Department of Medical Sciences

Department of
Medical Sciences
Annual Report 2011
Fastställd av Eva Tiensuu Jansson 2012-04-29
1

Introduction
The Department of Medical Sciences has had yet another successful year. The Department, being the
largest clinical department at the Faculty of Medicine and Pharmacy at Uppsala University with a staff of
194, has grown both in number of employees but even more in income which underscores the ability of the
researchers at the Department to attract grants.
The excellence of the Department's research groups is also shown by the over 550 peer reviewed
publications and 13 theses produced during 2011, and through the report of evaluation (KoF11) of the
research at all faculties that was carried out last year in order to assess the quality of the research at Uppsala
University. The positive judgment by the review panel of the research conducted at the Department came as
no surprise, but we were pleased to read in the final report that the panel was "impressed by the overall
quality of the research, with several groups reaching the highest international standards". The progress
made since KoF07 was also acknowledged and the panel members were impressed by the emphasis on new
genetic information, and also by the commendable joint ventures with veterinary studies. With respect to
KoF11, I would like to take this opportunity to thank all research groups for their time spent on collecting
the requested plentiful data for the evaluation, and for their excellent presentations to the review panel.
The Department of Medical Sciences harbors several different clinical specialties ranging from internal
medicine through clinical microbiology to occupational and environmental medicine. This wide variety of
research areas provides a special challenge and an arena for inter-disciplinary collaboration. The research
activities at the Department are organized into six programs, denoted Cancer, Cardiology and Clinical
physiology, Diabetes and Metabolic Diseases, Epidemiology, Inflammation and autoimmunity, and
Microbiology and Infectious diseases. During 2011 researchers at the Department have achieved major
advances in their research and this will be presented on the following pages.
Teachers at our department are very active in several of the undergraduate programs at the Faculty of
Medicine. In total about 2000 students pass courses for which we are responsible every year. The
department aims to provide a good environment for learning combined with education given at a high
academic level. In this context I would like to congratulate MartinWohlin to the Optimus award, given by
the Medical study council for the course with highest ranking in the student's course evaluation, and Violeta
Armijo del Valle who was awarded a pedagogy stipend for her work with diabetes patients.
During 2011 several persons retired after long and very successful careers. On behalf of the Department I
would like to thank Gunnar Birgegård, Jonas Blomberg, Roger Hällgren, Ingrid Stolt, Carin Muhr, Agneta
Trulson and Karin Wikblad for their long services and many important contributions. Finally I would like
to thank all personnel at the Department for their excellent work during 2011.
Eva Tiensuu Janson
Head of department
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Contents
Contents __________________________________________________________________ 3
Organization of the Department of Medical Sciences _____________________________ 5
Group leaders 2011 _________________________________________________________ 6
Funding ___________________________________________________________________ 7
Scientific Reports ___________________________________________________________ 8
Cancer _______________________________________________________________ 8
Endocrine Oncology
Eva Tiensuu Janson and Kjell Öberg _____________________________ 8
Haematology
Martin Höglund _____________________________________________ 15
Cancer Pharmacology and Computational Medicine
Rolf Larsson _______________________________________________ 21
Endocrine tumour biology
Britt Skogseid ______________________________________________ 28
Biochemical endocrinology
Mats Stridsberg _____________________________________________ 31
Epidemiology ________________________________________________________ 34
Cardiovascular epidemiology
Lars Lind __________________________________________________ 34
Respiratory medicine and allergology
Christer Janson _____________________________________________ 45
Metabolic bone disease
Östen Ljunggren ____________________________________________ 52
Clinical Pharmacogenetics and Osteoporosis
Håkan Melhus ______________________________________________ 56
Occupational and environmental medicine
Eva Vingård ________________________________________________ 62
Inflammation and autoimmunity _________________________________________ 71
Autoimmunity
Olle Kämpe ________________________________________________ 71
