There is strong evidence for an important role of genetics in both of these components. However identifying the genes responsible for the development of the disease has proven problematic because of complex background. Linkage analysis using the Goto-Kakizaki (GK) rat, a well-established genetic model for T2D, provides an ideal tool for understanding the pathogenesis of the disease by highlighting the chromosomal regions, which might harbor candidate diabetogenes. Furthermore by creating reciprocal crosses or changing environmental conditions, the effects of parent-of-origin or environmental factors on the manifestation of a quantitative trait locus (QTL) can be elucidated at the genome-wide level.
We have successively created three cohorts of F2 intercrosses of GK and F344 rats, founded by either GK grandmothers (F2GK) or grandfathers (F2F344). Parental, F 1, and F2 rats underwent a number of phenotypic assays i.e. intraperitoneal glucose tolerance test (IPGTT) with measurement of glucose, insulin and body weight. The first genome-wide scan with 253 markers revealed three glucose-related loci, Niddm I (LOD 11), Niddm2 (LOD 4.5) and Niddm3 (LOD 4.6), and one locus, Weight1 (LOD 6.2), for body weight on chromosomes 1, 2, 10, and 7 respectively, supporting the polygenic inheritance pattern of T2D in the GK rat. Furthermore clearly different models of inheritance for hyperglycemia at baseline vs. during the IPGTT were demonstrated, implicating different regulatory mechanisms at these two states. In this study paternal inheritance of diabetes of the GK rat was observed, in that GK fathers conferred significantly higher glucose and insulin levels in the IPGTT than GK mothers in the F I progeny.
By comparison of linkage analyses between two reciprocal crosses, four major parent-of-origin-specific QTLs were uncovered, implicating potential importance of mitochondrial and/or epigenetic effects in the GK rat. Niddm4, a major locus on chromosome 9 affected fasting insulin paternally (LOD 6.9 in F2F344 rats vs. 0.66 in F2GK rats). The locus also exerted a significant maternal-specific effect on glucose-induced insulin levels at 120 min, thus showing dual characteristics.
In this study we exhibited a distinct distribution pattern of QTLs in two reciprocal crosses, which indicated that genetic susceptibility genes to T2D might be fixed in the GK rat, but their effects were expressed in a manner that depends on the parent-of-origin. We also elucidated the additive and epistatic effects of QTLs. Mitochondrial genomes of the GK and F344 rats have been sequenced and the resulting sequences were checked against the published rat mtDNA sequence. In total 31 sequence variants were found in the GK rat as compared to the sequence of the F344 rat.
We uncovered seven gender-influenced QTLs giving strong evidence for linkage on chromosomes 1, 2, 5, 7, 10, and 18 in GK and F344 crosses. By analyzing the gene-gene interaction conditionally on gender effect, eleven locus-pairs showing epistatic interaction (p-value less than 0.0001) were identified to contribute to diabetic susceptibility in the F2 progeny.
Using the same approach in the study of experimental autoimmune neuritis (EAN) in rats, a model of GuillainBarré syndrome (GBS), a new region showing linkage to EAN phenotypes was found on chromosome 17. This locus showed strong evidence for linkage in affected rats vs. weak linkage in unaffected rats. Moreover the linkage to serum levels of anti-peripheral nerve myelin (anti-PNM) IgG2b and IgGI was much stronger in the cross with a Dark Agouti (DA) female founder and among male rats respectively.
A good linkage map with high accuracy and resolution is essential for a successful QTL mapping. Therefore we completed a linkage map of GK and F344 crosses based on a large number of meiosis (564 rats). The map consists of 530 markers and spans the entire rat genome in a total length of 1826.9 cM with an average interval of 3.4 cM. Subsequently based on the linkage map an integration of 7 linkage and 2 radiation hybrid maps of the rat was created. The integration provides reference to 8627 rat genetic markers. Among them there are more than 550 genes with homology information in human and mouse indicated.
In conclusion, by using the GK rat as a diabetic model we have demonstrated the complex genetics of T2D even in an inbred strain. In additional to the polygenic inheritance, effects of susceptibility genes were found to manifest conditionally, e.g. to depend on gender or parental origin, to respond to environment, or to interact with other genes. Our results provide an annotation on the genetics of TEND with detailed information and a platform to a further molecular and cellular analysis.
Genetic dissection of multifactorial disease models in the rat
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/434282023-02-21T09:49:27Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Mariga, Shelton Tendai
2014-12-04T16:29:51Z
2014-12-04T16:29:51Z
2005-05-03
91-7140-279-9
20050524tend
http://hdl.handle.net/10616/43428
Chemotherapy remains the most reliable means for the control of Plasmodium falciparum malaria. Unfortunately the parasite has been able to develop resistance to the majority of the antimalarials currently employed.
Success in the treatment of resistant infectious diseases such as leprosy, TB and HIV with combination therapy has generated wide interest in its application in malaria. Presently, WHO recommends the deployment of any novel antimalarial regimens for the treatment of P. falciparum only as drug combinations. Artemisinin (ART) combination therapy (ACT) represents the main combination option. Whilst, Quinoline antimalarials are the most important partners in this globally employed chemotherapy strategy.
The major objective of this work was to contribute, using the in vitro P.falciparum continuous culture model, the pharmacodynamic interactions between antimalarials as a tool for combination therapy strategies. Special emphasis was conferred on quinoline structures. These include amodiaquine (AQ), its active metabolite desethylamodiaquine (DAQ), quinine (QNN), lumefantrine (LUM), desbutyl-benflumetol (DBB) and pyroniridine (PYRON), with drugs of diverse structure ART, atovaquone (ATQ).
Drug susceptibility tests were performed for monocompounds along with drug combinations, according to chequerboard titration designs, of which the raw data obtained were calculated using two evaluation methods, O/E ratios (EC50, EC90, EC99) and isobolograms (sigmaFICs). AQ and DAQ showed high potency against P. falciparum, were superior to most recent antimalarials effective against chloroquine (CQ). Also confirmed was the high potency of DBB over LUM. DBB deserves further and more detailed preclinical/toxicological investigations.
AQ and DAQ were able to synergise with such compounds as, quinoline (QNN) and endoperoxide (ART) type of structures. AQ was also shown to synergise markedly with ATQ, a naphthoquinone ATQ. These results discern AQ and DAQ as flexaible partners in the context of combination therapy. In particular, their evident synergism with ART supports its present use in ACT strategies.
ART mainly synergised with the two Mannich base-containing quinolines herein tested, AQ and PYRON. Conversely, why ART does not synergise with CQ as much remains an open question, even though this observation could relate to the fact that CQ does not harbour a Mannich base in its structure.
AQ exhibited marked synergism with its active metabolite DAQ, even at trace concentrations. We further confirmed that this drug/metabolite phenomenon also occurs between quinoline methanols: LUM and its putative metabolite, DBB. This is the first time it has been shown that some antimalarials can significantly synergise with their own structurally similar active metabolites.
Pharmacodynamic interactions of quinolines with other antimalarial compounds in vitro
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/449582022-09-17T13:51:18Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Malone, David
2016-01-27T14:18:06Z
2016-01-27T14:18:06Z
2016-01-27
978-91-7676-143-4
http://hdl.handle.net/10616/44958
Natural killer (NK) cells have a key role in control and clearance of viral infections. To carry
out this function NK cells are capable of recognising infected cells and responding with
induction of apoptosis in these cells, and production of pro-inflammatory cytokines. Target
cells are recognised through various stress or infection related activating signals alongside
‘missing self’ recognition of down-regulation of human leukocyte antigen molecules.
Additional stimulation for NK cells comes in the form of the type I interferon (IFN), IFN-α,
which is released by infected cells and the immune system’s sentinels, the dendritic cells (DC).
As well as stimulating NK cells, IFN-α induces an anti-viral state in cells through upregulation
of expression of IFN-stimulated genes.
Infections with hepatitis B, C, and δ viruses (HBV, HCV, HDV) cause viral hepatitis and are
major risk factors for developing liver fibrosis. Despite these infections causing similar clinical
manifestations, and until recently treatment for all three utilising IFN-α, these three viruses
differ greatly. Human immunodeficiency virus (HIV) is the causative agent of acquired
immune deficiency syndrome (AIDS). This disease is characterised by loss of CD4 expressing
cells resulting in a diminished immune system that leaves the host susceptible to
opportunistic infections. HIV-1 is the cause of the AIDS pandemic, while HIV-2 associates
with a slower disease progression.
Each of these viruses is able to cause chronic infection. Part of the pathology of chronic
infection, particularly HIV infection, is persistent immune activation and microbial
translocation. In attempting to clear the infection the immune system can become perpetually
activated, a condition associated with immune dysfunction. During this phase the immune
response can contribute to disease progression through off-target effects, or appear as
exhausted and dysfunctional.
In this thesis I will show that the phenotype and function of NK cells are altered during
infection, primarily dependent upon the stage of hepatitis infection irrespective of infecting
virus. For HIV infections NK cell activation is dependent upon the level of viral replication.
During IFN-α therapy for hepatitis infections there is an increase of the chronic inflammation
and microbial translocation marker sCD14, while NK cell function is altered due to
fluctuations in intracellular STAT signalling.
eng
info:eu-repo/semantics/openAccess
Innate immunity in the immunopathogenesis of chronic viral infection
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/44958/3/Thesis_David_Malone.pdf
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Thesis_David_Malone.pdf.txt
oai:openarchive.ki.se:10616/381692023-02-21T17:58:07Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Siddiqui, Anwar J
2010-10-21T20:28:39Z
2010-10-21T20:28:39Z
2005-09-30
91-7140-511-9
20051021sidd
http://hdl.handle.net/10616/38169
Angiogenesis is the formation of new blood vessels induced by the proliferation and migration of endothelial cells. Because angiogenesis is a complex process, therapeutic efficacy may be improved by overexpression of combined angiogenic factors. Angiogenic effects of a single factor phVEGF-A (V) / phAng-1 (A) or their combination (V+A) were investigated in the myocardium.
In the ischemic myocardium, phVEGF-A gene transfer alone increased myocardial capillary and arteriolar densities more than double and phAng-1 had a similar effect. Transient overexpression of VEGF-A boosts angiogenesis at the arteriolar level more than at the capillary level. Combination with Ang-1 further boosts this effect and induced up to a 7.5 fold increase in vessel growth. Overexpressed growth factors (V, A, and V+A) stimulated the mouse VEGF-Ang system whereas placebo plasmid had no such effects. Phosphorylation of antiapoptotic Akt and its downstream effector GSK3-alpha/beta were lower during myocardial ischemia and there was no difference between any of the treatments.
Upregulation of the endogenous ligands / receptors of the VEGF-angiopoietin system could be the mechanism for the therapeutic angiogenic booster effect during myocardial ischemia, a process that may occur independent of the Akt pathway. Hypercholesterolemia and aging are associated with impaired vascular density associated with downregulation of mVEGF, VEGFR- 1, VEGFR-2, eNOS, Akt and upregulation of apoptotic protein p38 MAPK phosphorylation. phVEGF gene transfer in combination with simvastatin corrected impaired vascularity concurrently with stimulation of the VEGF system, increased eNOS production and reduced p38 MAPK phosphorylation.
In the non-compromised heart enalapril and candesartan both specifically inhibit phVEGF-A induced myocardial angiogenesis associated with inhibition of hVEGF-A expression and decreased endogenous expression of the mVEGF ligand /receptor system. Combined overexpression of VEGF and angiopoietin has an angiogenic booster effect that occurs due to stimulation of the endogenous VEGF-Angiopoetin system. Aging and hypercholesterolemia have negative effects on angiogenesis. Commonly used cardiovascular drugs can stimulate or inhibit angiogenesis.
eng
info:eu-repo/semantics/openAccess
Therapeutic myocardial angiogenesis and its pharmacological modulation
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38169/1/thesis.pdf
File
MD5
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4175668
application/pdf
thesis.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38169/2/thesis.pdf.txt
File
MD5
4cd8a303e123f0d6276cf3716359a9b0
63
text/plain
thesis.pdf.txt
oai:openarchive.ki.se:10616/440692023-12-16T16:32:23Zcom_10616_1com_10616_46998col_10616_219col_10616_47000
Publications from KI
author
Nyberg, Filippa
2014-12-04T16:30:28Z
2014-12-04T16:30:28Z
1999-01-01
91-628-3344-8
19990122nybe
http://hdl.handle.net/10616/44069
Lupus erythematosus (LE) is an autoimmune disease in which the skin is one of the main target organs. Photosensitivity is a common feature for the different subtypes of cutaneous LE, but photosensitivity has not been well defined. Polymorphous light eruption (PLE) is a common form of photosensitivity in otherwise healthy individuals, and the differential diagnosis can be difficult. The keratinocytes and dermoepidermal junction have been extensively studied in LE, contrary to the cells in the dermis, especially fibroblasts and endothelial cells. We studied different aspects of UV-induced cutaneous reactions in LE patients, with emphasis on early cellular events in evolving lesions. We also investigated the roles of endothelial cells and fibroblasts.
Methods: A mailed questionnaire with questions about worsening by sunlight and about history of PLE was sent to 387 consecutive patients from dermatological university clinics in Finland and Sweden. Sixty- seven of the responders were interviewed about their photosensitivity, and went through phototesting and photoprovocations with UVB and UVA. Consecutive biopsies from UV-induced, evolving cutaneous reactions were obtained from LE and PLE patients until the reactions subsided, and from healthy, photoprovoked individuals. The biopsies were analysed with direct immunofluorescence using antibodies against IgG, IgM, C3 and C1q, with immunohistochemistry for expression of ICAM-1, VCAM-1 and E-selectin and with routine histopathology. Levels of soluble CAMs were analysed with ELISA kits in a retrospective study on frozen sera from LE patients and controls. Fibroblasts were cultured from scarring and non-scarring LE lesions and healthy controls. The cells were counted every third day during nine days. Cytokines and soluble CAMs in supernatants were analysed before and after irradiation of the cells with UVA.
Results: LE patients reported worsening by sunlight in 242 (72%) of 337 responders to the questionnaire. A history consistent with PLE was reported by 165 (49%). PLE had started before LE in the majority of patients with both diagnoses. UVA and UVB induced reactions with clinical and micromorphological features of LE or PLE. A specific, granular epidermal staining pattern ("dust-like particles"), was found in immunofluorescence biopsies from the first two weeks after irradiation in LE patients and within 3 days at the earliest. Complement (C1q) was often present. Specific patterns of CAM expression were seen in different diagnostic groups and as an early event in lesions of different duration. UVA but not UVB possibly had a direct influence on endothelial VCAM-1 and E-selectin expression. Soluble (s)E-selectin was elevated in serum from DLE patients with active, widespread lesions compared to controls and patients with limited disease. sICAM-1 and sVCAM-1 were elevated in patients with SLE and SCLE, and correlated to systemic but not to cutaneous symptoms. Cultured fibroblasts from scarring LE lesions, showed markedly impaired proliferation compared to fibroblasts from non-scarring LE lesions and controls. UVA irradiation did not significantly influence levels of cytokines and CAMs in supernatants from cultured fibroblasts.
Conclusions: The photosensitivity in LE patients displays a clinical spectrum from transient, PLE-like reactions to persistent, clinically typical LE lesions. CAM expression patterns are influenced by the patient's disease. Complement, endothelial cells and fibroblasts seem to play roles in the pathogenesis of UV-induced LE lesions. Hypothetically, an altered expression of CAMs, induced by an unbalanced cytokine network brought about by an altered T-cell/B-cell repertoire in genetically susceptible individuals, could be a unifying concept for the findings in our studies.
Photosensitivity in cutaneous lupus erythematosus clinical and experimental studies
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/421602023-12-25T11:41:36Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Lind, Katharina
2014-09-18T12:08:01Z
2014-09-18T12:08:01Z
2014-09-18
978-91-7549-614-6
http://hdl.handle.net/10616/42160
Infections with Coxsackieviruses are common and in most cases the infection is asymptomatic and efficiently cleared. On rare occasions, however, an infection can lead to severe diseases including myocarditis, hepatitis and pancreatitis. Infections with Coxsackieviruses have also been implicated in the pathogenesis of type 1 diabetes (T1D). Upon a virus infection, the innate immune response plays an important role in restricting viral replication and further dissemination to susceptible organs. An inability to mount an appropriate immune response may increase virus-induced damage.
This thesis focuses on the cross-talk between host and Coxsackievirus. The aims were to identify mechanisms by which the host restricts infection and to unravel strategies used by the virus to evade the host immune response. We identified that the intracellular virus receptor melanoma differentiation associated factor 5 (MDA5) has an important role in the host response to a Coxsackievirus infection. Absence of this receptor led to a decreased ability to control viral replication, which resulted in severe tissue damage and increased mortality. Polymorphisms in interferon induced with helicase C domain (IFIH1), the gene encoding MDA5, regulate the risk for T1D development, further implicating the involvement of Coxsackieviruses in T1D pathogenesis. Studies in this thesis showed that the Ala946Thr polymorphism in IFIH1 regulates how human pancreatic islets respond to a Coxsackievirus infection. The predisposing allele 946Thr was associated with lower induction of interferons (IFNs) and IFN-inducible genes. It has previously been shown that type I IFNs play an important role in the host defense against Coxsackievirus. Type III IFNs are a recently described group of IFNs that mainly act on epithelial cells and provides protection against virus infection. This thesis established a novel role for the type III IFNs in inducing an antiviral state in infected human pancreatic islets. Moreover, it demonstrated that type III IFNs protect primary human cells, inlcuding pancreatic islets and hepatocytes, from a Coxsackievirus infection. Due to the potent antiviral effect of IFNs, most viruses have developed mechanisms to inhibit their actions.
In this thesis, strategies utilized by Coxsackieviruses to inhibit the induction of type III IFN were identified, which further underlines the importance of this group of IFNs in controlling a Coxsackievirus infection. The findings presented in this thesis further our understanding of how the host recognizes and combats a Coxsackievirus infection, and also describe evasion strategies used by the virus to inhibit these protective mechanisms. The studies also demonstrate that a polymorphism in IFIH1 affects the ability of human pancreatic islets to respond to a Coxsackievirus infection. A better understanding of the host-pathogen interactions may help in the development of therapeutic strategies to reduce the severity of Coxsackievirus infections.
eng
info:eu-repo/semantics/openAccess
A battle between host and pathogen : the innate immune response and enterovirus evasion strategies
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/42160/1/Thesis_Katharina_Lind.pdf
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MD5
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oai:openarchive.ki.se:10616/465402024-03-20T15:30:20Zcom_10616_1com_10616_201com_10616_46998col_10616_219col_10616_202col_10616_47000
Publications from KI
author
Pudelko, Linda
2018-11-27T09:08:57Z
2018-11-27T09:08:57Z
2018-11-27
978-91-7831-231-3
http://hdl.handle.net/10616/46540
Glioblastoma (GBM) is the most aggressive form of brain cancer. Despite today’s combinatory therapy consisting of surgery, radio- and chemotherapy, the prognosis remains dismal. Fostered by extensive tumor heterogeneity, cancer cell plasticity and the presence of cancer stem cells, GBM evades almost any therapeutic strategy, leading to high mortality. Thus, the development of novel therapies is of urgent need. With the identification of the Hallmarks of Cancer several cancer specific characteristics have been described that could serve as promising anti-cancer targets, including the combination of an elevated proliferation rate, crucial changes in cancer metabolism and consequently, an altered redox environment. Cancer cells and GBM in particular depend on effective anti-oxidant defense systems and non-oncogenic addiction enzymes such as MTH1, an enzyme that detoxifies oxidized bases to prevent DNA damage and subsequent cell death.
While potential anti-cancer targets are constantly being identified, the development of novel therapies against GBM is, amongst other reasons, hampered by the lack of orthotopic animal models that support large drug discovery screens. During the last decade, the zebrafish has been introduced as a clinically relevant model for human malignancies including cancer. Owing its biological and technical advantages, the zebrafish is the only vertebrate animal suitable for automated drug discovery screens to facilitate the identification and validation of novel cancer therapies. In this thesis, we primarily focused on complementing established biochemical and cellular assays with a broad application of the zebrafish model to: 1. Describe factors that render cancer cells sensitive to MTH1 inhibitors; 2. Validate MTH1 as a target in GBM and GBM stem cells; 3. Develop a new orthotopic in vivo model for GBM.