Biological structure and function
Anders Larsson _____________________________________________ 75
Coagulation and Inflammation Science
Agneta Siegbahn ____________________________________________ 83
Dermatology and Venereology
Anders Vahlquist ____________________________________________ 87
Gastroenterology and hepatology
Per Hellström ______________________________________________ 92
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Molecular Medicine
Ann-Christine Syvänen _______________________________________ 96
Renal Medicine
Bengt Fellström ____________________________________________ 101
Rheumatology
Lars Rönnblom ____________________________________________ 106
Clinical Microbiology and Infectious Diseases ____________________________ 112
Björn Olsen, Jan Sjölin, Hilpi Rautelin, Jonas Blomberg _____________ 112
Cardiology and Clinical physiology _____________________________________ 131
Cardiology
Bertil Lindahl ______________________________________________ 131
Cardiology-Arrhythmia
Carina Blomström-Lundqvist __________________________________ 145
Clinical physiology
Hans Hedenström __________________________________________ 149
Diabetes and Metabolic diseases _______________________________________ 156
Diabetes
Per-Ola Carlsson ___________________________________________ 156
Endocrinology, Diabetes and Metabolism
Anders Karlsson ___________________________________________ 160
Diabetes Nursing Research
Karin Wikblad______________________________________________ 162
Emergency medicine _________________________________________________ 165
Åsa Muntlin Athlin __________________________________________ 165
Undergraduate Teaching ___________________________________________________ 166
Core Facilities ____________________________________________________________ 167
The SNP&SEQ Technology Platform in Uppsala _____________________________ 167
Uppsala Array Platform ________________________________________________ 169
Awards and Appointments 2011 _____________________________________________ 172
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Organization of the Department of Medical Sciences
Chair, head of department
Eva Tiensuu Janson
Deputy head of department
Lars Lind
Assistant heads of department
Jan Sjölin, responsible for graduate studies
Christer Janson, responsible for undergraduate studies
Department board
Eva Tiensuu Janson chair
Jan Sjölin teacher
Håkan Melhus teacher
Johan Sundström teacher
Lars Rönnblom teacher
Åsa Forsberg technical staff
Jessica Nordlund PhD student
Julia Wei student representative
Lovisa Sylvén student representative
Deputies
Marie Thörn teacher
Torbjörn Linde teacher
Christer Janson teacher
Hans Thörmä teacher
Sofia Nordman technical staff
Christofer Bäcklin PhD student
Viktor Mill student representative
Vacant student representative
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Group leaders 2011
Carina Blomström-Lundqvist carina.blomstrom.lundqvist@akademiska.se
Per-Ola Carlsson per-ola.carlsson@medsci.uu.se
Bengt Fellström bengt.fellstrom@medsci.uu.se
Hans Hedenström hans.hedenström@medsci.uu.se
Per Hellström per.hellstrom@medsci.uu.se
Martin Höglund martin.hoglund@medsci.uu.se
Christer Janson christer.janson@medsci.uu.se
Anders Karlsson anders.karlsson@medsci.uu.se
Olle Kämpe olle.kampe@medsci.uu.se
Anders Larsson anders.larsson@akademiska.se
Rolf Larsson rolf.larsson@medsci.uu.se
Lars Lind lars.lind@medsci.uu.se
Bertil Lindahl bertil.lindahl@ucr.uu.se
Östen Ljunggren osten.ljunggren@medsci.uu.se
Håkan Melhus hakan.melhus@medsci.uu.se
Björn Olsen bjorn.olsen@medsci.uu.se
Lars Rönnblom lars.ronnblom@medsci.uu.se
Agneta Siegbahn agneta.siegbahn@medsci.uu.se
Jan Sjölin jan.sjolin@akademiska.se
Britt Skogseid britt.skogseid@medsci.uu.se
Mats Stridsberg mats.stridsberg@medsci.uu.se
Ann-Christine Syvänen ann-christine.syvanen@medsci.uu.se
Eva Tiensuu Janson eva.tiensuu_janson@medsci.uu.se
Anders Vahlquist anders.vahlquist@medsci.uu.se
Karin Wikblad karin.wikblad@medsci.uu.se
Eva Vingård eva.vingard@medsci.uu.se
Kjell Öberg kjell.oberg@medsci.uu.se
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Funding 2011
GRANTS
SWEDISH RESEARCH COUNCIL 19 MSEK
SIDA (Swedish International Development Cooperation Agency) 10 MSEK
THE SWEDISH RESEARCH COUNCIL FORMAS 5 MSEK
THE SWEDISH HEART-LUNG FOUNDATION 11 MSEK
EU (6 th and 7 th FRAME PROGRAMS) 8 MSEK
VINNOVA 3 MSEK
SWEDISH FOUNDATION FOR STRATEGIC RESEARCH 6 MSEK
THE SWEDISH CANCER FOUNDATION 4 MSEK
OTHER FUNDINGS 23 MSEK
GOVERNMENT FOR RESEARCH (ALF) - FUNDING 50 MSEK
GOVERNMENT OFFICE 3 MSEK
TOTAL 142 MSEK
CONTRACT RESEARCH
VARIOUS COMMISSIONING AGENTS 37 MSEK
TOTAL 37 MSEK
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Scientific Reports
Cancer
Cancer research at the Department of Medical Sciences is carried out by
several independent research groups, and spans all the way from basic
studies of carcinogenesis, detection and monitoring of cancers,
development and characterization of cancer drugs, and to clinical trials.