In Paper I we have demonstrated that the cellular redox environment and activation of the hypoxia signaling axis determine sensitivity to MTH1 inhibition in vitro and in vivo, thus suggesting that MTH1 inhibition may present a promising approach to treat cancers characterized by deregulated hypoxia signaling and redox imbalance. In Paper II we have tested this hypothesis and showed that depletion or inhibition of MTH1 efficiently reduces viability of patient-derived GBM cultures independent of aggressiveness i in vitro and in vivo, thus providing supporting data that MTH1 represents a promising target for GBM therapy in particular. In Paper III we addressed the lack of an orthotopic animal model for GBM which is suitable for large drug discovery screens. We found that GBM cultures transplanted into the blastoderm of zebrafish embryos form a congregated tumor in the central nervous system, fully recapitulating the human disease. As no intracranial transplantation is required, we have developed an orthotopic animal model for GBM that could readily be implemented in fully automatable drug discovery screens in order to accelerate the identification and development of novel therapies against GBM.
eng
info:eu-repo/semantics/openAccess
Fishing for cures : the zebrafish as a powerful tool to identify novel therapies against glioblastoma by targeting MTH1 and beyond
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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URL
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oai:openarchive.ki.se:10616/451972019-09-29T22:25:16Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Dyberg, Cecilia
2016-09-23T11:02:13Z
2016-09-23T11:02:13Z
2016-09-23
978-91-7676-424-4
http://hdl.handle.net/10616/45197
Neuroblastoma and medulloblastoma are embryonal malignant tumors of the central and
peripheral nervous systems, respectively. The overall survival for both diagnoses is 60-75%
despite intense multimodal therapy. This warrants the search for novel therapeutic
approaches. Hedgehog (HH) and Wingless (WNT) signaling pathways are important
regulators of embryogenesis that have been associated with the development of cancer
including medulloblastoma. HH signaling is characterized by Smoothened (SMO)-dependent
activation of the GLI transcription factors. WNT signaling is divided into canonical and noncanonical signaling. Canonical signaling involves the key molecule β-catenin while noncanonical signaling includes the planar cell polarity pathway (PCP). PCP signaling including
the Rac/Rho cascade are important for proper migration and differentiation of neural crest
cells during neuritogenesis. In this thesis we have assessed the role of HH and WNT
signaling in neuroblastoma and medulloblastoma, with the aim to gain insights and develop
novel therapeutic approaches based on biological understanding of the diseases.
Key molecules within the HH signaling pathway are overexpressed in neuroblastoma. We
investigated the effects of inhibiting HH signaling in neuroblastoma and found that inhibition
of GLI was more effective in reducing neuroblastoma growth compared to inhibition of SMO
located more upstream in the signaling pathway. The GLI inhibitor GANT61 effectively
repressed neuroblastoma growth in vitro and in vivo, downregulated c-MYC, GLI1, MYCN
and Cyclin D1 expression and augmented the cytotoxic effects when combined with
clinically used chemotherapeutic drugs. These findings suggest that inhibition of HH
signaling is a highly relevant therapeutic target for high-risk neuroblastoma (Paper I). The
DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is frequently
overexpressed in cancers and is coupled to chemoresistance. In a search for new inhibitors for
MGMT we investigated cellular regulators of MGMT expression in multiple cancers
including neuroblastoma and medulloblastoma. We found a significant correlation between
WNT signaling and MGMT expression that was confirmed by bioinformatic analysis and
studies of protein expression of MGMT and β-catenin. Pharmacological as well as genetic
inhibition of WNT activity downregulated the MGMT expression and restored
chemosensitivity of the DNA-alkylating drug temozolomide in vitro and in vivo. These
results have possible therapeutic entailments for chemoresistant cancers, especially of brain
tumors where temozolomide is commonly used in treatment (Paper II).
Investigating non-canonical WNT signaling in neuroblastoma revealed that overexpression of
PCP core genes Prickle1 and Vangl2 led to suppression of neuroblastoma cell growth and
reduced Wnt/β-catenin signaling. On the other hand, overexpression of Vangl2 in neural stem
cells produced accumulation of active β-catenin and decreased differentiation, suggesting
different roles of PCP proteins in tumorigenic cells compared to normal cells (Paper III).
Furthermore, genetic analyses demonstrated that neuroblastoma tumors harbor frequent
mutations of genes controlling neuritogenesis associated with the Rac/Rho signaling cascade.
The majority of these mutations were described to result in inhibition of Rac or activation of
Rho. Inhibition of ROCK, a key enzyme downstream of Rho, resulted in differentiation,
inhibition of neuroblastoma cell growth and migration and degradation of MYCN protein.
Small molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth both in
a transgenic and in a xenograft model. This study proposes that manipulation of Rho
signaling might offer new therapeutic alternatives for neuroblastoma (Paper IV).
Taken together, the work in this thesis demonstrates that the embryonal signaling pathways
HH and WNT may offer new therapeutic targets for neuroblastoma and medulloblastoma.
eng
info:eu-repo/semantics/openAccess
Targeting dysfunctional developmental signaling cascades as a tool for tailored therapy in embryonal tumors
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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Thesis_Cecilia_Dyberg.pdf.txt
oai:openarchive.ki.se:10616/412812022-10-23T22:40:02Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Kruusmägi, Markus
2012-11-26T14:18:37Z
2012-11-26T14:18:37Z
2012-11-26
978-91-7457-996-3
http://hdl.handle.net/10616/41281
Neurons communicate via synapses; the strength of each synapse is defined both pre and postsynaptically. Presynaptically, the strength of the synapse is defined by which neurotransmitter is being released and how much. On the postsynaptic membrane a corresponding receptor will receive the transmitter. Receptor abundance and availability determines the strength of the synaptic connection.
Protein function is as tightly linked to structure as it is to location. Due to the fluidic nature of the plasma membrane, any membrane protein will be highly mobile unless it is being anchored or confined within a compartment by an intracellular protein or cytoskeletal complex. High mobility facilitates interactions between proteins and ensures proper localization through free energy minimization without the need of directed transport. The dynamic regulation of protein mobility is fundamental in defining the function of the protein. The overall abundance and availability of postsynaptic proteins are dependent on many processes such as exocytosis/endocytosis, activation/inactivation, and lateral diffusion.
The aim of this thesis was to study how postsynaptic proteins can be regulated in the dendritic membrane by availability and mobility. Dopamine is an important modulatory neurotransmitter that is involved in cognition, memory, motoric functions and reward-mechanisms. Calcyon is an accessory protein that has been suggested to modulate dopamine receptor signaling. We show that calcyon is a neuron-specific vesicular protein with a high intracellular mobility. Furthermore we show that calcyon forms vesicular clusters located just beneath the plasma membrane. We propose a role for calcyon in the trafficking of proteins that are important for synaptic plasticity, to and from the dendritic plasma membrane.
Dopamine receptors are divided into two groups, the D1-like and D2-like group, each with distinct downstream signaling pathways. We show that the two isoforms of the D1-like group, the D1 and D5 receptors have distinctly different subcellular localization in striatal neurons and interact differently with the NMDA receptors. We propose that the two isoforms, due to differences in localization and interactions with other receptors, have distinct roles in neuronal dopaminergic signaling.
Most G-protein coupled receptors are transported to the plasma membrane of the soma and are then transported via lateral diffusion to the site of action. We studied several GPCRs, involved in mood regulation and behavior, to elucidate whether GPCRs share a common mode of transport. We show that the 5-HT1B receptor, in contrast to other GPCRs, is transported in vesicles in the lumen of the dendrites. We show that the vesicles release the receptors to the membrane close to inhibitory synapses, followed by subsequent lateral diffusion and confinement in inhibitory as well as excitatory synapses. We propose that this special mode of transport serves as an additional mode of regulation, which enables fine-tuning of serotonergic signaling.
The Na,K-ATPase is an essential ion transporting protein that is found in all cells where it is responsible for the generation of the plasma membrane ion gradient that is the driving force for many important cellular processes. Different isoforms of the catalytic, ion-pumping, α subunit are expressed in different cell types. We show that the neuron-specific α3 isoform is responsible for the sodium clearance in dendrites following synaptic signaling, which is essential for proper neuronal function. Furthermore we show that the α3 subunit is highly mobile in the postsynaptic membrane and that it is confined in excitatory synapses. We show that mobility is modulated by neuronal activity; excitatory stimulation results in an increased mobility in both the synaptic as well as the extrasynaptic region.
eng
info:eu-repo/semantics/openAccess
Spatial control of postsynaptic proteins : a role in brain plasticity
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/462732019-09-29T21:35:45Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Pyko, Andrei
2018-04-26T07:20:56Z
2018-04-26T07:20:56Z
2018-04-26
978-91-7831-072-2
http://hdl.handle.net/10616/46273
Transportation noise exposure is increasing because of rapid urbanization and transportation
growth. Environmental noise exposure affects a large part of the population and gives rise to
widespread annoyance and sleep disturbances. However, the evidence on metabolic and
cardiovascular effects of long-term exposure to transportation noise from different sources is
mostly limited and of low quality, hampering comprehensive risk assessment, although such
effects may be of great public health significance. The main aim of this thesis was to study
the development of obesity and cardiovascular outcomes in relation to exposure to noise from
road traffic, railways and aircraft, and particularly the role of interactions.
The four cohorts under study were based in Stockholm County and included a total of more
than 22,000 adults followed for up to 20 years. Three of the papers in the thesis used only one
of these cohorts, the SDPP cohort, including close to 8,000 subjects at recruitment. Individual
assessment of exposure to noise from road traffic, railways or aircraft was based on a detailed
residential history for each study participant as well as a newly developed database
containing longitudinal information on determinants of noise levels generated by the three
transportation noise sources. Data on air pollution exposure was obtained from dispersion
models based on a similar methodology. Information on covariates and health outcomes was
based on questionnaires and registers, and the health outcome data were further supplemented
with information from clinical investigations.
For obesity markers, the strongest associations were observed in relation to aircraft noise. A
10 dB higher level in exposure was associated with a waist circumference increase and
weight gain of 0.16 cm/year (95% CI 0.14–0.17) and 0.03 kg/year (95% CI 0.01–0.04),
respectively. Road traffic noise exposure was related to a waist circumference increase of
0.04 cm/year (95% CI 0.02–0.06) per 10 dB Lden, while no clear association was observed for
railway noise. The incidence rate ratio of central obesity in relation to number of sources of
transportation noise exposure increased from 1.22 (95% CI 1.08–1.39) among those exposed
to only one source to 2.26 (95% CI 1.55–3.29) among those exposed to all three
transportation noise sources. Moreover, aircraft noise exposure was related to incidence of
hypertension (hazard ratio: 1.16; 95% CI 1.08–1.24 per 10 dB Lden), but no associations
appeared for other transportation noise sources. No clear or consistent associations were
observed between transportation noise exposure and risk of ischemic heart disease (IHD) or
stroke. However, there appeared to be an increased risk of IHD in women related to road
traffic noise exposure, while the opposite held true for men. Higher risks appeared of both
IHD and stroke incidence in those exposed to all three noise sources, with hazard ratios of
1.57 (95% CI 1.06–2.32) and 1.42 (95% CI 0.87–2.32), respectively.
In conclusion, our findings indicate adverse effects of long-term transportation noise
exposure on some metabolic and cardiovascular outcomes, and suggest that combined
exposure to different transportation noise sources may be particularly harmful.
eng
info:eu-repo/semantics/openAccess
Long-term exposure to transportation noise in relation to metabolic and cardiovascular outcomes
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46273/3/Thesis_Andrei_Pyko.pdf
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MD5
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Thesis_Andrei_Pyko.pdf
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Thesis_Andrei_Pyko.pdf.txt
oai:openarchive.ki.se:10616/452852019-09-29T21:22:11Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Clay, Leonard
2016-10-19T13:59:17Z
2016-10-19T13:59:17Z
2016-10-19
978-91-7676-461-9
http://hdl.handle.net/10616/45285
BACKGROUND: The optimal method for surgical repair of giant ventral hernia remains to be determined. Different concepts for reinforcement have been used, which have decreased the risk for recurrence. However, the use of foreign material has shown potential adverse effects such as pain, enterocutaneus fistula and decreased comfort of the corset caused by stiffness and pain. In an attempt to explore ways to decrease surgical complications in giant ventral hernia repair, a randomized study comparing synthetic material with autologous full thickness skin transplantation was planned and executed. In order to conduct such a study and detect any differences, it was first necessary to develop instruments for the evaluation of patient related outcome measurements. This included assessment of pain which is known to be an outcome in inguinal hernia surgery. Also, the effect on abdominal strength after medialization of the rectus muscles is something that has been previously discussed but not explored in randomized studies. Similarly, the effectiveness of using a post- operative elastic girdle in connection with abdominal surgery and abdominal wall reconstruction has not been previously studied in detail. Giant ventral hernia affect the integrity of the abdominal wall. Abdominal rectus diastasis (ARD) elicit a similar affect on abdominal wall integrity. This being the case, the effectiveness of ARD repair could shed some light on the repair of giant ventral hernia.
METHODS: A questionnaire was tailored to evaluate hernia related pain and its interference with the daily activities of a patient’s life. This questionnaire was validated compared to the existing BPI questionnaire assessing general pain. For validation purposes, focus groups with patients operated for ventral hernia were utilized. Test retest reliability was assessed by distributing the VHPQ and BPI to patients who had previously undergone ventral hernia repair. In total, 225 patients were involved in this study.
To be able to evaluate the effect of surgical reconstruction of ARD where the abdominal muscles are brought together, 57 patients underwent evaluation with the VHPQ and their results were compared with abdominal wall strength measured with the Biodex pre- and postoperatively.
A randomized trial evaluating the effect of wearing an elastic abdominal girdle was conducted with 48 patients after midline laparotomy. Postoperative cough-PEF, spirometry, pain and wound healing were evaluated.
Ultimately, as planned, the randomized study of abdominal wall reconstruction in patients with giant ventral hernia was designed and initiated, including 52 patients. Randomization was performed to create parallel groups for reconstruction using synthetic mesh or autologous full-thickness skin transplant. The primary outcome was surgical complications after 3 months. Post-operative evaluation was performed by a surgical specialist not otherwise involved in the study and blinded to the reconstruction method used.
RESULTS: The VHPQ showed good validity and reliability when compared to the BPI and evaluation of test-retest stability. A relationship between preoperative ratings on VHPQ questions regarding performing sports and sitting for more than 30 minutes and the effect of surgical repair in terms of improved muscle strength was revealed for patients with ARD. The use of a post-operative elastic abdominal girdle following laparotomy did not impair respiratory function but seemed to decrease post-operative pain.
Abdominal wall reconstruction using full-thickness skin grafts instead of synthetic mesh for abdominal wall reinforcement showed a similar complication profile at 3 month follow-up. Patients reconstructed with full-thickness skin grafts experienced less post- operative pain at 3-month follow-up.
DISCUSSION: This thesis evaluated the effect of autologous full thickness skin grafts as onlay reinforcement in the surgical repair of giant ventral hernia. Our hypothesis that the use of skin grafts would give less surgical complications was not confirmed but patients with full thickness skin grafts suffered less abdominal wall discomfort compared to those reconstructed using synthetic mesh. In the future, these patients will also be evaluated for recurrence, abdominal muscle force and adverse events at 12 and 36 months after surgery. As a precursor to embarking upon a study to evaluate abdominal wall reconstruction, a useful tool for evaluation of pain in the abdominal wall after ventral hernia surgery was generated. This instrument makes it possible to compare different surgical techniques with regard to patient experience. It may also provide a possible tool for the selection of patients with ARD who might benefit most from surgical repair. The use of an individually fitted girdle does not hinder respiratory function or wound healing. Nor does it provide a supportive effect for cough-PEF. One positive effect from wearing a girdle postoperatively is that it seems to reduce postoperative pain.
eng
info:eu-repo/semantics/openAccess
The evaluation, preoperative and operative aspects of abdominal wall reconstruction for giant ventral hernia
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/45285/1/Thesis_Leonard_Clay.pdf
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MD5
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oai:openarchive.ki.se:10616/407612023-10-25T16:01:15Zcom_10616_1com_10616_153com_10616_46998col_10616_219col_10616_154col_10616_47000
Publications from KI
author
Mårtensson, Johan
2011-11-09T12:05:39Z
2011-11-09T12:05:39Z
2011-11-09
978-91-7457-544-6
http://hdl.handle.net/10616/40761
Acute kidney injury (AKI) is a common and potentially fatal complication in critically ill patients. The diagnosis relies on functional markers of decreased glomerular filtration rate (GFR) such as creatinine. Unfortunately, a rise in plasma creatinine lags behind the early structural changes that occur in response to various renal insults. Future treatment of AKI will most certainly be based on early biomarkers of structural damage. In addition, better real-time measures of GFR are needed to be able to monitor the course of the disease. Cystatin C outperforms creatinine as a marker of GFR in stable patients and human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL) has emerged as an early biomarker of AKI since it is readily synthesized by tubular cells following kidney damage. However, HNL/NGAL is also released by neutrophils in response to bacterial infections. Consequently, sepsis may affect HNL/NGAL concentrations in plasma and urine.
The aim of this thesis was to investigate the ability of HNL/NGAL and cystatin C to predict AKI and/or mortality in critically ill patients as well as to assess the impact of sepsis on HNL/NGAL and cystatin C levels in plasma and urine. In addition, we wanted to study the ability of two enzyme-linked immunosorbent assays (ELISAs) to detect HNL/NGAL released in urine from kidney epithelial cells and neutrophils, respectively, during the development of AKI.
Cystatin C predicted long-term mortality independently of AKI severity. Even in patients without AKI, elevated cystatin C was associated with increased mortality. During the first week in the intensive care unit cystatin C gradually increased, in patients both with and without AKI. This increase was similar in septic and non-septic patients. Cystatin C predicted sustained AKI, worsening AKI or death. HNL/NGAL in plasma was not predictive of AKI in patients with septic shock since sepsis per se increased plasma levels of HNL/NGAL. Urinary HNL/NGAL was less affected by sepsis and performed well as an AKI predictor. In combination, our two ELISAs effectively distinguished monomeric HNL/NGAL, released from kidney tubular cells, from dimeric HNL/NGAL, mainly released by activated neutrophils, during the development of AKI.
eng
info:eu-repo/semantics/openAccess
Biomarkers of acute kidney injury
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/434842023-02-21T08:28:32Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Bengtsson, Sara L
2014-12-04T16:29:54Z
2014-12-04T16:29:54Z
2005-11-18
91-7140-563-1
20051209beng
http://hdl.handle.net/10616/43484
Human movements are impressively flexible and precise. They are also coloured by the characteristics with which each person performs an act. This is evident in everyday activities, in sports, in art, and in music performance. How does the human brain control a movement pattern and give it its character, given all possible degrees of freedom?
In this thesis we have investigated the cortical organization of two fundamental aspects of sequential movements; the explicit temporal control of when to move, and the spatial control of where to move, with a particular focus on the temporal control. As model behaviour we have used sequence production with the fingers, and with functional resonance imaging we localized the associated neural activation. We measured the behaviour of the participants' rhythmic motor performance to enable interpretation of the brain activation. Finally, we studied the plasticity of the white matter as a function of practicing in pianists using diffusion tensor imaging.