There are three groups working in the area of neuroendocrine tumours,
studying carcinogenesis, development of biomarkers, exploring new
treatment concepts and conducting clinical trials. Research on
haematological malignancies is focused on development and testing of
new drugs and development of registers for malignant haematological
disorders. The cancer pharmacology and comput-ational medicine
research program acts at the intersection of clinical pharmacology,
oncology and medical bioinformatics. Key issues are related to drug
resistance and improved multi-compound therapies.
Endocrine Oncology
Eva Tiensuu Janson and Kjell Öberg
Neuroendocrine tumours (NETs) are life-threatening diseases that have been the subject of investigation for
more than a century. NETs derive from cells that have the unique ability to synthesize, store and secrete a
variety of metabolic active products including peptides, and amines, which cause specific clinical
syndromes in different parts of the body. The majority of neuroendocrine tumour patients are usually
diagnosed late, and surgery for neuroendocrine tumour patients with metastasis is seldom curative.
Although new powerful medical treatments are available, the need of identifying novel diagnostic,
prognostic and predictive biomarkers to broader the knowledge about disease course and response to
therapy are clearly warranted.
The research group with Eva Tiensuu Janson as principal investigator focuses on research concerning
neuroendocrine tumours with a special emphasis on tumours derived from the gastric mucosa and small
intestine, as well as a new line of research including neuroendocrine differentiation in breast cancer. The
research group of Kjell Öberg has two main objectives; the first is to develop new potential biomarkers for
small intestinal and lung neuroendocrine tumours, and the second is to develop new NET-therapies.
Genetics in familial and sporadic neuroendocrine tumours
Eva Tiensuu Janson and Janet Cunningham
Ileal carcinoid is a clinically distinct endocrine tumour that has generally been considered a sporadic
disease. We have now, however, identified a large number of families with an inherited variant of ileal
carcinoid tumours. Through comprehensive clinical and molecular studies we could show that familial
tumours are clinically indistinguishable from sporadic tumours and that the genetic changes involves
chromosome 18. We are now performing exome and whole genome sequencing of familial patients’
tumours and blood in order to define the specific genetic events which lead to tumour development. This
work is performed in collaboration with researchers at the department of genetics and pathology at Uppsala
University (professor Jan Dumanski) and Karolinska Institutet.
In a different genetic study of ileal carcinoids we have performed the first study to investigate the role of
constitutional genetic polymorphisms predisposing individuals to this disease. Our genome-wide
association study (GWAS) of 239 cases and 110 controls identified four copy-number variants (CNVs) in
multiple cases that were absent in the controls. The obtained results will provide a valuable resource for
future work and they warrant for a replication study in an independent cohort.
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Expression of neuroendocrine markers in tumours
Malin Grönberg, Ylva Naesser, Apostoles Tsolakis, Clary Georganzi and Eva Tiensuu Janson
One of our main objectives is to identify the expression of tumour markers in neuroendocrine tumours in
order to predict response to treatment and prognosis. We have a special focus on the proliferation marker
Ki67, and have shown that even very small increases of proliferation in ileal carcinoids may have an impact
on the survival of patients. This is further investigated in larger cohorts to confirm our previous results.
Another area of interest is the expression of ghrelin and obestatin in normal tissues and tumours. We have
shown that these two peptides are expressed in normal breast tissue and more recently in the majority of
breast cancer specimens collected from a cohort at the university hospital in Malmö. Ghrelin expression
was significantly correlated to better recurrence-free survival and breast cancer-specific survival. In related
projects we have e.g. studied the expression of somatostatin receptors on neuroblastomas, and found
frequent expression of these receptors, suggesting that treatment with somatostatin analogs should be
further explored in neuroblastomas.
Studies of neuroendocrine carcinomas (NEC)
Staffan Welin, Eva Tiensuu Janson
As a collaborative project between the Nordic countries we are studying NECs. In our ongoing study,
factors of possible prognostic and predictive significance are investigated as well as the effect of different
treatments given to these patients. This study will include a comprehensive series of >300 patients with
NEC in the gastrointestinal tract and will hopefully shed new light on the difficulties of how to diagnose
and treat these patients.