Firstly, we investigated if the relative timing and the ordinal sequence of spatial locations of a movement can be handled independently by the brain. We found evidence for a parallel processing of the two aspects. In study I, we found that once a rhythmic sequence is learned it can be executed with different spatial movement patterns with little extra training. In study II we showed that the two aspects mainly activate different brain regions. Processing the temporal information activated motor areas of the medial wall, the inferior frontal cortex, the temporal lobe, and the lateral cerebellum, whereas the ordinal sequencing activated the parietal cortex, the dorsal premotor cortex, the cerebellum and the putamen. In study III, we found that pianists use two parallel visual pathways to guide their movements when playing from written music. The dorsal visual stream appears to be involved in the spatial melody processing, whereas the ventral visual stream processes the rhythmical information of the music. We argue that the parallel processing of the relative timing and the ordinal sequence of spatial locations of a movement gives flexibility in performance since each aspect could be manipulated individually.
Secondly, we investigated if rhythm sequence control relies on a central mechanism, or if it processed within the structures required for a particular task. In studies I and IV we observed that individuals differed from each other in their rhythm production profile, when performing a rhythm with different body parts and different spatial movement patterns, but showed remarkably high intra-individual consistency. This suggests that the same representation of the explicit rhythmic structure is used to time movements. From the brain imaging results we propose a set of brain areas involved in rhythm control: the supplementary motor area (SMA) and preSMA, the dorsal premotor cortex, the superior temporal lobe, the inferior frontal cortex, the insula, and the cerebellum. These areas were active during rhythm production, irrespective of body part used (study IV) or spatial movement pattern (study II). In addition, listening to rhythms without motor performance engaged these areas (study V).
Finally, we investigated if the structure of the white matter, containing myelinated axons that transmit neural signals between brain regions, changes as a consequence of longterm training of rhythmic finger movements. In study VI, we found an increased degree of organization of the white matter in professional pianists, which correlated with the number of hours practiced in different ageperiods. The data suggest that childhood practising is of particular importance, since the most widespread changes were seen after intense childhood practising.
On the mind's time : production, perception, and pianists performance of rhythms : neural correlates and neuroanatomical changes
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/391952022-11-05T23:09:48Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Farra, Anna
2010-10-21T20:31:25Z
2010-10-21T20:31:25Z
2007-05-04
978-91-7357-201-9
20070525farr
http://hdl.handle.net/10616/39195
Aims: The general aims of the present studies were to assess the levels of antibiotic resistance, in relation to antibiotic consumption at the Karolinska University Hospital, Solna (KS) and at 11 other Swedish hospitals, furthermore to assess the role of the membrane protein OprD and penicillin-binding proteins in Pseudomonas aeruginosa resistance to imipenem.
Methods: Resistance figures were retrieved from the microbiology service databases for the period 1989-99, at the 12 above mentioned hospitals, including their intensive care units (ICU). Antibiotic consumption figures were obtained from the National Corporation of Swedish Pharmacies database during the same period. In order to study molecular mechanisms of carbapenem resistance, we produced transconjugants from clinical isolates of carbapenem resistant P. aeruginosa in a sensitive PAO18 after selection for a proline marker (proB). The active sites of penicillin-binding proteins PBP1b, PBP2, PBP3 and PBP6 were sequenced, and the expression of oprD, pbp2 and pbp3 genes was measured using quantitative real-time PCR.
Results: Resistance to ciprofloxacin increased in Escherichia coli and P. aeruginosa in parallel with an increased quinolone consumption in all included hospitals. The use of cephalosporins increased two and a half times, while the level of resistance in E. coli to cefuroxime and cefotaxime remained stable at KS. A third pattern was observed for co-trimoxazole resistance in E. coli, which increased at KS as well as the other 11 Swedish hospitals, while consumption of co-trimoxazole and trimethoprim decreased during the 12 year study period. Resistance rates at KS were still generally low, but there were increasing trends for some antibtiotic-microbe combinations. E. coli resistance to ciprofloxacin increased from 0% in 1991 to 11% in 1999 and co-trimoxazole resistance increased in E. coli from 7.5% to 14% during the study period. For E. coli, resistance to ciprofloxacin was higher at the hospital than at the ICUs. There were considerable fluctuations in resistance prevalence over time, especially at the ICU. Imipenem resistance in P. aeruginosa was particularly noticeable at the ICU, with resistance peaks of 15% and 28% in 1992 and 1999, respectively. These peaks were due to outbreaks. Sequencing of P. aeruginosa genes for PBP1b, PBP2, PBP3 and PBP6 showed no differences in amino acid sequence, but the gene for OprD porin was downregulated in all imipenem resistant clinical strains and their transconjugants.
Conclusions: The significant trend of increased resistance to antibiotics over time constitutes an important warning system. The relation between antibiotic consumption and antibiotic resistance was not always parallel. Three different patterns were observed which suggests that different mechanisms were operating. We also found in some cases, higher resistance rates at the hospital than at the ICUs emphasizing the importance of including all sectors of a hospital. Also, antibiotic resistance figures fluctuated substantially over time, illustrating the value of long surveillance periods. Finally, in imipenem resistant P. aeruginosa, a previously unknown gene for regulation of oprD, is most likely located close to the proB marker.
eng
info:eu-repo/semantics/openAccess
Antibiotic resistance and antibiotic consumption with focus on Escherichia coli and Pseudomonas aeruginosa
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39195/1/thesis.pdf
File
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thesis.pdf.txt
oai:openarchive.ki.se:10616/467592024-03-19T10:49:30Zcom_10616_1com_10616_180com_10616_46998col_10616_219col_10616_181col_10616_47000
Publications from KI
author
Lin, Xin-Xuan
2019-05-10T11:29:11Z
2019-05-10T11:29:11Z
2019-05-10
978-91-7831-487-4
http://hdl.handle.net/10616/46759
Aging is recognized as a major risk factor for many diseases. Thus, the identification of a means to target aging would bear great potential to improve human health and quality of life. This thesis tries to help this identification by improving our understanding of how aging is regulated, and by developing and applying new strategies to identify aging-preventive pharmaceuticals.
The transcription factor (TF) FOXO, also known as DAF-16 in Caenorhabditis elegans (C. elegans), is considered a central nexus for aging regulation. It is located downstream of the insulin/insulin-like growth factor 1 signaling (IIS) pathway, and is activated by low IIS as well as many other stresses and aging-regulatory stimuli. Studies in many model organisms have shown that DAF-16/FOXO activation not only leads to longer lifespan, but also increased stress resistance. While the mechanisms leading to DAF-16 activation and its target genes have been extensively studied, the mechanism of how DAF-16 relays aging-regulatory stimuli to activate the transcriptional response remains unclear. In paper 1, we used C. elegans to determine that DAF-16 can form a complex with HLH-30 transcription factor, a master regulator in autophagy and lysosomal biogenesis, and known to be important for longevity in C. elegans. These two TFs require each other to mediate longevity in daf-2 (low IIS mutant) and glp-1 (a germline deficient mutant whose longevity also depends on DAF-16) animals. Moreover, they co-regulate many target genes and co-occupy many promoter regions, indicating that HLH-30 plays an important role in DAF-16-dependent transcriptional responses and longevity. Interestingly, even though both TFs are important for longevity and different types of stress resistance, we found that their genetic interaction is context-dependent. They function in the same genetic pathway to cope with oxidative stress, while they act through independent pathways to cope with heat stress. Finally, we observed that they have opposing roles for dauer formation (a developmental diapause state that enables worms to survive in harsh environments). By further mechanistic exploration, we provide a model whereby DAF-16 forms a transcriptional regulatory module with HLH-30 that relays diverse distress signals to stimulate the appropriate transcriptional responses, thereby ensuring the organism’s survival.
Despite a growing understanding of how aging is regulated, we are still lacking suitable methods of screening for pharmacological interventions which, by targeting these pathways, would lead to aging-preventive effects in humans. In paper 2, we developed and applied an in silico screening method to identify aging-preventive pharmaceuticals, also known as geroprotectors. We started by building machine-learning-based algorithms using age-stratified human tissue transcriptomic data from the Genotype-Tissue Expression (GTEx) project and applied them for in silico screen from more than 1300 compounds in the Connectivity Map (CMap) database. These compounds were ranked by the likelihood of their geroprotective ability, and the best candidates were further validated in C. elegans. We found that two heat shock protein 90 (HSP90) inhibitors, monorden and tanespimycin, can improve the worms’ lifespan and healthspan. We argue that HSP90 inhibitors activate the cytosolic unfolded protein response by elevating HSP expression through the TF HSF-1 (heat shock factor 1). This in turn improves protein homeostasis, leading to cytoprotection, and ultimately better health and a longer life.
eng
info:eu-repo/semantics/openAccess
Discovering and targeting the mechanisms that govern age-related decline
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46759/3/Thesis_Xin_Xuan_Lin.pdf
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MD5
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URL
http://openarchive.ki.se/xmlui/bitstream/10616/46759/4/Thesis_Xin_Xuan_Lin.pdf.txt
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Thesis_Xin_Xuan_Lin.pdf.txt
oai:openarchive.ki.se:10616/417032022-10-25T13:17:57Zcom_10616_1com_10616_159com_10616_46998col_10616_219col_10616_160col_10616_47000
Publications from KI
author
Enervald, Elin
2013-10-04T08:33:54Z
2013-10-04T08:33:54Z
2013-10-04
978-91-7549-322-0
http://hdl.handle.net/10616/41703
Maintaining genome stability is critical to cell survival and normal cell growth and most human cancers display some form of genome instability. Genome instability is caused by multiple reasons and the ability to properly recognize, signal and subsequently repair DNA damages is crucial. DNA double-strand breaks (DSBs) are considered as the most toxic type of DNA lesion and therefore the ability to accurately repair these breaks are of outmost importance.
The cohesin complex is a large DNA-binding complex with numerous functions vital for maintaining genome integrity. The canonical role of the cohesin complex is to mediate cohesion between the sister chromatids from the time they are generated to their separation in mitosis. However, cohesin has over the years been assigned with additional functions independent on cohesion, such as regulation of gene transcription, DSB repair and activation of DNA damage checkpoints.
We have investigated the role of cohesin and its loading partner NIPBL, in the cellular responses to DSBs, using human cell cultures and budding yeast as model systems.
There are two main mechanisms used to repair DSBs, homologous recombination (HR) and nonhomologous end joining (NHEJ). More recently, a new “alternative” pathway for DSB repair has emerged, termed alternative end joining (AEJ). By studying B-cells derived from patients with Cornelia de Lange Syndrome, we have observed a strong correlation between heterozygous loss-of-function mutations in the NIPBL gene and a shift towards the use of the microhomology-based A-EJ mechanism for DSB repair during class switch recombination. Furthermore, the early recruitment of 53BP1 to DSBs was reduced in the NIPBL-deficient patient cells. Our results suggest that NIPBL plays an important role for NHEJ, potentially by regulating DNA end resection.
In budding yeast postreplicative cells, the cohesion is reactivated in response to a DSB. This reactivation includes additional Scc2-dependent loading of cohesin to the region around the DSB and formation of new cohesion, both proximal to the DSB and on undamaged areas of the genome. This phenomenon is known as damage-induced (DI) cohesion. By analyzing the role of DNA polymerase η in DI cohesion we discovered that establishment of DI cohesion at the vicinity of a DSB and on undamaged chromosomes, genome wide, are regulated differently. We concluded this based on our finding that Polη is required for genome-wide DI cohesion while it is dispensable for S phase cohesion and DSB-proximal cohesion. Cohesion establishment, both during S phase and following a DSB, depend on the acetylation activity of the highly conserved acetyltransferase Eco1. Using in vitro studies, we found that Polη is an Eco1 substrate. In addition, we provide results suggesting that Eco1 acetylation of Polη regulates its activity in DI-cohesion.
All together, these studies highlight the importance of cohesin, and its regulators, for genome stability. Future investigations, aimed at addressing the different mechanisms by which cohesin functions in the DNA damage response will most likely advance our understanding of how genome stability is maintained.
eng
info:eu-repo/semantics/openAccess
Studies of cohesin functions in the yeast and human DNA damage response
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/459142023-12-11T00:10:19Zcom_10616_1com_10616_159com_10616_46998col_10616_219col_10616_160col_10616_47000
Publications from KI
author
Yeung Wong, Maggie
2017-05-26T10:45:20Z
2017-05-26T10:45:20Z
2017-05-26
978-91-7676-734-4
http://hdl.handle.net/10616/45914
Many cells have a shorter life span than the organism itself and are continuously being replaced. However, for many cell types in the human body it is still largely unknown whether they turn over at all once development is complete. The work presented in this thesis focuses on understanding the occurrence of cell renewal in the human brain and how it may affect brain function. We further explore if the ability of cell renewal may also be affected in the diseased brain. To investigate cell turnover in the human brain we used a methodology developed in the Frisén laboratory. The developed strategy takes the advantage of the integration of the 14C (carbon-14) isotope, produced from the nuclear bomb tests during the Cold War, into genomic DNA, to determine the age of cells in humans.
In Paper I we assessed the dynamics of oligodendrocyte generation and myelination in the human brain. We found that the number of oligodendrocytes in the corpus callosum is established in childhood and remains constant thereafter. We revealed that myelin is continually exchanged, whereas white matter oligodendrocytes are remarkably stable with an annual exchange of 1 in 300 oligodendrocytes. This suggests that myelin modulation in humans may be carried out by mature oligodendrocytes. Moreover, we also found different kinetics of oligodendrocyte generation and turnover between gray and white matter, with a longer period of oligodendrocyte generation and higher turnover rate throughout life in gray matter, showing the possibility of de novo myelination in the sparsely myelinated cortex. However, how generation kinetics of the oligodendrocyte population may change under pathological conditions such as in the demyelination disease multiple sclerosis has been unknown.
In Paper II we investigated the oligodendrocyte generation dynamics in multiple sclerosis patients. We observed no induced generation of oligodendrocytes in normal appearing white matter, except in a subsets of multiple sclerosis patients with a very aggressive progression of the disease. We also revealed that oligodendrocytes in remyelination lesions were old in multiple sclerosis patients, showing that existing and not new oligodendrocytes are regenerating myelin in multiple sclerosis.
In Paper III we examined the extent of postnatal olfactory bulb neurogenesis in humans. We report that the olfactory bulb neurons are almost as old as the individuals, establishing that there is very limited, if any, postnatal neurogenesis in the human olfactory bulb.
Together the findings presented in this thesis highlight a conceptual and fundamental difference in human brain plasticity compared to other mammals.
eng
info:eu-repo/semantics/openAccess
Brain matter matters : renewal in the human brain
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/428412023-02-26T19:33:20Zcom_10616_1com_10616_192com_10616_46998col_10616_219col_10616_193col_10616_47000
Publications from KI
author
Sánchez, Fabio
2014-12-04T16:29:11Z
2014-12-04T16:29:11Z
2002-05-15
91-7349-225-6
20020605sanc
http://hdl.handle.net/10616/42841
Genetics of susceptibility to infection is a complex trait in which many factors from the host, the parasite and the environment, interact to produce different clinical manifestations of disease.
This thesis explores the relationship between the first infectious susceptibility gene ever cloned, SLC11A1 and the occurrence of intracellular infections (leprosy, leishmaniasis and HIV infection) in several populations of humans. It also demonstrates the use of an animal model as the basis for mapping new susceptibility loci for tuberculosis.
Through this work it was found that part of the effect of susceptibility to leprosy per se in Vietnamese families is under the control of SLC11A1 In addition, this gene appears to influence the immune response to the Mitsuda reaction (which indicates acquired immunity to Mycobacterium leprae) providing proof of principle that qualitative measures of immune reactivity can be mapped to particular loci in family studies. In contrast, susceptibility to leishmaniasis does not seem to be under the control of SLC11A1.
Additionally, this thesis shows that allelic variants of SLC11A1 are associated with altered risk of HIV infection.
This work also includes further analysis on previously detected susceptibility loci in the A/Sn x I/St mouse model of tuberculosis. The results of the study allow a more precise location of candidate susceptibility regions and provide evidence that gene x gene interactions can be studied in animal models of disease. We found evidence of multigenic control to severity of disease in mice, since QTLs on chromosomes 9 (tbs2), 3 (tbs1) and 17, interacted to modify the phenotype. An additional interacting locus on chromosome X (lmr3) provided support for explaining previously observed sex effects on the phenotype.
Phagocytes derived from I/Sn animals appear to have a defect in their phagocytic activity compared to cells obtained from A/Sn mice since Mycobacterium tuberculosis infected cells are more abundant and contain more bacteria in I/St mice. The defect seems to be specific of alveolar phagocytes and seems to occur early during in vitro infection experiments.
Genetic factors influencing susceptibility to intracellular infections
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/464052019-09-30T00:47:53Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Carnlöf, Carina
2018-10-08T11:03:46Z
2018-10-08T11:03:46Z
2018-10-08
978-91-7831-133-0
http://hdl.handle.net/10616/46405
Background: Women and men differ in the prevalence of arrhythmias. Furthermore, there are sex and gender differences in referral for ablation, symptom severity, health-related quality of life (HRQOL), functional impairment and response to treatment, risk factors, and outcomes.
Aim: This thesis studies sex and gender differences in referral, treatment, outcome, symptom, HRQOL, and functional impairment in patients undergoing cardiac ablation of atrial fibrillation and paroxysmal supraventricular tachycardia (PSVT).
Method: The thesis is based on four studies. Study I and II are observational prospective studies based on questionnaires before and six months after ablation. Study I include 214 (109 women) patients referred for PSVT ablation and Study II includes 242 (121 women) patients with atrial fibrillation referred for pulmonary vein isolation (PVI). The following questionnaires were used: Symptom Checklist: Frequency and Severity, Short Form 36, and Sickness Impact profile. Referral patterns and socio-economic data and symptom duration were evaluated with a separate questionnaire. In Study III, 700 patients (359 women) who had undergone AV-nodal junction (AVJ) ablation between 1990 and 2010 were retrospectively studied. Data were sampled from medical records, the Swedish ICD and Pacemaker Registry, and from the National Patient Registry kept by the National Board of Health and Welfare. Study IV was conducted with 80 (40 women) patients randomized either to an active or a standard pain treatment during PVI using cry-or radiofrequency energy. Evaluation of the two treatments strategies was assessed with a questionnaire based on the Pain-O-Meter.
Results: In Study I, although women had more PSVT symptoms, they were referred in mean six years later than the men. In addition, women more often reported they were not believed when describing their arrhythmia symptoms and were consequently more often diagnosed with stress and anxiety. In Study II, no such sex difference was found, but women were more symptomatic, assessed a lower HRQOL and a greater functional impairment than the men. Furthermore, women more often received drug treatment and were less often than men referred for cardioversion before ablation. In Study III, heart failure was present in more men than women before the AVJ ablation. When indication presented before ablation, women less often than men received implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy (CRT). There were no differences between the sexes regarding primary cause of death, and cardiovascular mortality was the most common cause of death. The main parameter influencing survival was age at the time of AVJ ablation. In Study IV, over 90% of the patients experienced pain during the PVI. Premedication and regular administration of analgesic resulted in less pain and fewer drug administration occasions. Women experienced more pain than men regardless of energy type, cryo - or radiofrequency energy.
Conclusion: All four studies showed that there were sex and gender difference in either referral, morbidity, symptom, HRQOL, functional impairment or response to treatment. Women with PSVT and atrial fibrillation were treated more conservatively than men. Women with PSVT were referred for curative ablation later than men despite having more symptoms. Symptoms due to PSVT in women were more often incorrectly diagnosed as panic attacks, stress, anxiety, or depression. Furthermore, women with atrial fibrillation were more symptomatic, assessed a lower HRQOL and a greater functional impairment but despite that, were more seldom referred for cardioversion before PVI. Women less often received CRT or ICD implantation even when indication was present before AVJ ablation. We found no sex differences regarding survival or primary cause of death after AVJ ablation. The main factor influencing survival was age at the time of ablation. Women experienced more pain than men during PVI, but an active regular supply of analgesic and sedative drugs reduced pain and discomfort during PVI in both sexes.
eng
info:eu-repo/semantics/openAccess
Sex and gender differences in patients undergoing ablation of atrial arrhythmias
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46405/3/Thesis_Carina_Carnl%c3%b6f.pdf
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Thesis_Carina_Carnlöf.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/46405/4/Thesis_Carina_Carnl%c3%b6f.pdf.txt
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Thesis_Carina_Carnlöf.pdf.txt
oai:openarchive.ki.se:10616/451162019-09-29T22:22:54Zcom_10616_1com_10616_159com_10616_46998col_10616_219col_10616_160col_10616_47000
Publications from KI
author
Almuzzaini, Bader
2016-05-02T07:30:33Z
2016-05-02T07:30:33Z
2016-05-02
978-91-7676-277-6
http://hdl.handle.net/10616/45116
In mammalian cells, actin and myosin have emerged as regulators of nuclear structure and function, involved in chromatin remodeling and histone modifications, and in different phases of gene transcription. Actin and myosin have also been shown to be incorporated into nascent ribonucleoprotein complexes. In the cell nucleus, actin undergoes regulated polymerization and this may be linked to yet unknown mechanisms of nuclear reprogramming.
The aims of this thesis were to gain further insights into the functions of actin and myosin in transcription by RNA polymerase I and II (RNAP) and how these mechanisms are regulated. We investigated, in particular, the interplay between actin and a form of myosin 1c, termed nuclear myosin 1 (NM1), which localizes to the cell nucleus. We found that NM1 interacts with the chromatin and with actin to facilitate association of the RNAP with the gene promoter and the transcription start site. At this specific location, NM1 also promotes a chromatin state compatible with transcription activation. NM1 accomplishes this by facilitating chromatin remodeling by the WICH complex, with the subunits WSTF and SNF2h, and by promoting epigenetic reprogramming. In paper I and in paper IV, we show that these mechanisms apply to both RNAP I and RNAP II transcription activation. In paper II, we show that NM1 is regulated by GSK3β through a specific phosphorylation in the NM1 C-terminus that stabilizes the interaction of NM1 with rDNA chromatin. Finally, we show in paper III that knocking down the β-actin gene has a negative effect on transcription by RNAP I, which leads to a delay in cell cycle progression and defects in cell growth and proliferation.
eng
info:eu-repo/semantics/openAccess
Actin and myosin in transcription and chromatin regulation
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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Thesis_Bader_Almuzzaini.pdf.txt
oai:openarchive.ki.se:10616/469612024-03-15T19:38:48Zcom_10616_1com_10616_213com_10616_46998col_10616_219col_10616_214col_10616_47000
Publications from KI
author
Torbjörnsson, Eva
2020-01-09T10:27:15Z
2020-01-09T10:27:15Z
2020-01-09
978-91-7831-619-9
http://hdl.handle.net/10616/46961
Critical limb ischemia is the end stage of peripheral arterial disease. These patients have a high risk of amputation and death regardless of revascularization. One of the most important questions for the patient and the surgeon is the risk of amputation despite a revascularization attempt. Some patients with poor vascular anatomy may be better served by a primary below knee amputation than by a high-risk revascularization procedure. Furthermore, patients with critical limb ischemia that undergo an amputation have a high risk of stump complications and re-amputation. An amputation below knee is associated with more complications related to wound healing than an above knee amputation. On the other hand, a patient with an amputation below knee has a 50% higher chance to learn to walk compared to those having an above-knee amputation.
Mobility has been found to be an important factor for the patient´s Health-Related Quality of Life after an amputation. However, the association between mobility, use of prosthesis and perceived Health-Related Quality of Life among those amputated due to peripheral arterial disease is largely unknown. Furthermore, knowledge regarding the patients´ experience of the amputation decision and the first time after an amputation is sparse. Most of the performed studies consist of patients referred to a rehabilitation ward, resulting in a selection of healthier patients. As patients amputated due to peripheral arterial disease are older with significant co-morbidities, transferring results from studies of populations with trauma or cancer as indication is problematic.
The overall aims with this thesis was to study patient-related risk factors for amputation and re-amputation in patients revascularized for critical limb ischemia and to enhance the knowledge regarding the use of prosthesis, its impact on the patients’ perceived Health-Related Quality of Life, and their experience of having had an amputation. Paper I assessed risk factors for amputation in 855 patients amputated after a revascularization due to critical limb ischemia. It was a population-based cohort study using data from the Swedvasc Registry in 2009-2013 with follow-up data until 2017. Risk factors for amputation were assessed using a competing risk analysis and compared to a Cox’s proportional-hazards regression. Age (subdistribution hazard ratio [sub-HR], 0.98; confidence interval [CI], 0.97-1.00), preoperative ambulatory status (independent versus bedridden) (sub-HR, 4.10; CI, 2.14-7.86) and ischaemic wound versus rest pain (sub-HR, 3.03; CI, 1.72-5.36) were associated with an increased risk in the analysis using competing risk regression. In comparison, in the analysis using Cox regression, female versus male sex (hazard ratio [HR], 0.77; CI, 0.64-0.94), age (HR, 1.02; CI, 1.01-1.03), renal impairment (HR, 2.08; CI, 1.61-2.67), preoperative ambulatory status (independent versus bedridden) (HR, 3.45; 2.30-5.18) and ischaemic wound versus rest pain (HR, 2.41; CI, 1.78-3.25) were risk factors associated with an increased risk for amputation. Paper III was a prospective cohort study of 98 patients undergoing a major amputation due to peripheral arterial disease 2014-2018. The patients were included at the hospital in connection with their amputation. An interview regarding the patients’ functional level the week before the amputation as well as an assessment of Health-Related Quality of Life using the EQ-5D-3L questionnaire was performed at baseline. At the one-year follow-up a semi-structured interview by telephone was performed. Health-Related Quality of Life was measured using the EQ-5D-3L questionnaire. Prosthesis use and prosthesis wearing habit were evaluated using the Stanmore Harold Wood mobility scale and the Houghton scale. Out of the 73 patients that completed the one-year follow-up, 23 were classified as walkers. All patients had an increased Health-Related Quality of Life at follow-up in comparison to their baseline measure. The largest difference in EQ-5D-3L value index was in the group that walked with a prosthesis, 0.12 (IQR =0.09-0.36) at baseline compared to 0.78 (IQR=0.52-0.82) at follow-up, p<.001. Paper IV was an interview study of 13 patients who had undergone a major amputation due to peripheral arterial disease. The interviews were analyzed using content analysis and resulted in three themes: “From irreversible problem to amputation decision”, “A feeling of being in a vacuum” and “Adaptation to the new life”. The patients expressed a feeling of lack of knowledge of the process after the amputation and what to expect in the future. They did not feel that the healthcare givers had taken enough time to explain the whole process to them. Even so, the patients felt satisfied with their amputation decision, and some expressed that the decision should have been made earlier.
In conclusion: There is a risk for biased estimates using standard survival methods in cahoots with a high mortality. A competing risk regression that takes the competing event of death into account may improve the prediction of the actual risk of amputation. Patients with ischemic pain as indication for their amputation have a high risk of a re-amputation. Prosthesis use is important for the patients’ perceived Health-Related Quality of Life. Patients who walked or were able to use their prosthesis for independent movement had an increased level of Health-Related Quality of Life at follow-up compared to baseline. The patients need more information regarding the whole process of the amputation in order to increase their feeling of being involved in the care. To reduce unnecessary suffering and increase the patient´s Health-related Quality of Life, amputation may be presented earlier in the process as a treatment alternative.
eng
info:eu-repo/semantics/openAccess
Major lower limb amputation in peripheral arterial disease : treatment outcome, risk factors, and health-related quality of life
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/425212022-10-16T10:13:11Zcom_10616_1com_10616_153com_10616_46998col_10616_219col_10616_154col_10616_47000
Publications from KI
author
Bucinskaite, Violeta
2014-12-04T16:28:50Z
2014-12-04T16:28:50Z
2000-11-17
91-628-4343-5
20001208buci
http://hdl.handle.net/10616/42521
Defence mechanisms involve close interactions between the nervous and immune systems following an immune challenge. The vagal pathways which modulate major visceral functions under normal conditions are also important neural pathways for the transmission of information on peripheral conditions to the CNS. The aim of this thesis was to investigate the effects of CCK-8 and IL-1[beta] on gastric vagal afferent (VA) and vagal efferent (VE) activity, including the involvement of specific CCK receptors, in conditions of partial or total vagotomy. To this purpose the mass nerve activity of the vagus nerve was recorded by bipolar platinum wire electrode in anaesthetised rats. Drugs were applied either intravenously (i.v.) or into the cisterna magna (i.c.m.).
The effect of 1 nmol (bolus dose) i.v. of CCK-8 on VA activity recorded before and 2 hours after the injection of 2-4 [my]g·kg-1 IL-1[beta] was augmented by 183 ± 14 to 255 t 27 %, with shortening of the main latency of the response. This demonstrates that the response of visceral afferents to CCK-8 was sensitized by IL-1[beta] which may be one of the peripheral mechanisms of cytokine-induced anorexia.
The effect of CCK-8 on VE activity was more pronounced in conditions of partial than with total vagotomy (decrease to 28 ± 6 % vs 56 ± 2 % 30 s after I nmol) and could be blocked by the CCKA antagonist, L- 364,718 (10-100 x 10-6 g i.v. or I X 10-6 g i.C.M.) but not by CCKB antagonist, L-365,260. This shows that only the CCKA receptors are involved in the reflex inhibition of gastric VE activity in conditions of partial and total vagotomy.
OLETF rats, an animal model for NIDDM (non-insulin-dependent diabetes mellitus) and obesity, congenitally lack CCKA receptor gene expression. VA of OLETF rats were sensitive to CCK-8 (3 nmol·kg-1 i.v.) and the response was not abolished by L-365,260. Contribution of novel (non-CCKA, non-CCKB) receptors in the response of the VA to CCK-8 in OLETF rats was implicated. The effect of IL-1[beta] (2 [my]g·kb-1 on the VA activity in OLETF rats was more pronounced than in the control strain, possibly demonstrating one of the mechanisms of augmented illness responsiveness in obese individuals.
The effect of IL-1[beta] on VE activity was dependent on the integrity of vagal afferents. A dose which did not activate VA (1 [my]g·kg-1 induced a decrease in VE activity in partly vagotomized animals. This effect was diminished by pre-administration of indomethacin (5 mg.kg-1) or by total subdiaphragmatic vagotomy.
In summary, our results show that both subdiaphragmatic vagal afferents and efferents are involved in responses to exogenous IL-1[beta] and CCK-8. Altered sensitivity of vagal pathways may be important in the development of illness responses in both normal and obese individuals.
Neuro-immune communication: role of the vagus nerve : an electrophysiological study
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/377562022-11-06T01:37:54Zcom_10616_1com_10616_162com_10616_46998col_10616_219col_10616_163col_10616_47000
Publications from KI
author
Skillgate, Eva
2010-10-21T20:27:30Z
2010-10-21T20:27:30Z
2007-11-16
978-91-7357-405-1
20071207skil
http://hdl.handle.net/10616/37756
Introduction: Back and neck pain are common and constitute the main cause for persistent pain in the population. The knowledge about the etiology and about the effect of different treatments that are offered for back and neck pain is not fully understood, with a few exceptions.
Objectives: The overall aim was to give epidemiological aspects of some potential risk factors for back and neck pain, as well as on manual treatment of such pain. Objectives in Studies I and II were to expand the knowledge about life events and coping style, and how they affect the risk of low back and/or neck/shoulder pain. In Study III, the objective was to investigate how smoking and alcohol consumption, respectively, affect the risk of long-term sick leave due to back and/or neck pain. The objective in Study IV was to evaluate the effects of the in Scandinavia commonly occurring naprapathic manual therapy for patients with non-specific pain in the back and/or neck.
Materials and Methods: Studies I and II are based on the population-based MUSIC-Norrtälje case-control study that comprised men and women 20-59-years-old, living in and not working outside a municipality in Sweden. Cases (n=1,148) were subjects from the study base who sought care for a new episode of low back and/or neck/shoulder pain during the study period 1993-1997. Controls (n=1,700) were selected as a stratified random sample from the study base with consideration taken for sex and age. Life events and critical life changes were measured by semi-structured interviews, and the coping style was measured with a questionnaire. Study III is based on the HAKuL-Study, a three-year prospective cohort study. New periods of sick leave (> 28 days) due to back and/or neck pain were consecutively reported during three years from baseline, among 6,532 persons that in questionnaires at baseline had reported on their smoking and alcohol habits. Study IV is based on the BJÖRN-Trial, a randomized controlled trial with 409 patients with non-specific back and neck pain. The interventions compared were naprapathy, including spinal manipulation/mobilization, massage and stretching (Index Group), and support and advice on staying active and on pain coping strategies, according to the best scientific evidence available, provided by a physician (Control Group). Questionnaires were mailed to all participants after 3, 7 and 12 weeks, and the two groups were compared using the intention to treat principle.
Results and conclusions: Having experienced at least two life events or critical life changes during the preceding five years was associated with an increased risk of neck/shoulder pain. A covert coping style was more common among women and was associated with an increased risk of neck/shoulder pain among women, but not among men. In general, no associations were observed in relation to the risk of low back pain. An interaction effect between a covert coping style and psychosocial stress was observed among women (Studies I and II). Regarding the risk of long-term sick leave due to back and neck pain, smoking involved an increased risk, whereas alcohol consumption tended to involve a decreased risk (Study III). Naprapathic manual treatment were statistically and clinically significant more effective than evidence-based advice on staying active and on pain coping strategies for non-specific back and neck pain, after 7 and 12 weeks (Study IV).
eng
info:eu-repo/semantics/openAccess
Back and neck pain : epidemiological studies on some risk factors and treatments, including naprapathic manual therapy
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/37756/1/thesis.pdf
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thesis.pdf.txt
oai:openarchive.ki.se:10616/431312022-09-15T20:43:53Zcom_10616_1com_10616_186com_10616_46998col_10616_219col_10616_187col_10616_47000
Publications from KI
author
Larsson, Kajsa
2014-12-04T16:29:30Z
2014-12-04T16:29:30Z
2003-12-26
91-7349-735-5
20040116lars
http://hdl.handle.net/10616/43131
Since the start of treatment with allogeneic haematopoietic stem cell
transplantation (SCT), cytomegalovirus (CMV) has been one of the most
feared complications. With the help of different CMV-protective
strategies, the frequency of CMV-disease before day 100 after SCT has
decreased to 4-6%. The cost is an over-treatment with antiviral compounds
and the development of new types of problems. These studies were
undertaken to describe how the modern treatment modalities have changed
the pattern of CMV-related complications after SCT.
In a study of 584 consecutive allogeneic SCT patients, the overall
probability for CMVdisease was 8.9%, and the risk for death in
CMV-disease 5.7%. The risk varied depending on CMV-serologies in donors
and recipients. Unrelated or mismatched family donors and recipient
CMV-seropositivity were risk factors for both CMV-disease and CMV-related
death. In the models excluding low-risk patients, the use of preemptive
CMV-strategy was a protective factor against CMV-disease and CMV-related
death. Transplant related mortality (TRM) and overall mortality were also
significantly reduced with the preemptive treatment strategy against CMV.
Analyzing data on 262 consecutive patients, transplanted with
HLA-identical sibling donors and surviving more than three months after
SCT, the use of preemptive treatment strategy against CMV was the only
factor that significantly decreased the risk for extensive chronic GVHD.
The antiviral treatment that was actually given on the basis of
preemptive strategy was significantly associated to a decreased risk for
moderate to severe chronic GVHD.
In a study on 21 patients treated with allogeneic SCT due to malignant
disease, a persistent HHV-6 infection and a higher HHV-6 viral load
significantly increased the risk for an impaired recovery of the
CMV-specific lymphocyte proliferation, and for the need of several
courses with preemptive antiviral treatment against CMV, as did acute
GVHD grades II-IV. Unfortunately the number of cases was too small for an
adequate multivariate risk factor analysis.
CMV-retinitis (CMVR) has previously been a rare complication after SCT.
In a European multicentre study on 30 patients developing CMVR after SCT,
it was shown that 1.2% of all patients transplanted at the participating
centres after 1996 developed CMVR, and that the complication had become
almost four times more common during that period. Three cases of CMVR
were seen after autologous SCT, the rest after allogeneic SCT, in whom
fourteen were performed with alternative donors and nine with T-cell
depleted grafts. 23/27 allogeneic SCT patients (85%) were on
immunosuppressive treatment at time for the diagnoses, 18/23 (78%) on
regimens containing corticosteroids. CMVR was a late occurring
complication, with the median time of diagnosis being 145 days after SCT,
(range 19-537). Its clinical features were the same as in AIDS-patients,
and the outcome was poor, with 18/25 evaluable patients (72%) ending up
with decreased vision.
A risk factor analysis for development of CMVR was performed in 27
allogeneic SCTpatients transplanted after 1990 at twelve European centres
and the Fred Hutchinson Cancer Centre in Seattle, Washington. The risk
factors found were CMV-negative donor and CMVpositive recipient, and
antiviral prophylaxis against CMV after SCT.
In conclusion, these studies have shown that the preemptive treatment
strategy against CMV has decreased the risk for CMV-disease and
CMV-related death after SCT, as well as the risk for extensive chronic
GVHD. A persistent HHV-6 infection and a high HHV-6 viral load have been
identified as new possible risk factors for an impaired recovery of the
CMV-specific immunity. CMVR has become four times more common after 1996, and risk factors for its development were CMV-negative donor,
CMV-positive recipient, and the use of antiviral CMV-prophylaxis.
Cytomegalovirus after allogeneic haematopoietic stem cell transplantation : complications in the era of CMV-specific antiviral treatment
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/419112023-10-31T21:52:20Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Jahnmatz, Maja
2014-05-02T10:59:59Z
2014-05-02T10:59:59Z
2014-05-02
978-91-7549-458-6
http://hdl.handle.net/10616/41911
Despite years of vaccination efforts, whooping cough, or pertussis, is not under control. Although immunization has greatly reduced the disease incidence, thousands of children die of whooping cough each year. Therefore, there is an urgent need to improve the available vaccines as well as our understanding of the immunological mechanisms required for optimal protection against pertussis. The focus of this thesis was on B-cell responses after pertussis vaccination within the scope of two clinical trials.
The B-cell ELISpot protocol was optimized to ensure sensitive detection of B-cell responses. In paper I, the superiority of the novel protocol was demonstrated with regard to B-cell activation, detection sensitivity, antigen consumption, and assay time in comparison to an established protocol.
The first trial evaluated the safety and immunogenicity of a novel live, attenuated, whole-cell vaccine named BPZE1 in a phase 1 clinical setting (reported in papers II and III). This vaccine strain is genetically modified and is designed for intranasal administration and a subsequent nonpathologic infection in the immunized subjects. The second trial was a phase 4 booster study of a fifth consecutive dose of an acellular pertussis vaccine in adolescents. Memory B-cell and serological responses are reported in paper IV. In both studies, strong serological and B-cell responses were detected with ELISA and ELISpot. Colonization was crucial for the BPZE1 study, whereas both antigen content and concentration influenced the responses in the booster study.
Immunity against pertussis is still not fully understood. Evaluating several parameters of the immune response will give a better understanding of the immunological activities following pertussis infection or vaccination. More knowledge will enable better vaccines and contribute to the control of pertussis.
eng
info:eu-repo/semantics/openAccess
B-cell responses after pertussis vaccination
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