Members of the group during 2011
Eva Tiensuu Janson, Professor of Medicine
Staffan Welin, MD, PhD
Janet Cunningham, MD, PhD
Apostolos Tsolakis, MD, PhD
Ylva Naesser MD, PhD-student
Clary Georgantzi MD, PhD-student
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Malin Grönberg, PhD
Ylva Naesser MD, PhD-student
Clary Georgantzi MD, PhD-student
Åsa Forsberg, Laboratory technician
George Kanakis, MD, PhD-student
Åsa Forsberg, Laboratory technician
Novel biomarkers for small intestine and lung neuroendocrine tumors
Valeria Giandomenico, Tao Cui, Su-Chen Li, Kjell Öberg
We continue to investigate novel potentials biomarkers for small intestine (SI-) and lung-neuroendocrine
tumours (NETs). In separate projects we are investigating microRNAs as novel biomarkers for SI-NETs,
and analyzing specific genes and proteins expressed by SI-NETs and lung-NETs.
MicroRNAs during early tumourigenesis and tumour progression
MicroRNAs have a significant impact on the tumourigenesis of many malignancies so it is reasonable to
believe that they play a role in NETs as well. A growing number of potential oncogenic or tumour
suppressor miRNAs have been identified in SI-NETs and lung NETs and recent evidences support the use
of specific miRNA signatures to predict clinical outcome. We therefore genome-wide profiled miRNA
expression and could identify more than 30 miRNAs that could classify SI-NET at different stages. Among
these we selected 9 miRNAs for QRT-PCR analyses and verified that 5 miRNAs are significantly
upregulated and 4 significantly down regulated. We will now try to clarify whether they have a role in early
tumorigenesis and tumour progression of SI-NETs and lung NETs, and also to investigate their usefulness
as biomarkers.
OR51E1 as a novel therapeutic target
OR51E1 (olfactory receptor family 51subfamily E, member 1) is a G-protein couples receptor that has been
detected at the transcriptional level in normal EC cells and SI-NET cells. We have characterized the

expression of OR51E1 in more detail, using Q-RT-PCR and immunohistochemistry analyses on tumour
slides. OR51E1 is expressed in approximately 50 % of SI-NET tumor cells, and over 25% of liver
metastasis, but not in normal hepatocytes. Thus, high expression in a subgroup of patients might render
OR51E1 a novel tissue marker and may be developed as a radiological diagnostic tool and/or a therapeutic
target.
Targeted treatment of neuroendocrine tumours
Kjell Öberg
A majority of NETs express somatostatin receptors which consequently might be targets for new therapies.
Since almost 30 years back alpha interferon has been applied for treatment of small intestinal NETs with
significant clinical benefit, however with significant side effects. If the side effects could be prevented
significantly higher doses, and better efficacy, of alpha interferon could be achieved. In a collaboration
with Profs. Katarina Edwards and Lars Gedda we try to solve the problem by using interferon-loaded
nanoparticles, coated with somatostatin to target the particles to NETs. In a related project, together with
Prof. Magnus Essand, we are employing oncolytic adenoviruses modified with somatostatin motifs for
selective infection of neuroendocrine tumour cells.
Novel drugs to treat neuroendocrine tumours
Dan Granberg, Dhana Larsson and Kjell Öberg
We are working with Prof. Rolf Larsson to study dose response and mechanism of action of new drugs in
cell lines of NETs. We are using the Holow Fiber Assay and have e.g. shown that the drugs emetine and
CGP-74514A have antitumor activity and induced caspase-3 activation.
In collaboration with Ulrike Garske at the Dept. of Nuclear Medicine we are evaluating the clinical
treatment of patients with different types of NETs for effects of 177Lutetium-DOTA-Octreotate. So far 250
patients have been treated and the preliminary data indicate a significant anti-tumour effect in patients
expressing high content of somatostatin receptor on the tumour cells
Members of the group 2011
Kjell Öberg, Professor, MD, PhD
Valeria Giandomenico, PhD
Dan Granberg, MD, PhD
Dhana Larsson, PhD student
Funding
Eva Tiensuu Janson
Swedish Cancer foundation: 650 kSEK,
Lions foundation: 100 kSEK
ALF: 850 kSEK
Dan Granberg
Lions Research foundation: 100 kSEK
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Tao Cui, PhD student
Su-Chen Li, PhD student
Åsa Forsberg, PhD student
Kjell Öberg
Novartis research fellow grant: 400 kSEK
Novartis postdoc grant: 700 kSEK
Söderberg's foundation: 2.1 MSEK
Lions Research foundation: 250 kSEK
ALF: 800 kSEK
Valeria Giandomenico
Lions Research foundation: 100 kSEK

Publications 2009-2011
1. Welin S, Stridsberg M, Cunningham J, Granberg D, Öberg K, Eriksson B, Janson ET. Elevated
plasma chromogranin A is the first indication of recurrence in radically operated midgut carcinoid
tumors. Neuroendocrinology 2009; 89:302-307
2. Tsolakis AV, Grimelius G, Stridsberg M, Falkmer S, Valdum H, Saras J, Janson ET. Obestatin/ghrelin
cells in normal mucosa and endocrine tumours of the stomach. Eur J Endocrinol 2009;160:941-949
3. Larsson DE, Hassan S, Larsson R, Öberg KE, Granberg PDK. Combination analyses of anti-cancer
drugs on human neuroendocrine tumor cell lines. Cancer Chemother Pharmacol 2009;65(1):5-12
4. Vikman S., Sommaggio R., de la Torre M., Öberg K., Essand M., Giandomenico V., Loskog A., and
Tötterman T.H. Midgut carcinoid patients display increased numbers of regulatory T cells in
peripheral blood with infiltration into tumor tissue. Acta Oncologica, 48 (3): 391-400, 2009
5. Leja J., Essaghir A., Essand M, Wester K, Öberg K., Tötterman TH., Lloyd R, Vasmatzis G.,
Demoulin JB., Giandomenico V. Novel markers for enterochromaffin cells and gastro-intestinal
neuroendocrine carcinomas. Modern Pathology, 2009 Feb; 22(2):261-72
6. Granberg, D. Investigational drugs in neuroendocrine tumours. Expert Opinion On Investigational
Drugs 2009;18(5):601-608
7. Oberg KE. Is it time to widen the use of somatostatin analogs in neuroendocrine tumors? J Clin Oncol.
2009 Oct 1;27(28):4635-6
8. Oberg K, Jelic S; ESMO Guidelines Working Group. Neuroendocrine gastroenteropancreatic tumors:
ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20
Suppl 4:150-3
9. Oberg K, Jelic S; ESMO Guidelines Working Group. Neuroendocrine bronchial and thymic tumors:
ESMO clinical recommendation for diagnosis, treatment and follow-up. Ann Oncol. 2009 May;20
Suppl 4:147-9
10. Oberg K. Genetics and molecular pathology of neuroendocrine gastrointestinal and pancreatic tumors
(gastroenteropancreatic neuroendocrine tumors). Curr Opin Endocrinol Diabetes Obes. 2009
Feb;16(1):72-8
11. Oberg K, Ferone D, Kaltsas G, Knigge UP, Taal B, Plöckinger U; Mallorca Consensus Conference
participants; European Neuroendocrine Tumor Society. ENETS Consensus Guidelines for the
Standards of Care in Neuroendocrine Tumors: biotherapy. Neuroendocrinology. 2009;90(2):209-13
12. Grönberg M, Amini RM, Stridsberg M, Janson ET, Saras J. Neuroendocrine markers are expressed in
mammary glands. Regulatory Peptides 2010;160:68-74.
13. Cunningham JL, Tsolakis A, Jacobson A, Janson ET. Connective tissue growth factor expression in
endocrine tumours is associated with high stromal expression of alpha-smooth muscle actin.Eur J
Endocrinol 2010;163:691-7.
14. Kaltsas GA, Cunningham JL, Falkmer SE, Grimelius L, Tsolakis AV. Expression of connective tissue
growth factor and IGF1 in normal and neoplastic gastrointestinal neuroendocrine cells and their
clinico-pathological significance. Endocr Relat Cancer 2010;13: 61-71.