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protected against changes by unauthorised persons, e.g. by 
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as expressly stated in this Agreement.

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making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

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may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

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Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
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berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

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som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

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på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

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publicerade texter eller för Författarens agerande i övrigt.
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reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/419992022-11-01T00:55:33Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Fowler, Åsa
2014-05-05T09:34:13Z
2014-05-05T09:34:13Z
2014-05-05
978-91-7549-507-1
http://hdl.handle.net/10616/41999
Acute encephalitis is relatively uncommon but potentially devastating. The prognosis varies from complete recovery to severe sequelae or death. The diagnosis is difficult to establish and the etiology often remains unclear. Furthermore, the long-term prognosis of acute encephalitis in children is poorly described and prognostic markers in the acute phase are lacking. In this thesis, the aim was to characterize acute encephalitis in childhood in regard to etiology, clinical presentation and long-term outcome. Another aim was to study biomarkers in CSF of children with TBE and to identify markers predicting the long-term outcome.
Methods: We retrospectively studied the medical records of all children with acute encephalitis at Astrid Lindgren Children´s hospital in Stockholm during 2000–2004 (study I). This cohort was followed-up 3-8 years later using 2 questionnaires grading persisting symptoms and every day functioning. Seventy-one children were eligible for the follow-up (study II). In study III, 55 children with TBE in 2004-2008 were evaluated 2-7 years later. Two questionnaires were used grading persisting symptoms and executive functioning in everyday life. General cognitive ability was also investigated in a subgroup, using WISC-IV. In study IV, cytokines, chemokines and markers of neuronal damage were analyzed in CSF samples from 37 children with TBE in 2004-2010, using a multiplex assay.
Results: The etiology of childhood encephalitis was dominated by TBE, EV, VZV, influenza virus and RSV, but remained unknown in 52% of cases. Fever and encephalopathy were present in a majority of the children, seizures or focal neurological deficits were seen in 40%. EEG-examinations were pathological in 90%, and 55% of the children with acute encephalitis had pleocytosis. There were no mortalities, but 60% of the children had persisting symptoms at the time of discharge. In the long-term follow-up, persisting symptoms were reported by 54%, both in children with and without symptoms at discharge. Cognitive problems and personality changes were the dominating complaints. No other prognostic marker than the severity of the encephalitis leading to admission to the PICU was found. All children with encephalitis who made a full recovery did so within 6 to 12 months. In the acute phase of TBE, fever and headache were present in nearly all children, whereas seizures and focal neurological findings were less frequently seen. Nearly half of the children with TBE were classified as meningitis and the clinical picture were in these cases often unspecific and symptoms of CNS involvement vague. All children with TBE had pleocytosis. At follow-up, 69% experienced persistent problems; headache, fatigue and cognitive problems dominated. On more detailed tests of cognitive functions, problems with working memory and executive functioning were seen both in children with mild and with severe symptoms in the acute phase. In TBE, children with problems at follow-up had significantly higher levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF than children with a good outcome. Markers of neuronal damage did not discriminate between children with good or poor outcome.
Conclusion: We conclude that the etiology of encephalitis among Swedish children is at large the same as in other European countries endemic for TBE. EEG examination and analysis of CSF are essential for diagnosing CNS involvement, especially since CNS symptoms may be vague. Persisting symptoms were present in a substantial number of children at long-term follow-up, cognitive problems, headache, personality changes and fatigue dominated. The clinical picture in the acute phase cannot be used to predict outcome. In TBE, high levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF might indicate a risk of incomplete recovery. All children with acute encephalitis or TBE should be offered follow-up evaluations in order to detect long-term sequelae.
eng
info:eu-repo/semantics/openAccess
Acute encephalitis in childhood : clinical characteristics and outcome with special reference to tick-borne encephalitis
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/381862023-02-27T00:04:28Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Imreh, Marta P
2010-10-21T20:28:42Z
2010-10-21T20:28:42Z
2002-03-22
91-7349-171-3
20020412imre
http://hdl.handle.net/10616/38186
The aim of the study was to investigate the interplay of cellular and viral genes in Epstein-Barr virus (EBV) infected cells. Two aspects of this interaction have been investigated. The first aspect is related to the expression of major histocompatibility complex (MHC) class I molecules in virus infected malignant cells. MW class I expression plays a key role in the regulation of immune responses and is frequently altered in human tumors. We analyzed the mechanisms of this MW class 1 downregulation in Burkitt's lymphomas (BLs) that arise in HLA. All positive individuals by comparing five pairs of BL lines and Epstein-Barr virus (EBV) transformed lymphoblastoid cell lines (LCL) derived from the normal B cells of the same individuals. The cell lines were compared for the presence of HLA A11 gene and A11-specific mRNA, the reactivity to IFN-alpha treatment, the restoration of HLA All expression by transfection or hybridization, the activity of HLA All promoter driven chloramphenicol acetyl transferase reporter gene (pA l 1 CAT). Our results suggest that genetic defects and lack of transcription factors may contribute to the selective down- regulation of HLA AI 1 in BL cells. Furthermore we analysed the involvement of EBV LMP1 in the process. The BL phenotype-dependent transcriptional defect observed for the HLA AI 1 promoter was shown to involve other WC class I promoters including HLA A2. Since the virus LMP1 was shown to be mainly responsible for changing the phenotype of BL cells towards LCL-like characteristics, we have tested how the class I promoter activity is affected by expression of LMP1. We can conclude, that expression of LMP1 correlates with activation of the HLA All promoter and up-regulation of several components of the transcription factor family NF-kappa-B/Rel.
The second aspect of this thesis deals with viral strategies that promote escape from immune recognition. EBNA1 is expressed in all EBV associated malignancies and is the only viral protein expressed in BL. Endogenously expressed EBNA1 is not recognized by MHC class P restricted CTLs. This phenomenon is correlated with the presence of an internal glycine- alanine repeat (GAr) in the structure of the protein. The GAr generates a cis-acting inhibitory signal that interferes with antigen processing and MW class I restricted presentation by inhibiting the generation of antigenic peptides by ubiquitin-proteasome/dependent proteolysis. The mechanism of action of the GAr was investigated using as model a known target of the ubiquitin-poteasome system, the NF-kappa-B inhibitor I-kappa-B-alpha. Insertion of a minimal GA repeat of eight amino acids in different positions of I-kappa-B-alpha was sufficient to prevent tumor necrosis factor (TNF-alpha) induced ubiquitin-proteasome dependent degradation, and decrease its basal turnover in vivo. The chimeras are phosphorylated and ubiquitinated in response to TNF-alpha but than released and failed to associate with the proteasome. This explains how functionally competent I-kappa-N-alpha is protected from proteasomal disruption and identifies the GAr as a regulator of proteolysis. The analysis of the impact of length and amino acid composition on the capacity of various repeat sequences to inhibit the TNF-alpha-induced and physiological turnover of I-kappa-B-alpha demonstrated that inhibition is achieved by insertion of octamer peptides containing 3 hydrophobic amino acids, interspersed by no more then three consecutive glycines. The inhibitory activity was abolished by increasing the length of the spacer to four glycines, by elimination of the spacers, or by substitution of a single hydrophobic residue with a polar or charged residue. These findings suggest a model where inhibition of proteolysis requires the interaction of at least dime alanine residues of the GAr in a beta-strand conformation with adjacent hydrophobic binding pockets of a putative receptor.
The multifunctional EBNA1 protein is involved also in the replication of the EBV genome as an extra chromosomal element, and plays important role in the maintenance of the viral episome and is the key transcriptional regulator of latent viral gene expression including its own transcriptional regulation. We have investigated whether presence of the GAr modulates the functions of EBNA1. The GAr containing EBNA1 protein has an extremely slow turnover in virus infected cells while a GAr deleted EBNA1 is degraded by the ubiquitin-proteasome system. To assess the contribution of protein stability on EBNA l functions, destabilized variants were generated and studied for their capacity to promote the maintenance of oriP containing plasmids and regulate the viral Qp promoter. Both functions were strongly influenced by EBNA1 stability suggesting the GAr plays an important role in modulating the function of EBNA1 in virus infected cells.
eng
info:eu-repo/semantics/openAccess
Modulation of cellular and viral functions in Epstein-Barr virus infected cells
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/38186/1/thesis.pdf
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thesis.pdf.txt
oai:openarchive.ki.se:10616/478632024-01-04T15:09:35Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Li, Danyang
2022-02-03T11:14:16Z
2022-02-03T11:14:16Z
2022-02-03
978-91-8016-459-7
http://hdl.handle.net/10616/47863
Neurodevelopmental disorders (NDDs) are a group of conditions appearing in childhood, with developmental deficits that produce impairments of functioning. Autism spectrum disorder (ASD) is a common NDD with a high heritability affected by complex genetic factors, including both common and rare variants. Behavior interventions such as social skills group training (SSGT) have been widely used in school-aged autistic individuals to relieve social communication difficulties in a group setting. Studies have confirmed that intervention outcomes can be influenced by sex and age, but how the genetic risk contributes to the outcome variability remains elusive. Furthermore, although large population cohorts have been well studied and have found numerous genes associated with ASD and NDDs, the molecular and neuronal outcomes of risk variants and genes are unclear. Therefore, this thesis included four studies in which the effects of genetic factors on intervention outcomes and cellular level neuronal functions were investigated.
Results from this thesis may provide a genetic perspective for further studies to explore potential individualized treatments for ASD and other NDDs. Specifically, in STUDY 1-3, exome sequencing and microarray were performed on individuals from a randomized controlled trial of SSGT (KONTAKT®). Common and rare variants, including copy number variations (CNVs) and exome variants, were tested for association effects with SSGT and standard care intervention outcomes. Polygenic risk scores (PRSs) were calculated from common variants, and clinically significant rare CNVs and rare exome variants were prioritized. Molecular diagnoses were identified in 12.6% of the autistic participants. PRSs and carrier status of clinically significant rare variants were associated with intervention outcomes, although with varied effects on both SSGT and standard care. In addition, genetic scores representing variant loads in specific gene sets were obtained from rare and common variants in ASD-related pathways. Outcomes of interventions were differentially associated with genetic scores for ASD-related gene sets including synaptic transmission and transcription regulation from RNA polymerase II. After combining genetic information and behavior measures, a machine learning model was able to select important features and confirm that the intervention outcomes were predictable. In STUDY 4, genetic variants affecting Calcium/Calmodulin Dependent Serine Protein Kinase (CASK) gene, a risk gene for NDDs, were examined using human induced pluripotent stem cell-derived neuronal models to identify the cellular effects of these mutation consequences. CASK protein was reduced in maturing neurons from mutation carriers. Bulk RNA sequencing results revealed that the global expression of genes from presynaptic development and CASK network were downregulated in CASK-deficient neurons compared to controls. Neuronal cells influenced by CASK mutations showed a decrease of inhibitory presynapse size and changed excitatory-inhibitory (E/I) balance in developing neural circuitries.
In summary, this is the first study to investigate the association of genome-wide rare and common variants with ASD intervention outcomes. Differential variant effects were found for individuals receiving SSGT or standard care. Future studies should include genetic information at different levels to improve molecular genetic testing for diagnoses and intervention plans. Presynapses and E/I imbalance could be an option to be developed for the treatment of CASK-related disorders.
eng
info:eu-repo/semantics/openAccess
Genetic implications of individual intervention and neuronal dysfunction in neurodevelopmental disorders
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/47863/1/Thesis_Danyang_Li.pdf
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oai:openarchive.ki.se:10616/458872019-09-29T21:03:52Zcom_10616_1com_10616_165com_10616_46998col_10616_219col_10616_166col_10616_47000
Publications from KI
author
Tolf, Sara
2017-08-24T11:31:51Z
2017-08-24T11:31:51Z
2017-08-24
978-91-7676-781-8
http://hdl.handle.net/10616/45887
Introduction: The marketization of public health care, with its focus on choice and
competition, challenges hospital managers to take a market-oriented perspective and position.
A combination of lean and agile management strategies has been suggested as a way to
achieve efficiency and control costs (lean) and to respond flexibly (agile).
Aim: To increase our understanding of how hospital managers can combine lean and agile
management strategies as they face the challenges of choice and competition in public health
care.
Method: The thesis consists of four studies: an integrative literature review and three case
studies conducted at two Swedish hospitals. Study I reviews the empirical and theoretical
literature on the use of agile strategies in relationship to lean strategies. The specific focus is
how these strategies can be combined in hospital management. Study II is a case study of a
hospital that followed “operational plans” as it tried to decrease patient waiting times. Study
III is a case study of a hospital management team’s drivers and conceptualizations of lean and
agile strategies related to expected outcomes. Study IV, which is a case study of the same
hospital investigated in Study III, examines the mechanisms that enabled the hospital’s
management team to use the lean and agile strategies in practice.
Findings: Study I shows that agile was portrayed as a new paradigm following lean, as a
development of lean, or as a strategy that can be used in combination with lean. Unlike lean
strategies, agile strategies focus on the management of the external environment using
proactive, reactive, or embracive coping strategies. The study also examines various
organizational capabilities that hospitals require in order to make optimal use of agile
strategies. Study II finds that “operational plans” at various organizational levels were needed
in order to operationalize the goal of decreasing patient waiting times. The study also finds
that an aligned internal strategy can improve processes that span organizational boundaries
although with a narrow production focus. Study III finds that sudden and unexpected political
public health care policies and market pressure motivated a hospital management, already
lean in operations, to look for ways to increase their agility. Agility in the study is
conceptualised as the long-term capability for adapting to the environment and for managing
budget reductions. Lean was understood as the ability of the hospital to perform its functions
efficiently. Enablers were defined as the management’s ability to continuously react to
changes, to alter work assignments to accommodate changes in the influx of patients, and to
recruit employees with flexible work skills. Study IV finds that the mechanisms that help a
hospital to become lean and agile in practice are management’s market-orientation, the use of
established production processes, an organization-wide readiness for change, a rapid
transition capability, and the flexible use of physical and human resources.
Discussion: Hospitals in uncertain and dynamic environments (as is typically the case for
hospitals) needs to be both lean and agile. In combination, these two strategies help hospital
management to use existing resources efficiently and effectively while at the same time it
allows discovery of other assets.
Conclusion: Lean management may be viewed as a precondition for agile management. This
means that the use of efficient and structured (lean) resources can improve market orientation
and positioning (agile). To successfully combine lean and agile activities, hospital managers
need to exhibit certain ambidextrous and dynamic effective management capabilities
eng
info:eu-repo/semantics/openAccess
Lean, agile, and lean and agile hospital management : responses to introducing choice and competition in public health care
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/485772024-03-08T15:16:47Zcom_10616_1com_10616_213com_10616_46998col_10616_219col_10616_214col_10616_47000
Publications from KI
author
Awad, Akil
2023-03-31T14:05:09Z
2023-03-31T14:05:09Z
2023-03-31
978-91-8016-936-3
http://hdl.handle.net/10616/48577
Background: Cardiovascular disease, and in particular cardiac arrest with the subsequent associated brain injury, is the most common cause of death in many countries. Annually, around 6000 people suffer from Out-of-Hospital Cardiac Arrest (OHCA) in Sweden and only around 10% survive to hospital discharge. Apart from early cardiopulmonary resuscitation (CPR) and defibrillation, it has been difficult to find interventions that can increase survival in OHCA, in particular in the post-resuscitation phase.
Methods and results: Study I. A national observational retrospective study, evaluating the adherence to Targeted Temperature Management (TTM) guidelines in Sweden after the publication of the TTM trial, and if the change in targeted temperature level (from 33 oC to 36 oC) influences 6-month survival. In total, 2899 OHCA patients were included, and of those, 1038 were treated by means of TTM. The proportion of patients with initial shockable rhythm receiving any TTM, i.e., following international guidelines, decreased after publication of the TTM trial (from 70.5% to 54.5%). There was no difference in 6-month survival between the TTM33 (47.2%) and the TTM36 (47.3%) groups (adjusted odds OR 1.12, 95% CI 0.80–1.56).
Study II. A sub-analysis of the PRINCESS trial, in which 677 OHCA patients were randomized to trans-nasal intra-arrest cooling initiated by the emergency medical services (EMS) or cooling started after hospital arrival. In this sub-analysis, the association between early initiation of intra-arrest cooling and neurological outcome was evaluated. Early cooling (intervention group, n=150) was defined as cooling initiated ≤ 20 minutes from collapse, and these patients were propensity score-matched with comparable controls (n=150). The primary outcome was survival with good neurological outcome (defined as Cerebral Performance Category [CPC] 1–2) at 90 days. The proportion of cases with CPC 1–2 at 90 days was 23.3% in the intervention group vs. 16% in the control group (OR 1.92, 95% CI 0.95–3.85). In patients with shockable rhythm the corresponding figures were 50.9% (intervention) vs. 29.8% (control) (OR 3.25, 95% CI 1.06–9.97).
Study III. A nationwide observational retrospective study, evaluating the association between different levels of hyperoxemia at Intensive Care Unit (ICU) arrival after cardiac arrest, and 30-day survival. Partial oxygen pressure (PaO2) was recorded in a standardized way at ICU admission (± one hour). Hyperoxemia was defined as mild (13.4–20 kPa), moderate (20.1–30 kPa), severe (30.1–40 kPa) or extreme (>40 kPa). Normoxaemia was defined as PaO2 8–13.3 kPa and hypoxemia as PaO2 <8 kPa. In total, 9735 patients were included. Of these, 44.6% were hyperoxemic, 44.8% were normoxaemic and 10.5% were hypoxemic. Compared with the normoxemia group, the adjusted risk ratios (RRs) for 30-day survival in the hyperoxemia groups were: mild 0.91 (95% CI 0.85–0.91), moderate 0.88 (95% CI 0.82–0.95), severe 0.79 (95% CI 0.7– 0.89), and extreme 0.68 (95% CI 0.58–0.79).
Study IV. A post-hoc analysis of the TTM2 trial, in which 1900 resuscitated OHCA patients were randomized to either hypothermia (TTM of 33 oC) or normothermia (<37.8 oC) groups for 28 hours. This sub-analysis was carried out to evaluate if there is any association between the cooling method used, i.e., intravascular (IC) vs. surface cooling (SFC), in the TTM 33oC group, and neurological outcome. The primary outcome was survival with good neurological outcome (defined as modified Rankin scale [mRS] result of 0–3) at six months. In total, 876 patients were included in this study, in which 30% were treated by means of IC and 70% by SFC. At six months, after propensity score matching, 53.0% of the patients in the IC group and 42.3% of the patients in the SFC group were alive, with mRS scores of 0–3 (OR 1.5, 95% CI 1.05–2.15). The IC group demonstrated better cooling speed and precision compared with the SFC group.