15. Modlin IM, Gustafsson BI, Moss SF. Pavel M, Tsolakis AV, Kidd M. Chromogranin A –biological
function and clinical utility in neuroendocrine tumor disease. Ann Surg Oncol 2010;17:2427-43
16. Sandström M, Garske U, Granberg D, Sundin A, Lundqvist H. Individualized dosimetry in patients
undergoing therapy with 177 Lu-DOTA-D-Phe 1 -Tyr 3 -octreotate. Eur J Nucl Med 2010;37(2): 212-225
17. Kindmark H, Janson ET, Gustafsson B, Eriksson C, Larsson G, Granberg D, Kozlovacki G, Skogseid
B, Welin S, Öberg K, Eriksson B. Five patients with malignant endocrine tumors treated with imatinib
mesylate (Glivec®). Acta Oncol 2010;49(1):100-101
18. Giandomenico V. Molecular pathology of gastrointestinal tumours-selected topics. Diagnostic
histopathology, 2010 May (Vol. 16, Issue 5, Pages 243-250)
19. Cui T., Hurtig M., Elgue G., Li SC., Pelosi G., Essaghir A., Demoulin JB, Veronesi G., Alimohammadi
M., Öberg K., Giandomenico V. Paraneoplastic antigen ma2 autoanti-bodies as specific blood
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iomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS One,
accepted December 2010
20. Leja J., Nilsson B., Yu D., Gustafson E., Åkerström G., Öberg K., Giandomenico V., Essand M.
Double-detargeted oncolytic adenovirus shows replication arrest in liver cells and retains
neuroendocrine cell killing ability. PLoS ONE, 2010 Jan; (5) e8916
21. Walsh KM, Choi M, Oberg KE, Kulke MH, Yao JC, Wu C, Jurkiewicz M, Hsu LI, Hooshmand SM,
Hassan M, Janson ET, Cunningham J, Vosburgh E, Sackler RS, Lifton RP, Dewan AT, Hoh J. Endocr
Relat Cancer. 2010 Dec 7
22. Liu EH, Oberg K. The history and development of the gastroenteropancreatic endocrine axis.
Endocrinol Metab Clin North Am. 2010 Dec;39(4):697-711
23. Oberg K. [Neuroendocrine tumors--new diagnostics and treatment]. Ugeskr Laeger. 2010 Oct
25;172(43):2941.
24. Phan AT, Oberg K, Choi J, Harrison LH Jr, Hassan MM, Strosberg JR, Krenning EP, Kocha W,
Woltering EA, Maples WJ; North American Neuroendocrine Tumor Society (NANETS). NANETS
consensus guideline for the diagnosis and management of neuroendocrine tumors: well differentiated
neuroendocrine tumors of the thorax (includes lung and thymus). Pancreas. 2010 Aug;39(6):784-98.
25. Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP. Role of somatostatins in gastroenteropancreatic
neuroendocrine tumor development and therapy. Gastroenterology. 2010 Sep;139(3):742-53
26. Modlin IM, Moss SF, Oberg K, Padbury R, Hicks RJ, Gustafsson BI, Wright NA, Kidd M.
Gastrointestinal neuroendocrine (carcinoid) tumours: current diagnosis and management. Med J Aust.
2010 Jul 5;193(1):46-52.
27. Oberg K, Akerström G, Rindi G, Jelic S; ESMO Guidelines Working Group. Neuroendocrine
gastroenteropancreatic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol. 2010 May;21 Suppl 5:v223-7
28. Oberg K, Hellman P, Kwekkeboom D, Jelic S; ESMO Guidelines Working Group. Neuroendocrine
bronchial and thymic tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and
follow-up. Ann Oncol. 2010 May;21 Suppl 5:v220-2
29. Janson ET, Sørbye H, Welin S, Federspiel B, Grønbaek H, Hellman P, Mathisen O, Mortensen J,
Sundin A, Thiis-Evensen E, Välimäki MJ, Oberg K, Knigge U. Nordic Guidelines 2010 for diagnosis
and treatment of gastroenteropancreatic neuroendocrine tumours. Acta Oncol. 2010 Aug;49(6):740-56
30. Kos-Kudła B, O'Toole D, Falconi M, et al. Consensus Conference Participants. ENETS consensus
guidelines for the management of bone and lung metastases from neuroendocrine tumors.
Neuroendocrinology. 2010;91(4):341-50
31. Pavel M, Grossman A, Arnold R, et al Consensus Conference Participants. ENETS consensus
guidelines for the management of brain, cardiac and ovarian metastases from neuroendocrine tumors.
Neuroendocrinology. 2010;91(4):326-32.