Conclusions: After publication of the TTM trial, fewer OHCA patients in Sweden received any TTM and this change of practice did not affect six-month survival among patients who underwent TTM. In the PRINCESS trial, intra-arrest cooling started within 20 minutes of arrest, compared with cooling started after hospital admission, was not associated with a significantly better neurological outcome. In the subgroup with shockable rhythms, early cooling was associated with better neurological outcome. Among resuscitated OHCA patients, hyperoxaemia at ICU admission, compared with normoxemia, was associated with lower 30-day survival. The association was stronger in connection with higher PaO2 levels. In OHCA patients in the TTM2 trial treated by means of TTM 33 oC, intravascular cooling, compared with surface cooling, was associated with better cooling performance and better neurological outcomes after six months.
eng
info:eu-repo/semantics/openAccess
Aspects of intensive care after cardiac arrest
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/392632023-10-26T13:21:22Zcom_10616_1com_10616_177com_10616_46998col_10616_219col_10616_178col_10616_47000
Publications from KI
author
Rosenberg, Lena
2010-10-21T20:31:35Z
2010-10-21T20:31:35Z
2009-08-21
978-91-7409-561-6
20090911rose
http://hdl.handle.net/10616/39263
The general aim of this thesis was to increase knowledge about people with MCI or dementia and their significant others, particularly as users of everyday technology and assistive technology (AT). The overall aim included increasing knowledge about the interactions between people with MCI or dementia and their significant others, and technology.
In Study I the psychometric properties of the Everyday Technology Use Questionnaire (ETUQ), when used with older adults with and without cognitive deficits, were investigated using the Rasch rating scale model. Study II compared the perceived relevance of and difficulty in using everyday technology, measured with the ETUQ, in people with mild-stage dementia, people with MCI, and older adults without known cognitive impairment, using one-way ANOVA analyses. In Study III, actions and driving forces of the agents involved in the process of introducing AT to people with dementia were explored, using a case study methodology combined with grounded theory. Study IV explored and described how significant others of people with dementia related to technology, and their readiness to use AT together with the person with dementia, using a grounded theory approach with focus groups and individual interviews.
The findings of Study I suggested that the ETUQ demonstrates acceptable validity in terms of internal scale validity and person response validity, when used in this population. The ETUQ showed sensitivity in detecting differences between three subgroups in perceived difficulties in everyday technology use. Study II showed significant differences in perceived difficulty in everyday technology use between all three groups. Here everyday technology was perceived most difficult by people with dementia, followed by people with MCI, and older adults without known cognitive impairment. It also suggested that older adults with MCI or dementia experienced fewer technology artifacts and services as relevant to their daily lives, as compared to older adults without known cognitive impairment. In Study III, Doing the right thing was the main driving force among actors in this AT intervention process. However, as conflicting views appeared of what the right thing to do was, findings suggest that it is important to be attentive to who has decision power, as this person is likely to influence the process profoundly. Study IV's findings showed that the significant others took a utilitarian perspective on technology, as they refused technology for technology's sake but showed an overall readiness toward using technology if they considered it to benefit them and their relatives with dementia. Technology was found to be important for keeping an active lifestyle and for creating and maintaining self-images among people with dementia and their significant others.
The thesis contributed new knowledge about the perceived relevance of and difficulty in everyday technology use in older adults, particularly in those with MCI or dementia. Findings also indicate that the ETUQ is a tool that generates valid, sensitive measures of perceived difficulty in everyday technology use, and valuable information about its perceived relevance that may support researchers and clinicians. The thesis contributed new knowledge about the complex situation of a person with dementia and his/her significant others when AT is introduced in the home, suggesting the need of a more flexible and process-oriented procedure with ends-in-view instead of clearly set goals. Significant others of people with dementia were found to be generally ready to adopt technology, although they took a utilitarian perspective. Technology was perceived by them as important for keeping an active lifestyle and for creating and maintaining self-images, which suggests that such conceptions should be considered. Finally, the thesis contributes knowledge of design-related principles and conditions that may be decisive in transactions between people with dementia and technology. It is suggested that what is communicated through the interface of the technology is particularly crucial, as this is likely to guide the person through suitable use, whereas instructions are likely to be forgotten.
eng
info:eu-repo/semantics/openAccess
Navigating through technological landscapes : views of people with dementia or MCI and their significant others
info:eu-repo/semantics/doctoralThesis
URL
http://openarchive.ki.se/xmlui/bitstream/10616/39263/1/Thesis_Rosenberg.pdf
File
MD5
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oai:openarchive.ki.se:10616/471682024-03-13T10:07:30Zcom_10616_1com_10616_198com_10616_46998col_10616_219col_10616_199col_10616_47000
Publications from KI
author
Queckbörner, Suzanna
2020-05-27T07:48:21Z
2020-05-27T07:48:21Z
2020-05-27
978-91-7831-863-6
http://hdl.handle.net/10616/47168
The healthy endometrium has the unique capacity of shedding and regenerating its functional layer once every menstrual cycle, under the regulation of hormones, progenitor cell populations and inflammatory mediators. Thanks to this meticulously timed cycle the uterus is regularly renewed in preparation for blastocyst implantation. However, if any of these factors are perturbed, the result may be endometrial disorders with intrauterine scar formation, dysregulated proliferation and heavy menstrual bleeding. This PhD project addresses the interplay of these factors specifically within the endometrial stromal compartment in ensuring healthy endometrial regeneration and homeostasis, thereby investigating future therapeutic targets for benign gynecological disorders. Cells and tissue from endometrial biopsies and bone marrow aspirate were studied using multiple cellular and molecular techniques. Stromal cells have been characterized in terms of their phenotype, their transcriptome and their ability to immunomodulate, providing a starting point for future endometrial stromal cell therapy development.
In study I, the transcriptional profile of progesterone receptor modulator associated endometrial changes (PAEC) was studied in women with three months of continuous mifepristone treatment to understand the future implications of PAEC and the safety of longterm mifepristone use. Our microarray findings indicate that progesterone withdrawal and unopposed estrogen surge alter the endometrial structural organization and extracellular matrix composition, particularly affecting the stromal compartment in the tissue. No differentially regulated genes were involved in endometrial-cancer associated pathways. In study II, endometrial stromal cells (eSCs) were characterized in terms of their phenotype, immunomodulation and tumorigenicity for early pre-clinical cell therapy development. eSCs demonstrated a mesenchymal stromal cell (MSC) surface marker profile and multipotency, while retaining chromosomal stability and showing no tumorigenicity after in vitro expansion. When stimulated with pro-inflammatory cytokines, eSCs presented with an antiinflammatory phenotype and secreted immunomodulatory factors, but did not express human leukocyte antigen class II on their cell surface. eSCs suppressed CD4+ T cell proliferation and activation while significantly modulating their differentiation state, upregulating CD4+ effector memory T cells.
The cellular diversity within the endometrial functional layer’s stromal compartment was explored in study III using single cell RNA sequencing. Different computational tools and an external dataset were used for analysis and validation. The study revealed diverse stromal subsets with transcriptional profiles representing different stromal activation states and niches important in wound healing, regeneration and immunomodulation. Several of these stromal transcriptional profiles could be validated in placenta derived decidua, suggesting the transcriptional profiles can withstand cycle changes and placentation. In study IV we determined the effects of blood exposure on bone marrow (BM) MSC viability and immunomodulatory functions, exposing BM MSCs to human blood products in vitro and evaluating their interactions with complement and the peripheral immune repertoire. Plasma exposure induced lysis of BM MSCs, while surviving BM MSCs had C3c bound to their surface. The MSC secretome reduced monocyte number and recruitment with many remaining monocytes skewed towards a classical, anti-inflammatory phenotype. Frequencies of immune modulating myeloid derived suppressor cells (MDSCs), both monocytic and polymorphonuclear, were also increased in response to BM MSCs. These data indicate that MSCs rapidly die once exposed to blood, but can still exert an anti-inflammatory response through the skewing of monocytes and upregulation of MDSCs. We hypothesize that this shift in the peripheral repertoire indirectly regulates adaptive immune cells’ response to the long-term tolerogenic effect seen after MSC intravenous infusion.
In summary, endometrial regeneration is tightly regulated by hormones, immune cells and their interactions with stromal cells. Our research has provided new, detailed information on the stromal compartment by demonstrating there are multiple stromal subsets with different transcriptional profiles, presumably fulfilling multiple roles. Furthermore, eSCs have the ability to respond to inflammatory cues, as well as directly and indirectly modulating immune cells through their secretome. Additionally, BM MSCs exposed to blood can modulate the innate immune response even after cell death due to their release of soluble factors which induce an anti-inflammatory monocyte phenotype which lasts beyond their clearance from circulation. We conclude that stromal cells from different tissues have exceptional regulatory capacities in tissue homeostasis, inflammation and healing.
eng
info:eu-repo/semantics/openAccess
Endometrial regeneration : unraveling the mysteries of the stroma
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/47168/1/Thesis_Suzanna_Queckborner.pdf
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Thesis_Suzanna_Queckborner.pdf
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http://openarchive.ki.se/xmlui/bitstream/10616/47168/3/Thesis_Suzanna_Queckborner.pdf.txt
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Thesis_Suzanna_Queckborner.pdf.txt
oai:openarchive.ki.se:10616/426282022-09-30T22:38:44Zcom_10616_1com_10616_46998col_10616_219col_10616_47000
Publications from KI
author
Tornhamre, Susanne
2014-12-04T16:28:57Z
2014-12-04T16:28:57Z
1996-05-15
91-628-2109-1
19960605torn
http://hdl.handle.net/10616/42628
Human platelets lack 5-lipoxygenase activity, but possess enzymatic capacity to transform the unstable epoxide leukotriene (LT)A4 to the potent inflammatory agent LTC4 and lipoxins, a group of trihydroxylated tetraene-containing eicosanoids, which recently have been suggested to have an anti-inflammatory role.
A novel pathway for the formation of lipoxin (LX)A4 via platelet lipoxygenation of SS,6R-diHETE and 5S,6S-diHETE, enzymatic/non-enzymatic hydrolysis products of LTA4, was discovered in human platelets. In contrast, human platelets did not transform cysteinyl leukotrienes to the corresponding cysteinyl lipoxins. The results indicated that platelet-dependent lipoxin formation from LTA4 can proceed both via a direct lipoxygenation, yielding 15-OH-LTA4, and through initial hydrolysis to 5,6-diHETEs. The hydroxylation of LTA4 at C-15 was more efficiently catalysed by human platelet and porcine leukocyte 12-lipoxygenasesthan by rabbit reticulocyte and soybean 15-lipoxygenases.
In kinetic studies, human platelet 12-lipoxygenase was found to have a high affinity for LTA4, with a Km value comparable to those earlier reported for arachidonic acid. Platelet activation resulted in elevated lipoxin synthesis. This activation was due to stimulation of 12-lipoxygenase by endogenous 12-HPETE, formed after calcium-dependent phospholipase activation and liberation of arachidonic acid.
In contrast to the increased lipoxin formation, platelet activation attenuated the conversion of LTA4 to LTC4. This inhibition of platelet LTC4 synthase activity was observed both after receptor-mediated activation of human platelets as well as after direct stimulation of PKC with PMA. These effects were blocked by pretreatment with the protein kinase inhibitor stauro-sporine, supporting the possible regulation of LTC4 synthase through phosphorylation pathways. This was further suggested by kinetic studies demonstrating non-competitive inhibition of the enzyme after incubation of intact platelets with thrombin or PMA.
However, receptor-mediated attenuation of LTC4 formation could not be reversed by specific PKC inhibitors, even though these drugs efficiently prevented the PMA-induced effect. These results indicate that the LTC4 synthase activity in platelets is phosphoregulated, both via PKC-dependent and via receptor-mediated, PKC-independent mechanisms. Involvement of protein tyrosine phosphorylations in the latter process was suggested by the finding that a tyrosine phosphatase inhibitor induced dose-dependent inhibition of LTC4 production in platelet sonicates. In agreement with the findings in platelets, PKC-induced down-regulation of the LTC4synthase activity was also demonstrated in human granulocytes.
Aspirin treatment in vivo was found to block attenuation of platelet LTC4 synthase activity induced by arachidonic acid or collagen ex vivo. The results suggest that aspirin treatment can uncouple mechanisms that normally restrict the production of cysteinyl leukotrienes, which are important bronchoconstrictors and asthma mediators. These findings may therefore be relevant for our understanding of the pathophysiology of aspirin-induced asthma. The effects of the anti-inflammatory drug sulfasalazine on the arachidonic acid cascade inhuman platelets and leukocytes were investigated. The drug was found to inhibit the production of leukotrienes and tromboxanes but allowed formation of prostaglandin E2. This pharmacological profile may contribute to the clinical mechanism of action of this drug.
In conclusion: Platelet 12-lipoxygenase is well suited to initiate the conversion of LTA4 tolipoxins, indicating a physiological role for this enzyme in lipoxin formation. Also, platelet activation may lead to elevated formation of putative anti-inflammatory lipoxins paralleled by suppressed formation of the pro-inflammatory LTC4. According to the present findings, regulation of LTC4 synthase activity can be exerted via receptor-mediated, phosphoregulatory mechanisms and may be of importance in aspirin-induced asthma.
Studies on the formation of leukotriene C4 and lipoxins from leukotriene A4 in human platelets
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/473852024-03-11T18:06:39Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Persson, Anna
2020-11-24T13:27:13Z
2020-11-24T13:27:13Z
2020-11-24
978-91-8016-024-7
http://hdl.handle.net/10616/47385
The overall aim of this thesis was to investigate the auditory and early speech development in a group of children born with moderate hearing loss (HL) who were fitted with hearing aids (HAs) before the age of 6 months, and to compare their development to a group of children with normal hearing (NH). More specific aims were to examine the impact of auditory variables on the early speech development in the children with HL and to validate a questionnaire of auditory development in the children with NH.
This PhD project consisted of four longitudinal studies. Participants included a group of children with moderate HL (n=11) and a reference group of children with NH (n=29). Data was collected at the ages of 10, 18, 34, 30 and 36 months with assessments of early speech development and auditory variables that were compared between groups. In Study I, the Swedish version of the LittlEARS® Auditory Questionnaire (LEAQ) was externally validated in children with NH. In Study II, HA use from first fitting to 36 months of age and the impact of hours of HA use on auditory development and functional performance were investigated. In Study III, consonant production in babbling and early speech at 10 and 18 months and consonant proficiency at 36 months were examined. In Study IV, expressive vocabulary between the ages of 18 to 30 months was investigated and compared between groups.
The Swedish version of the LEAQ showed equal validation properties to the original version albeit found to be similar in content to an inventory of vocabulary. The variability in hours of HA use was large and only two children reached full-time HA use at all ages. Auditory development was found similar between the groups but the children with HL presented with lower scores on functional auditory performance in noise at 30 and 36 months of age. The children with HL showed delays in their consonant production in babbling and early speech at 10 and 18 months compared to the children with NH. At 36 months, there was no significant difference between the groups on consonant proficiency. The number of produced words was similar between the groups at 18 months but at 24 months of age there was a gap which increased even further at the age of 30 months, disadvantaging the children with HL. The most prominent auditory variable found to impact the outcomes on the early speech measures was hours of HA use, meanwhile scores on auditory development, functional auditory performance, and aided audibility showed weaker relationships.
Despite early fitting with HAs the children with moderate HL showed delays in their early speech development and challenges in auditory functional performance in noise. The findings from this thesis suggest that careful monitoring at specific ages with appropriate methods of early speech development and auditory variables could help professionals to identify children at risk and work in a preventive way. This calls for cross-professional collaboration within the clinical setting. Attention is also needed to make sure that parents and other caregivers outside the clinic (e.g. preschool teachers) receive information so they can use appropriate strategies to reduce the risks of language delays in children with moderate HL. Albeit acknowledging the limitations to generalize the findings from this thesis to a larger population, the results and experiences from the longitudinal project are in line with current research that promotes monitoring of auditory and spoken language development the first three years in children with HL.
eng
info:eu-repo/semantics/openAccess
Swedish children with moderate hearing loss : on the importance of monitoring auditory and early speech development the first three years
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/47385/3/Thesis_Anna_Persson.pdf
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http://openarchive.ki.se/xmlui/bitstream/10616/47385/4/Thesis_Anna_Persson.pdf.txt
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oai:openarchive.ki.se:10616/402612022-09-16T01:01:57Zcom_10616_1com_10616_46998col_10616_219col_10616_47000
Publications from KI
author
Backman, Ann-Sofie
2010-10-29T07:50:37Z
2010-10-29T07:50:37Z
2010-10-29
978-91-7457-043-4
http://hdl.handle.net/10616/40261
Background: This study was developed with the main objective of evaluating users of
emergency departments (ED) triaged as non-urgent following a period of time when large
cutbacks in hospital and ambulatory care were taking place in Sweden.
Aim: To analyse patients seeking medical attention for conditions triaged as non-urgent
at an ED and patients who used non-scheduled services in primary care (PC) in relation to their
symptoms, perceptions and the physicians’ assessments of urgency, and to register their
subsequent health care use within one month. The question was; are non-urgent patients at the
ED similar to unscheduled PC patients?
Methods: In this cross-sectional study subjects from a defined catchment area were
identified and interviewed at the time of a non-scheduled PC visit, or a non-referred, non-urgent
(triage level 4) ED visit. Structured face-to-face interviews and a concomitant questionnaire to
the treating physician were used to collect the data in office hours during a nine-week period.
The subjects’ subsequent health care contacts within a month were registered through a
population based registry.
Results: Of 924 eligible patients, 736 (80%) agreed to participate, 194 at the ED and
542 at the nine PC centres. The two groups shared demographic characteristics except for
gender. A majority (47%) of the patients at the PC centres had respiratory symptoms, whereas
most non-urgent ED patients (52%) had digestive symptoms, musculoskeletal symptoms, or
symptoms due to trauma. Both groups had used health care frequently, but ED patients had
previously been more often hospitalized (35%) than PC patients (21%) (p<0.001). ED patients
were more anxious about and disturbed by their symptoms and had had a shorter duration of
symptoms. Regular monitoring of chronic disease was associated with an increased probability
of another physician visit the following month (OR 2.0; CI 95%, 1.2-3.4). The majority of
patients was found to have complaints appropriate for the setting, but general practitioners
considered to a higher extent than their ED colleagues that patients had chosen an appropriate
level of care (p<0.001). General practitioners were older and had longer clinical experience than
physicians at the ED. ED patients, having chosen an appropriate care level as judged by the
physician, were distinguished by different symptom presentation, shorter duration of symptoms,
and more regular previous health care use. Men without previous regular health care use were
more likely to present symptoms assessed as inappropriate for the ED (p <0.001), and this group
was also less likely to use health information or advice before seeking care (p<0.01).
Conclusions: Non-urgent ED patients and PC patients had similar socio-demographic
characteristics but differed regarding types of diseases, previous hospitalizations and current
perception of symptoms. Patients with disorders that ED physicians considered inappropriate
for the setting had low previous regular health care use but their treating physicians were less
experienced than the physicians in PC. General practitioners agreed with their patients´ choice
of health care level to a large extent. Information concerning appropriate health care level could
be targeted to individuals with low previous health care use. No evidence was found for any
widespread misuse of the ED service during the time of the study.
eng
info:eu-repo/semantics/openAccess
Emergency care seeking behaviour : in relation to patients' and providers' perceptions and attitudes
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen ---


<u>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</u>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

<u>1. Grant of rights</u>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

<u>2. The Library's obligations</u>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

<u>3. The Author's obligations</u>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

<u>4. Paper printouts, etc.</u>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

<u>5. Assignment of the agreement, etc.</u>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

<u>6. Termination of the agreement</u>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

<u>7. Processing of personal data</u>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

<u>8. Liability</u>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

<u>9. Full regulation</u>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


--------


<u>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</u>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

<u>1. Upplåtelse</u>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

<u>2. Bibliotekets åtaganden</u>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

<u>3. Författarens åtaganden</u>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

<u>4. Pappersutskrifter m.m.</u>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

<u>5. Överlåtelse av avtalet m. m.</u>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

<u>6. Avtalets upphörande</u>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

<u>7. Behandling av personuppgifter</u>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

<u>8. Ansvar</u>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

<u>9. Fullständig reglering</u>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/485622023-10-17T10:22:13Zcom_10616_1com_10616_156com_10616_46998col_10616_219col_10616_157col_10616_47000
Publications from KI
author
Radziun, Dominika
2023-04-28T12:37:46Z
2023-04-28T12:37:46Z
2023-04-28
978-91-8016-985-1
http://hdl.handle.net/10616/48562
Lack of vision is associated with large-scale brain plasticity. Vision, touch, proprioception, interoception, and other sensory modalities are thought to play a vital role in developing and maintaining bodily awareness. How do blind people perceive their bodies, and what kind of compensatory neuroplasticity processes are involved?
This thesis comprises a series of experiments focused on a profoundly understudied topic – the perception of one’s body following blindness.
Study I shows that blind individuals are significantly better at perceiving their heartbeats than sighted individuals. The results indicate that blind individuals experience signals from inner organs differently than sighted individuals, which has implications for further research on emotional processing and bodily awareness.
Study II provides a broader insight into tactile perception following blindness by studying discriminative and affective touch plasticity in blind and sighted groups. A key novel finding is changed pleasantness sensation due to affective touch, that is, slow, gentle, caress-like stroking of the skin, especially on the palm, in blind participants compared to sighted participants. The results have implications for understanding social and physical interactions in blind individuals.
Study III re-examines a classic paradigm to study multisensory bodily awareness, the somatic rubber hand illusion, in a large sample of blind participants with a well-matched sighted control group. The results present strong evidence that blind individuals are “immune” to this illusion which suggests that they rely more on unisensory processing rather than multimodal integration of sensory signals, compared to sighted individuals.
Study IV investigates the effect of short-term visual deprivation by a two-hour blindfolding procedure on the bodily senses of cardiac interoception, thermosensation, and discriminative touch in sighted participants. The results show no effect on these senses, which suggests that the changes observed in blind individuals on these sensory functions relate to their long-term lack of visual experience and associated brain plasticity changes.
Finally, Study V uses structural magnetic resonance imaging to analyze cortical thickness in a group of blind individuals and a matched sighted control group and relate the cortical thickness measure to the behaviorally registered changes in cardiac interoceptive accuracy. The key finding is that blind individuals with thicker occipital cortices are better at sensing their heartbeats; this finding advances our understanding of the limits of cross-modal plasticity following blindness and suggests that the visual cortex supports the awareness of inner bodily sensations in blind individuals.
Overall, this thesis is the first systematic characterization of differences and similarities between blind and sighted individuals in body perception and functioning of the bodily senses, opening a line of research with important links to mental health.
eng
info:eu-repo/semantics/openAccess
Body perception and brain plasticity in blind and sighted individuals
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
http://openarchive.ki.se/xmlui/bitstream/10616/48562/2/Thesis_Dominika_Radziun.pdf
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MD5
b22e00b4d676936a73b68ba3e24b08ae
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application/pdf
Thesis_Dominika_Radziun.pdf
URL
http://openarchive.ki.se/xmlui/bitstream/10616/48562/3/Thesis_Dominika_Radziun.pdf.txt
File
MD5
0e73c55ed8950625d3c2fe2679e39812
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text/plain
Thesis_Dominika_Radziun.pdf.txt
oai:openarchive.ki.se:10616/480492024-03-09T17:22:26Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Holmberg, Johan
2022-04-28T11:51:34Z
2022-04-28T11:51:34Z
2022-04-28
978-91-8016-630-0
http://hdl.handle.net/10616/48049
Background: Intensive care settings have been shown to present a demanding work setting with health related and work-related consequences for intensive care medical staff. The health-related consequences observed are high levels of burnout, traumatic stress, symptoms of anxiety, depression, and fatigue. Specific stressors mentioned by staff is high workload, moral distress, end-of-life issues, and interpersonal issues/conflicts with colleagues, patients, and relatives. During the covid-19 pandemic, the need for healthcare organizations to attend to the occupational psychological health of staff has been evidently clear. Although, the prevalence of stress in intensive care has been previously observed and reported on, at least since the 70s.
Purpose and aims: Overall purpose of thesis was threefold; to improve knowledge on occupational psychological health among healthcare staff, particularly in intensive care settings, to develop a behavioural intervention to improve communication skills and management of distress to enhance occupational health, and to evaluate the implementation of psychological support to ICU staff. The thesis included four studies and the specific aim of study I was to evaluate the reliability and validity of a Swedish version of the Work-related Acceptance and Action Questionnaire (WAAQ), a self-report questionnaire measuring psychological flexibility at work. Study II evaluated the relationship between psychological flexibility (measured by WAAQ) and other aspects of occupational psychological health, i.e., perceived stress, general mental health, and work engagement, in a sample of intensive care medical staff. Study III evaluated the effects of a Behavioral Skills Training (BST) program on dependent measures of occupational psychological health in a sample of intensive care medical staff. Finally, study IV evaluated the implementation and feasibility of a psychological support model rapidly developed and implemented for ICU staff during the first wave of the covid-19 pandemic.
Methods: Four studies were included in the thesis. Study I used a cross-sectional design to evaluate reliability and validity of a measure of psychological flexibility, WAAQ, in a sample of healthcare professionals. In a subsample of participants, a longitudinal design was used to evaluate test-retest reliability. Measures used in the study were three self-report questionnaires, WAAQ, PSS-10 (Perceived Stress Scale-10), and UWES (Utrecht Work Engagement Scale) and the sample consisted of 184 healthcare professionals. Study II evaluated the relationship between psychological flexibility (WAAQ), work engagement (UWES), perceived stress (PSS-10), and general mental health (GHQ-12) in a cross-sectional design in a sample of intensive care medical staff. A longitudinal design was used in a subsample (n=46) to further evaluate the relationship between WAAQ and UWES. Study III evaluated the effects of the BST program in a pre-post uncontrolled trial with three assessment points (pre, mid, and post). Study IV used a cross-sectional and qualitative design to evaluate implementation of the support model.
Results: In study I, WAAQ showed good internal consistency and good test-retest reliability. Furthermore, it showed a significant negative relationship with perceived stress and significant positive relationship with work engagement. In study II, a hierarchical regression analysis showed WAAQ to explain variance in UWES when controlling for PSS-10 and GHQ-12. Additionally, WAAQ had a significant indirect effect on the relationship between perceived stress (PSS-10) and work engagement (UWES), and the relationship between general mental health (GHQ-12) and work engagement (UWES). In Study III, dependent t-test and linear mixed model analysis of occupational psychological health showed decrease in perceived stress (PSS-10) and improved general mental health (GHQ-12). It showed no change on measures of psychological flexibility (WAAQ) or work engagement (UWES) Study IV showed that although all support efforts were used, daily group sessions followed by peer support had the highest attendance ratings in relation to awareness. Furthermore, interviews with psychologists delivering support showed three themes labelled utility, challenges, and keys to implementation.
Conclusions: Results from study I support the use of the Swedish version of WAAQ as a measure of psychological flexibility among healthcare professionals, and considering the sample composition, especially among highly educated female samples. Study II showed support for the utility of psychological flexibility and work engagement to assess and characterize occupational psychological health among intensive care medical staff. Although tentative, findings of study III, support the use of the BST program to promote occupational psychological health among intensive care medical staff. Lastly, the process evaluation of the support model delivered during the pandemic, suggested the importance of a rapid implementation of support when needed, and that success is dependent on the managers to facilitate and implement the interventions, as well as access to competent resources.
eng
info:eu-repo/semantics/openAccess
Psychological factors and communication skills training in intensive care medical staff
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
URL
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oai:openarchive.ki.se:10616/400262023-02-21T10:32:27Zcom_10616_1com_10616_147com_10616_46998col_10616_219col_10616_148col_10616_47000
Publications from KI
author
Iversen, Aina
2010-10-21T20:33:36Z
2010-10-21T20:33:36Z
2005-11-18
91-7140-517-8
20051209iver
http://hdl.handle.net/10616/40026
Enterococci belong to the normal intestinal flora of humans and animals. An increased prevalence of antibiotic resistant enterococci causing nosocomial infections has drawn attention to the epidemiology and emergence of antibiotic resistance in this genus.
In the present thesis we have studied the enterococcal flora in samples from humans, animals, and the environment, in order to be able to follow the movement of bacteria between different ecological niches, as well as to determine the prevalence of antibiotic resistant enterococci in these samples. In a European study, 17,157 enterococcal isolates from 2,868 samples from humans, animals and the environment in Sweden, Denmark, the United Kingdom, and Spain were studied (study I-III). The diversities of enterococci in environmental samples were generally high. Samples from hospital sewage, urban sewage, and manure contained enterococcal populations that reflected those in faecal samples of hospitalised patients, healthy humans and animals. Thus, such samples could be used as pooled faecal samples and replace cumbersome samplings from many individuals.
Vancomycin resistant enterococci (VRE, resistant to 20 mg/L vancomycin), were identified in 8.2% of all samples and most frequently and at similar levels in untreated urban sewage in Sweden, Spain and the UK (in an average of 71% of the samples). In contrast, pig faeces and manure were more often VRE-positive in Spain than in Sweden (30% vs. 1%), most probably reflecting the former use of the vancomycin analogue avoparcin as a feed additive. Most VRE were E. faecium carrying vanA both among humans and animals. Typing of VRE showed a high degree of polyclonality and no evidence were found for transmission of VRE strains between humans and animals.
The high prevalence of VRE in Swedish sewage samples (19-60% in 118 samples) was unexpected. Typing of 35 isolates revealed a high diversity (Di 0.97). Four of five VRE from hospital sewage were E. faecium with vanB, which is the most common type in infections and among hospitalised patients in Sweden. However, the origin of VRE from urban sewage remains unclear. A majority of VRE from urban sewage were E. faecium with vanA (17 of 29), but a larger proportion than found in the other countries was E. faecalis with vanA (11of 29). Either these VRE represent a higher carriage rate among healthy individuals in the community than earlier reported or perhaps they harbour in the sewage system.
An ampicillin and ciprofloxacin resistant E. faecium (ARE) strain, named FMSE1, was in a previous study found to dominate among faecal ARE isolates from patients in several Swedish hospitals. In study IV, the prevalence of the same PhP-type as the FMSE1 PhP-type, was searched for among typing data from 9676 isolates from Sweden and Denmark. FMSE1 was most common in samples of hospital sewage (50%), surface water (35%), treated sewage (28%), and untreated sewage (17%), but were rare in samples from healthy children (0.8%) and animals (2%). PFGE typing of FMSE1-like isolates from hospital sewage indicated that they were closely related to the nosocomial FMSE1 strain. According to study I-III the enterococcal flora in sewage and hospital sewage resembled that of the flora in individual faecal samples. This fact led to an idea for a new concept for monitoring antibiotic resistance in the community and in hospitals, based on samplings of sewage water.
In study V and VI the feasibility of this concept was evaluated. Up to 24 enterococcal isolates from each sample of hospital sewage (N=9), sewage treatment plants (N=14), and sewage from an anthroposophic village, were screened for resistance, using breakpoint concentrations of antibiotics in microplates. The resistance rates found for ampicillin, ciprofloxacin and erythromycin were markedly higher in hospital sewage (30, 35 and 30%) than in community sewage (4, 6 and 15%l), whereas tetracycline resistance was found at the same level in all sewage types (28%). Differences in resistance rates for enterococci isolated from different types of sewage samples were obvious and easy to monitor using this method.
eng
info:eu-repo/semantics/openAccess
Population structure and antibiotic resistance of the genus enterococcus in humans, animals and the environment
info:eu-repo/semantics/doctoralThesis
URL
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oai:openarchive.ki.se:10616/393892023-02-20T15:15:01Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Zhang, Pu
2010-10-21T20:31:51Z
2010-10-21T20:31:51Z
2005-03-18
91-7140-281-0
20050408zhan
http://hdl.handle.net/10616/39389
Infertility affects approximately 15% of couples globally. The most effective treatment today is in vitro fertilization. However, not all couples can be helped with the current techniques. To achieve better success, techniques of storage and in vitro maturation of ovarian follicles have to be improved. Meanwhile, understanding of the molecular mechanisms of follicle/oocyte maturation and embryo development would doubtlessly facilitate technique development. Nonetheless, little work has been done in these areas due to the limited availability of human research material. Therefore, we performed five studies on the collection, cryopreservation, culture and gene expression of human ovarian follicles/oocytes respectively.
In Article I, we examined if follicular aspirates obtained during oocyte retrieval for IVF were a good source of human ovarian follicles. The presence of follicles in the aspirates was examined by mechanical/enzymatic isolation, culturing and histological analysis. We found only 14 follicles in 86 aspirates. The results indicate that follicular aspirates are not a reliable source of human ovarian follicles.
In Article II, we evaluated whether serum-free cryoprotectants could be used for cryopreservation of human ovarian cortical tissue. Biopsies of ovarian cortical tissue donated by healthy women were frozen and thawed using two kinds of cryoprotectants containing either human serum or human serum albumin. Light microscopy, transmission electron microscopy and live/dead fluorescence assay were performed to evaluate the structure and viability of the follicles. The results showed that the majority of the follicles retained normal structure and viability after thawing. Cryoprotectants containing human serum albumin were equally effective as those containing human serum. Therefore, serum free cryoprotectants are suitable for the cryopreservation of human ovarian cortical tissue.
In Articles III and Article IV, we tested the effect of two secondary messengers, cGMP and cAMP, on human ovarian follicles cultured in ovarian cortical slices. Donated ovarian cortical biopsies from healthy women were cut into slices and cultured in parallel in the presence and absence of 8-br-cGMP or 8-br-cAMP for 1-3 weeks. Oestrdiol production, developmental stage, size and viability of the follicles were recorded. The results showed that both 8-br-cGMP and 8-br-cAMP enhance the survival and development of human early follicles cultured in ovarian cortical tissue.
In Article V, to expose the gene expression profile of human germinal vesicle oocytes (hGVO) and reveal different gene expression patterns between hGVO, embryonic stem cells and foreskin fibroblasts, we performed microarray (Affymetrix U133 plus 2.0) analysis and RT-PCR. In total, 11,191 unigenes were expressed in normal human GV oocytes. Forty-nine percent of these genes are as yet unclassified by biological function. A few oocyte specific genes that are obligatory for oocyte maturation/early embryo development in animals were found expressed in hGVO for the first time. Furthermore, known components of MOS-MPF, TGF-beta superfamily, and WNT pathway were identified in hGVO. Last, twelve gene expression patterns were found between hGVO, embryonic stem cells and fibroblasts, suggesting potential candidate genes involved in oocyte maturation and embryonic development.
Our findings will help improve the technique of cryopreservation and culture of human ovarian follicles. Further, our last study provides a rich source for continued research in elucidating the molecular mechanism of oocyte maturation and embryo development in humans.
eng
info:eu-repo/semantics/openAccess
Human ovarian follicles and oocytes : collection, cryopreservation, culture and gene expression
info:eu-repo/semantics/doctoralThesis
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oai:openarchive.ki.se:10616/414582023-10-30T15:31:24Zcom_10616_1com_10616_195com_10616_46998col_10616_219col_10616_196col_10616_47000
Publications from KI
author
Skog, Amanda
2013-04-11T12:52:55Z
2013-04-11T12:52:55Z
2013-04-11
978-91-7549-094-6
http://hdl.handle.net/10616/41458
Congenital heart block (CHB) is a rare but life-threatening disease associated with the presence of Ro and La autoantibodies in the mother of the child affected. CHB is one of the manifestations of neonatal lupus erythematosus (NLE) that may also include several other manifestations such as a skin rash and cytopenias. Although the link between Ro and La autoantibodies and the risk for CHB has been recognized for decades, a recurrence rate of 12-17% in subsequent pregnancies suggests that other risk factors also contribute to disease pathogenesis. Furthermore, as CHB is rare disease, little is known about outcome and health in these children. The aim of this thesis was therefore to investigate outcome, health and antibody levels in children with CHB as well as risk factors for CHB development.
In our results we reveal that increased maternal age and seasonal timing of birth are novel risk factors for CHB in autoantibody-positive pregnancies. Furthermore, when analyzing antibody levels in children born to mothers with Ro/SSA autoantibodies, we have demonstrated that maternal autoantibodies decrease rapidly in the infant circulation during the first few weeks of life among both breast-fed and non-breast-fed infants and are not correlated to NLE skin manifestations. We have also demonstrated that an autoantibody-associated complete CHB diagnosis after the neonatal period is possible, advocating testing of maternal serology at the time of diagnosis.
Our results demonstrate that newborns with fetal signs of atrioventricular block (AVB) II-III have a significantly lower weight at birth than those with AVB I or normal conduction and do not show signs of catch-up during the first 12 months of life. Fetuses with AVB I or normal atrioventricular conduction have significant but smaller weight retardation at birth, but showed a rapid catch-up during the first two postnatal months, indicating that they have a good prognosis. Looking at long-term growth, we demonstrate that children with complete CHB are weight restricted both in comparison to their siblings without CHB and the Swedish reference standards from birth to 2-3 years of age, when a catch-up is initiated. From the age of 9-11 they have normal body measurements as a group and do not significantly deviate from the reference standards. When investigating neurodevelopment, our data indicate that in addition to well established factors such as male sex and being born preterm, both maternal SLE and CHB may influence neurodevelopment as learning impairment was significantly influenced by maternal SLE (p < 0.005), while attention deficits was influenced by both maternal SLE (p < 0.05) and CHB in the child (p < 0.05).
In conclusion, our results indicate that maternal age and seasonal timing of birth are risk factors for CHB development, information that may be useful to consider when pregnancy is planned. As antibody levels decreased in the infants and were not correlated to NLE skin manifestations, we conclude that there is no reason not to recommend breast feeding in children born to anti-Ro and or La positive women. Although children with CHB are weight retarded during their first years of life, they appeared to spontaneously initiate a catch-up in weight around the age of 2-3 years. However, as the group of children with CHB did not reach the reference standards until the age of 9-11, careful follow-up of individuals with CHB regarding nutrition and growth is recommended. In addition, follow-up of neurodevelopment should be considered for children with CHB, especially if the mother is diagnosed with SLE. An early diagnosis is one way to help these children overcome their difficulties during childhood and school years and make sure that they obtain the support needed.
eng
info:eu-repo/semantics/openAccess
Being born with congenital heart block : risk factors, growth and development
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


A<b>GREEMENT ON ELECTRONIC PUBLICATION OF THESES</b>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