32. Oberg K. Cancer: antitumor effects of octreotide LAR, a somatostatin analog. Nat Rev Endocrinol.
2010 Apr;6(4):188-9
33. Bushnell DL Jr, O'Dorisio TM, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide.
J Clin Oncol. 2010 Apr 1;28(10):1652-9
34. Larsson DE, Wickström M, Hassan S, Oberg K, Granberg D. The cytotoxic agents NSC-95397,
brefeldin A, bortezomib and sanguinarine induce apoptosis in neuroendocrine tumors in vitro.
Anticancer Res. 2010 Jan;30(1):149-56
35. Klimstra DS, Modlin IR, Adsay NV, et al. Pathology reporting of neuroendocrine tumors: application
of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg
Pathol. 2010 Mar;34(3):300-13
36. Cunningham J, Diaz de Ståhl T, Sjöblom T, Westin G, Dumanski J, Janson ET. Common pathogenetic
mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors. Genes
Chromosomes and Cancer 2011;50:82-94
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37. Georgantzi K, Tsolakis AV, Stridsberg M, Jakobsson Å, Christofferson R, Janson ET. Differentiated
expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma.
Pediatric Blood and Cancer 2011;56:584-589.
38. Walsh KM, Choi M, Öberg K, et al A pilot genome-wide association study shows rare copy-number
variants enriched leucocytic genome of patients with ileal neuroendocrine tumors. Endocrine Related
Cancer 2011;18:171-180.
39. Ludvigsen E, Stridsberg M, Janson ET, Sandler S. Altered expression of somatostatin receptors in
pancreatic islets from NOD mice cultured at different glucose concentrations in vitro and in islets
transplanted to diabetic NOD mice in vivo. Experimental Diabetes Research 2011;2011:623472
40. Grönberg M, Fjällskog ML, Jirström K, Janson ET. Expression of ghrelin is correlated to a favorable
outcome in invasive breast cancer. Acta Oncologica. 2011, Nov, e-publ.
41. Norlén O, Stålberg P, Oberg K, Eriksson J, Hedberg J, Hessman O, Janson ET, Hellman P, Åkerström
G. Long-term results of surgery for small intestinal neuroendocrine tumors at a tertial referral center.
World J Surg. 2011 Oct 8,
42. Öberg K. Neuroendocrine tumors: recent progress in diagnosis and treatment. Endocrine-Related
Cancer. 2011;18:E3-E6.
43. Antonodimitrakis P, Tsolakis A, Welin S, Kozlovacki G, Öberg K, Granberg D. Gastric carcinoid in a
patient infected with Helicobacter pylori : A new entity?. World Journal of Gastroenterology.
2011;17(25):3066-3068.
44. Yao J, Ito T, Öberg K. Advances in Pancreatic Neuroendocrine Tumor Treatment REPLY. New
England Journal of Medicine. 2011;364(19):1874-1875.
45. Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Öberg K. Clinical effect of temozolomidebased
chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line
chemotherapy. Cancer. 2011;117(20):4617-4622.
46. Kulke M, Siu L, Tepper J, Fisher G, Jaffe D, Haller D, et al. Future Directions in the Treatment of
Neuroendocrine Tumors : Consensus Report of the National Cancer Institute Neuroendocrine Tumor
Clinical Trials Planning Meeting. Journal of Clinical Oncology. 2011;29(7):934-943.
47. Yao J, Shah M, Ito T, Bohas C, Wolin E, Van Cutsem E, et al. Everolimus for advanced pancreatic
neuroendocrine tumors. New England Journal of Medicine. 2011;364(6):514-523.
48. Leja J, Yu D, Nilsson B, Gedda L, Zieba A, Hakkarainen T, et al. Oncolytic adenovirus modified with
somatostatin motifs for selective infection of neuroendocrine tumor cells. Gene Therapy.
2011;18(11):1052-1062.
49. Pavel M, Hainsworth J, Baudin E et al. Everolimus plus octreotide long-acting repeatable for the
treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a
randomised, placebo-controlled, phase 3 study. The Lancet. 2011;378(9808):2005-2012.
50. Schott M, Öberg K. Neuroendocrine neoplasms. Hormone and Metabolic Research. 2011;43(12):823-
824.
51. Yao J, Pavel M, Phan A, Kulke M, Hoosen S, St Peter J, et al. Chromogranin A and Neuron-Specific
Enolase as Prognostic Markers in Patients with Advanced pNET Treated with Everolimus. Journal of
Clinical Endocrinology and Metabolism. 2011;96(12):3741-3749.
Reviews
1. Öberg K. Somatostatin analog octreotide LAR in gastro-entero-pancreatic tumors. Expert Rev
Anticancer Ther. 2009 May; 9(5):557-66.