A<b>VTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/448122019-09-29T22:11:33Zcom_10616_1com_10616_183com_10616_46998col_10616_219col_10616_184col_10616_47000
Publications from KI
author
Rekha, Rokeya Sultana
2015-10-14T08:19:09Z
2015-10-14T08:19:09Z
2015-10-14
978-91-7676-078-9
http://hdl.handle.net/10616/44812
Antimicrobial peptides (AMPs) are effector molecules of the innate immune system in multicellular organisms. They are mainly expressed in epithelial cells and immune cells, providing the first line of defense against a wide range of pathogens. AMPs are able to kill pathogens and show additional important functions such as chemotaxis, angiogenesis, and wound healing. These peptides are constitutively expressed; however, their expression can also be induced or suppressed by different stimuli in a cell and tissue specific manner. The overall aim of the present thesis was to elucidate the role of AMPs in tuberculosis and respiratory tract infections by clinical and mechanistic studies.
Vitamin D3 (vitD3) is known as a potent inducer of AMPs. Low levels of serum vitD3 are associated with an increased risk of respiratory tract infections (RTIs). One of our objectives was to elucidate whether supplementation with vitD3 could reduce infectious symptoms and antibiotic consumption in patients with antibody deficiency or frequent RTIs. Patients (n=140) were included with symptoms of respiratory tract infections for more than 42 days over a 12-month period. They were randomized and received either vitD3 (4000 IU) or placebo daily for one year. The primary endpoint was an infectious score based on five parameters: symptoms from the respiratory tract, sinuses, and ears, malaise, and antibiotic consumption. Secondary endpoints were serum 25-hydroxyvitamin D3 [25(OH)D3] levels, microbiological outcomes, and the levels of the antimicrobial peptides LL-37 and Human Neutrophil Peptides (HNP) 1-3 in nasal fluids. We observed that vitD3 supplementation reduced infectious score, antibiotic consumption, and increased serum 25(OH)D3 concentrations in the patients compared to placebo control group. However, no major changes were observed for LL-37 and HNP 1-3.
To control the global spread of tuberculosis (TB) and multi-drug resistance TB, development of new anti-tuberculosis drugs and alternative treatment strategies are urgently required. PBA is a potent inducer of AMPs, and together with 1,25-dihydroxyvitamin D3, it synergistically induces the expression of LL-37 in lung epithelial cell line. Thus, we aimed to estimate a therapeutic dose of PBA alone, or in combination with vitD3 for the induction of LL-37 expression in immune cells, and enhanced antimycobacterial activity in monocyte-derived macrophages (MDMs). Healthy volunteers were enrolled in an 8-days open trial (n=15). The expression of the CAMP (cathelicidin antimicrobial peptide) gene encoding LL-37 was measured in immune cells both in mRNA and peptide levels. MDM-mediated killing of Mycobacterium tuberculosis (Mtb) (H37Rv) was performed. From this trial, we demonstrated that 500 mg PBA twice daily with 5000 IU vitD3 once daily was the optimal dose for the induction of LL-37 in MDMs and lymphocytes, and the enhancement of intracellular killing of Mtb by MDMs. Using these findings, we further investigated if oral adjunctive therapy with 5000 IU vitD3 and/or 2x500 mg PBA along with standard anti-TB therapy would lead to an enhanced recovery in sputum smear-positive pulmonary TB patients. Adult TB patients (n=288) were enrolled in a randomized, double-blind, placebo-controlled trial. Primary endpoints were the proportion of patients with a negative sputum
culture at week 4, and the reduction in clinical symptoms at week 8. Secondary endpoints included sputum smear conversion time, radiological findings, concentrations of 25(OH)D3 in plasma, expression of the antimicrobial peptide LL-37 in immune cells and intracellular killing of Mtb by MDMs. We found that the adjunct therapy with PBA and vitD3 treatment significantly reduced the sputum culture conversion time together with better clinical recovery in pulmonary tuberculosis patients. Additionally we observed that PBA and vitD3 treatment enhanced the expression of LL-37 in immune cells and increased intracellular killing of Mtb by MDMs.
Next, we explored the potential mechanisms of PBA and LL-37-induced intracellular killing of Mtb in macrophages by autophagy. We observed that Mtb infection of MDMs downregulated the expression of LL-37 and certain autophagy-related genes (Beclin1 and ATG5) at both mRNA and protein levels. We also found that PBA and/or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] were able to overcome the Mtb-induced suppression of LL-37 expression. In addition, autophagy process was activated by stimulation of MDMs with PBA and promoted co-localization of LL-37 and LC3-II (a marker of autophagy) in autophagosomes. When LL-37 expression was silenced, PBA treatment failed to induce autophagy in Mtb-infected THP-1 cells. On the other hand, when LL-37 knockdown cells were supplemented with synthetic LL-37, autophagy was restored. Additionally, we found that LL-37-induced autophagy was mediated via the P2RX7 receptor and intracellular free Ca2+, the AMPK and the PI3K pathways. These results suggest that PBA induces autophagy in LL-37-dependent manner and promotes intracellular killing of Mtb in human MDMs.
In summary, vitD3 supplementation could beneficial for the patients with antibody deficiency or frequent RTIs. PBA and vitD3 supplementation improves the clinical outcomes through the increased expression of LL-37, indicating that this supplementation might be an alternative strategy to treat pulmonary TB patients. The enhanced expression of LL-37 activates the cellular host defense mechanism autophagy, and subsequent killing of Mtb in human macrophages.
eng
info:eu-repo/semantics/openAccess
Role of antimicrobial peptides in tuberculosis and respiratory tract infections : clinical and mechanistic studies
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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oai:openarchive.ki.se:10616/432072023-02-17T13:43:07Zcom_10616_1com_10616_204com_10616_46998col_10616_219col_10616_205col_10616_47000
Publications from KI
author
Nordemar, Sushma
2014-12-04T16:29:36Z
2014-12-04T16:29:36Z
2004-04-28
91-7349-872-6
20040519nord
http://hdl.handle.net/10616/43207
Head and Neck squamous cell cancer (HNSCC) is the fifth most common malignancy in the western countries and in Sweden it comprises 2- 3% of all cancer cases. Alcohol and tobacco are known as principal etiological factors but other carcinogenic attributes i.e. viruses and bethel chewing have also been recognised. The HNSCC is classified according to the TNM classification and morphologically graded into well, moderately and undifferentiated tumors. Curative treatment implies surgery and/or radiotherapy. Despite therapeutic advances such as chemotherapy concomitant to radiation, intensified radiation regimes and advanced surgical approaches the long term clinical outcome of the patients with HNSCC has not improved significantly in the last decades.
Cancers diagnosed at an early stage have better cure rates than late stage diseases. The aim of this thesis was to elucidate and investigate if laminin-5 and DNA-analysis (aneuploidy) are useful for risk assessment and diagnosis in HNSCC.
Laryngeal cancer in situ (CIS) lesions can progress to invasive cancer and there is no reliable predictor for this. Distinction between CIS and invasive cancer can at times be difficult to asses and hence delay appropriate therapy. In a retrospective study of laryngeal CIS lesions we found that lesions which progressed to invasive cancer during 5-year followup were significantly more often laminin positive than the lesions that did not progress. Various mucosal lesions are frequently encountered in the oral cavity. A marker to identify the truly preneoplastic lesions in order to warrant appropriate treatment and follow-up would be of utter clinical value.
In a retrospective study of dysplastic and reactive lesions which later progressed to cancer or CIS lesions on the same site, we found that 60% of precursor lesions were laminin-5 positive and hereby differed significantly from the matched control lesions that did not progress. Although these investigations are small, our data indicates that laminin-5 expression can help to identify CIS laryngeal lesions with invasive potential and identify oral mucosal lesions at risk for tumor progression.
Distinction between branchial cleft cyst (BCC) and cystic metastases of HNSCC can at times be difficult by cytomorphology. A vast majority of HNSCC exhibit aneuploidy at time of diagnosis. We performed Image cytometry DNA analysis on the fine needle aspiration (FNA) specimens of "BCC"s both in a retrospective and a prospective study. We found that all benign lesions were diploid whereas in the former study 53% of the "BCC"s which later proved to be malignant by histopathology showed aneuploidy.
In the latter study INA from all 14NSCC cystic metastasis which could be assessed showed aneuploidy. Our data suggests that ICM DNA analysis is a valuable supplement when distinction between BCC and cystic metastases of HNSCC is required especially when conventional cytological evaluation is ambiguous.
Methods for early diagnosis of head and neck cancer
info:eu-repo/semantics/doctoralThesis
oai:openarchive.ki.se:10616/480422024-03-09T12:53:32Zcom_10616_1com_10616_189com_10616_46998col_10616_219col_10616_190col_10616_47000
Publications from KI
author
Sellberg, Malin S
2022-05-19T08:40:25Z
2022-05-19T08:40:25Z
2022-05-19
978-91-8016-638-6
http://hdl.handle.net/10616/48042
Clinical training for health profession students is important prior to commencing their future professions. The literature describes a tension between the education assignment and patient care in clinical environments with high demands. Understanding students and supervisors’ experiences in the clinical learning environment isimportant to enhance the quality of clinical education.
The overall aim was to explore the clinical learning environment from students’ and supervisors’ perspectives. Study I compared physiotherapy, medical, speech-language pathology, and nursing students’ perceptions of their clinical learning environments. Study II explored physiotherapy students’ experience of supervisors’ preparedness and supervision practices during their first clinical placement. Study III explored medical students’ experiences in the early stages of clinical training. Study IV explored clinical physiotherapy supervisors’ experience of giving feedback to students. To describe and compare students’ perceptions of their clinical learning environments, the Undergraduate Clinical Education Environment Measure was used. Individual semi-structured interviews were conducted with physiotherapy and medical students. Focus group interviews were performed with physiotherapy supervisors.
The findings suggests that students experienced their clinical learning environment differently, the medical students scoring lower than the other students. The physiotherapy students appreciated supervisors who established a relationship with them, encouraged cooperation in the community, and used intended learning outcomes. The medical students were encouraged to push themselves forward in the clinic and ad hoc solutions concerning supervision occurred. Rather than trying to change the circumstances, they opted to adapt to the busy clinical learning environment. The physiotherapy supervisors found it challenging to provide feedback to students but found support within their network.
Undergraduate students are generally satisfied with their clinical learning environments, but medical students’ low ratings need attention. It is important that supervisors take the initiative to establish a relationship with students and that focus is given for learning outcomes. Supervisors, need support in their educational role, which otherwise risks being downgraded, resulting in clinical training of variable quality for students. The workplace network provides key support for supervisors’ development of their ability to provide feedback to students.
eng
info:eu-repo/semantics/openAccess
Students’ and supervisors’ experiences of supervision and training in clinical learning environment
info:eu-repo/semantics/doctoralThesis
--- Svensk avtalstext följer efter den engelska språkversionen --- 


<h3><b>AGREEMENT ON ELECTRONIC PUBLICATION OF THESES</b></h3>

In accordance with a decision at the meeting with the Board of 
Doctoral Education on 12/05/2004, electronic publication of the 
summary is obligatory for all doctoral theses at KI from 1 January 
2005.

The following agreement has been made on the date hereof between 
Karolinska Institutet University Library, hereinafter referred to
as "the Library", and the author of the thesis, hereinafter referred 
to as "the Author".

1. <b>Grant of rights</b>

1.1 The Author hereby grants the Library a non-exclusive right to 
make the summary contained in the Author's thesis or, as appropriate,
the entire thesis (monograph), hereinafter referred to as "the 
Thesis", available in electronic form on the Library website on the 
Internet without any right to remuneration.

1.2 The Author is aware of and accepts the scope and contents of 
this grant of rights and right to make available via the Internet.

2. <b>The Library's obligations</b>

2.1 The Library shall endeavour to make the Thesis or parts thereof 
available in the format in which the Thesis was supplied to the 
Library, including text, tables, graphics, images, etc. The Library 
has no obligation to proofread the Thesis or check that it coincides 
with any master copy. The Library may make such changes to the Thesis
as may be necessary for technical reasons to enable it to be made 
available on the Internet.

2.2 The Author is responsible for ensuring that the Thesis is
protected against changes by unauthorised persons, e.g. by 
write-protecting the electronic document. 

2.3 The Library  may not dispose of the Thesis in any way other than 
as expressly stated in this Agreement.

3. <b>The Author's obligations</b>

3.1 The Author shall comply with the Library's instructions for 
making the Thesis available.

3.2 The Author shall, when granting the right to publish the Thesis 
to journals, publishing companies or other such parties, safeguard 
the Library's interests in making the work available in accordance 
with this agreement.

3.3 The Author guarantees that he/she is the author of the Thesis and
has a full right to dispose of the Thesis in its entirety. The same 
applies to material attached or otherwise linked to the Thesis, for 
example as appendixes or through links or any other technical 
procedures.

3.4 If the Thesis or parts thereof has been published in 
journals/publications or if for any other reason interested right 
holders other than the author exist, the Author shall obtain the 
necessary permissions from them.

3.5 The Author guarantees that the Thesis contains no material that 
may be considered to infringe any valid right and contains no links 
or other connections to any such material.

3.6 If the Library becomes obliged to compensate any third party 
because the Author has failed to fulfil his or her obligations and 
guarantees under this agreement, the Author shall compensate the 
Library for such damage.

4. <b>Paper printouts, etc.</b>

4.1 The Library has a right to make the Thesis available on the 
Internet in a manner that enables the document to be printed out. 
The Library may also make individual paper printouts and other 
copies of the Thesis, though solely for the Library's internal use.

5. <b>Assignment of the agreement, etc.</b>

5.1 The Library may only assign its rights and/or obligations under 
this agreement to a third party if the Author's interests under the 
agreement are protected.

5.2 Neither party shall have a right to compensation from the other 
party for publication under this agreement in addition to what is 
contemplated in this agreement.

6. <b>Termination of the agreement</b>

6.1 The Library may,  without limitation, cease to make the Thesis 
available.

6.2 The Author has a right to cancel this agreement in writing only 
if an exemption from the obligation to publish is granted by one of 
the disputation committees or a corresponding body within KI. The 
term for notice of termination is three (3) months.

7. <b>Processing of personal data</b>

7.1 The Author gives his or her consent for the Library to process 
personal data relating to the Author to enable publication and 
archiving under this agreement, including use in databases and 
Internet search tools. That consent includes permission to distribute
relevant information for use in similar external databases or search 
tools, regardless of the country in which these are established. 

7.2 The Author gives his or her consent for his or her name and other
personal particulars directly relating to the authorship to be made 
available on the Internet, though only if such conforms to good 
practice. The Library processes personal data in accordance with the
Personuppgiftslagen, PuL [Swedish Data Protection Act] (SFS 
[Svensk författningssamling - Swedish Code of Statutes] 1998:204).
Data contained in the register of theses is covered by the principle
of public access to official documents.

7.3 Authors who have protected personal data can give contact details 
to the Department of Student Affairs at KI.

7.4 The Author has a right, once per calendar year, to issue a written
request for an extract from the register of theses free of charge. 
That request must be made in writing and must be signed by the person
concerned and submitted to Karolinska Institutet University Library.

8. <b>Liability</b>

8.1 Under no circumstances shall the Library be liable for the
contents of published texts or for the Author's actions in general.
The Library is only liable for damage in connection with this
agreement if such damage was caused wilfully by the Library or
through gross negligence on its part. That liability only relates 
to direct damage.

9. <b>Full regulation</b>

9.1 This agreement and any appendixes hereof constitute the full 
regulation by the parties of all matters to which the agreement 
relates. All written or verbal commitments and undertakings prior 
to this agreement are replaced by the contents of this agreement 
and its appendixes.


I have been informed that my summary chapter (thesis frame, "kappa") that is uploaded here may be reviewed in the anti-plagiarism tool iThenticate.

I have read and hereby accept the above agreement with Karolinska 
Institutet University Library.


---SVENSKA---


<h3><b>AVTAL OM ELEKTRONISK PUBLICERING AV AVHANDLINGAR</b></h3>

Enligt beslut vid möte med Styrelsen för forskarutbildning 2004-05-12
är elektronisk publicering av ramberättelsen obligatorisk för alla
doktorsavhandlingar vid KI fr o m den 1 januari 2005.

Mellan Karolinska Institutet Universitetsbiblioteket, nedan kallade
Biblioteket, och avhandlingens författare, nedan kallad Författaren, 
har denna dag träffats följande avtal.

1. <b>Upplåtelse</b>

1.1 Författaren upplåter härigenom, utan rätt till ersättning, en
icke exklusiv rätt för Biblioteket att tillhandahålla ramberättelsen
i Författarens avhandling eller i  förekommande fall hela
avhandlingen (monografi), nedan kallad Avhandlingen, i elektronisk
form på Bibliotekets hemsida/webbplats på Internet.

1.2 Författaren är medveten om, och accepterar, omfattningen och
innebörden i aktuell upplåtelse och tillhandahållande via Internet.

2. <b>Bibliotekets åtaganden</b>

2.1 Biblioteket skall eftersträva att tillhandahålla Avhandlingen
eller delar därav i det utförande Avhandlingen gjorts tillgänglig för
Biblioteket, innefattande text, tabeller, grafik, bilder m.m.
Biblioteket har ingen skyldighet att korrekturläsa Avhandlingen eller
kontrollera dess överensstämmelse med eventuell förlaga. Biblioteket
får göra sådana ändringar i Avhandlingen som av tekniska skäl är
nödvändiga för att möjliggöra tillhandahållandet på Internet.

2.2 Författaren ansvarar för att Avhandlingen skyddas mot ändringar
av obehöriga t. ex. genom skrivskydda det elektroniska dokumentet. 

2.3 Biblioteket får inte förfoga över Avhandlingen på annat sätt än
vad som uttryckligen anges i detta Avtal.

3. <b>Författarens åtaganden</b>

3.1 Författaren skall följa Bibliotekets anvisningar för
tillhandahållandet.

3.2 Författaren skall vid upplåtelse av rätten att publicera
Avhandlingen till tidskrifter, förlag eller andra aktörer, tillvarata
Bibliotekets intresse att göra verket tillgängligt enligt detta avtal.

3.3 Författaren garanterar att han/hon är upphovsman till
Avhandlingen och har fullständig rätt att råda över Avhandlingen i
dess helhet. Detsamma gäller material som är bifogat eller på annat
sätt kopplat till Avhandlingen, till exempel som bilaga eller genom
länkning eller annat tekniskt förfarande.

3.4 Om Avhandlingen eller delar av densamma har publicerats i
tidskrifter/publikationer eller om det av annan anledning finns andra
berörda rättighetshavare än författaren, skall Författaren inhämta
erforderliga tillstånd från dessa.

3.5 Författaren garanterar att Avhandlingen inte innehåller material
som kan anses strida mot gällande rätt eller innehåller länkar eller
andra kopplingar till sådant material.

3.6 Om Biblioteket skulle bli ersättningsskyldigt gentemot tredje
part på grund av att Författaren inte uppfyllt sina åtaganden och
garantier enligt detta avtal skall Författaren kompensera Biblioteket
dess skada.

4. <b>Pappersutskrifter m.m.</b>

4.1 Biblioteket har rätt att tillhandahålla Avhandlingen på Internet
på ett sätt som möjliggör utskrift av dokumentet. Biblioteket får
också göra enstaka pappersutskrifter och andra kopior av
Avhandlingen, dock enbart för Bibliotekets interna bruk.

5. <b>Överlåtelse av avtalet m. m.</b>

5.1 Biblioteket får överlåta sina rättigheter och/eller skyldigheter
enligt detta avtal till tredje part endast med bevarande av
Författarens intressen enligt avtalet.

5.2 Ingen av parterna skall ha rätt till ersättning från den andra
parten för publicering enligt detta avtal, utöver vad som följer av
detta avtal.

6. <b>Avtalets upphörande</b>

6.1 Biblioteket får utan inskränkning avbryta tillhandahållandet av
Avhandlingen.

6.2 Författaren har rätt att skriftligen säga upp avtalet endast om
dispens från publiceringsobligatoriet ges av någon av
disputationskommittéerna eller motsvarande funktion vid KI.
Uppsägningstiden är tre (3) månader.

7. <b>Behandling av personuppgifter</b>

7.1 Författaren samtycker till att Biblioteket databehandlar
personuppgifter hänförliga till Författaren, för att möjliggöra
publicering och arkivering enligt detta avtal, innefattande
användning i databaser och sökverktyg för Internet. Samtycket
omfattar medgivande till utlämnande av relevanta uppgifter, för
användning i dylika externa databaser eller sökverktyg, oavsett i
vilket land dessa är etablerade. 

7.2 Författaren samtycker till att hans/hennes namn och andra
personuppgifter direkt hänförliga till författarskapet görs
tillgängliga på Internet, dock endast i den omfattning som det är
förenligt med god sed. Biblioteket behandlar personuppgifter enligt
Personuppgiftslagen, PuL, (SFS 1998:204). Uppgifter i
avhandlingsregistret omfattas av offentlighetsprincipen.

7.3 Författare som har skyddade personuppgifter kan ange
kontaktuppgifter till Studentavdelningen på KI.

7.4 Författaren har rätt ett en gång per kalenderår skriftligen
begära ett kostnadsfritt utdrag ur avhandlingsregistret. Denna
begäran måste vara skriftlig och personligen undertecknad och
tillställs Karolinska Institutet Universitetsbiblioteket.

8. <b>Ansvar</b>

8.1 Biblioteket är inte på något vis ansvarigt för innehållet i
publicerade texter eller för Författarens agerande i övrigt.
Biblioteket ansvarar endast för skador i samband med detta avtal om
dessa orsakats av Biblioteket uppsåtligen eller genom grov
vårdslöshet. Ansvaret omfattar enbart direkta skador.

9. <b>Fullständig reglering</b>

9.1 Avtalet med dess eventuella bilagor utgör parternas fullständiga
reglering av alla frågor som avtalet berör. Alla skriftliga eller
muntliga åtaganden och utfästelser som föregått avtalet ersätts av
innehållet i detta avtal med bilagor.


Jag är medveten om att min ramberättelse (kappa) som laddats upp här kan komma att granskas i anti-plagieringsverktyget iThenticate.

Jag har tagit del av och accepterar härigenom ovanstående avtal med
Karolinska Institutet Universitetsbiblioteket.
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