2. Öberg KE. Gastrointestinal neuroendocrine tumors. Ann Oncol. 2010 Oct;21 Suppl 7:vii72-vii80
3. Öberg K. Pancreatic endocrine tumors. Semin Oncol. 2010 Dec;37(6):594-618.
4. Cunningham J, Janson ET. The biological hallmarks of ileal carcinoids. Eur J Clin Invest
2011;41:1353-1360.
13

5. Culler M, Öberg K, Arnold R, Krenning E, Sevilla I, Díaz J. Somatostatin analogs for the treatment of
neuroendocrine tumors. Cancer Metastasis Review. 2011;30(1):9-17.
6. Essand M, Leja J, Giandomenico V, Öberg K. Oncolytic Viruses for the Treatment of Neuroendocrine
Tumors. Hormone and Metabolic Research. 2011;43(12):877-883.
7. Lindholm D, Öberg K. Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine
tumors. Hormone and Metabolic Research. 2011;43(12):832-837
8. Öberg K.Circulating biomarkers in gastroenteropancreatic neuroendocrine tumours. Endocr Relat
Cancer. 2011 Oct 17;18 Suppl 1:S17-25.
9. Öberg K, Castellano D., Current knowledge on diagnosis and staging of neuroendocrine tumors.
Cancer Metastasis Rev. 2011 Mar;30 Suppl 1:3-7.
Books
1. Öberg K. Neuroendocrine Tumours. In: Management of Rare Adult Tumours. Paris: Springer; 2010.
p. 539-550.
14

Haematology
Martin Höglund
The Dept of Haematology performs research on all the major fields of haematology, with the following
focus areas;
� Development and testing of new drugs and therapy strategies in malignant haematological
diseases, in particular acuto leukemias (AML, ALL).
� Studies based on data from national population based registries (e.g. CML, AML, ALL, MDS,
Myeloma)
� Studies on myeloproliferative neoplasms (MPN), CML myeloma and infectious complications in
the immunocompromised host
An important part of the activities of the Haematology group is also leadership and participation in
national and international research groups for initiating international studies, for guidelines and for
development of centres of clinical excellence. We participate actively in the U-CAN project (structured
biobanking at diagnosis, follow-up and relapse)
Preclinical and clinical studies in leukaemia
Anna Eriksson, Martin Höglund
The overall aim of the group, which collaborate closely with the Pharmacology Cancer group (prof Rolf
Larsson, Caroline Haglund), is preclinical development of new drugs in haematological malignancies. We
are studying the antiapoptotic/cytotoxic effects and mechanisms of resistance of new drugs on cell lines as
well as on primary tumour cells from patients with different kinds of leukaemia..A recent focus is
preclinical characterization of new signal transduction inhibitors in AML. Through collaboration with
Akinion Pharmaceuticals, we have gained access to a number of new small molecular tyrosine kinase
inhibitors, e.g. the compound AKN-028. Through in vitro and in vivo studies we have shown that AKN-
028 has a significant dose-dependent cytotoxic effect in AML cells, and a clear antileukemic effect with
low toxicity in mice. In current studies we are aiming to in more detail characterise the mechanism of
action of AKN-028 as well as its specificity.
Population-based registry studies in CML and acute leukemia
Martin Höglund, Helene Hallböök
The Swedish CML and AML registries are internationally unique, including more than 700 patients with
CML, and more than 5000 patients with acute leukaemia, respectively. Recent analysis shows e.g. that the
estimated 5 yrs survival for patients with CML is 80% and in certain diagnostic subgroups 95%. At present,
our acute leukaemia registry based studies focus on short and long term outcome of allogeneic
haematopoietic stem cell transplantation and on the early mortality in patients with newly diagnosed acute
promyelocytic leukaemia.
Chronic myelogenous leukaemia (CML)
Ulla Strömberg, Bengt Simonsson, and Stina Söderlund
In collaboration with Dept. of Clinical Immunity we are investigatíng pre-existing and developing antitumour
immunity during treatment with tyrosine kinase inhibitors (TKIs). Patients enrolled in clinical trials
within a Nordic network are evaluated for immunological phenotype and function. Before treatment and at
different time-points the patients donate blood for research purposes. Different TKIs are investigated, and
the results are then correlated to TKI efficacy. In a similar study on CLL we have recently shown that
cytotoxic populations of CD4+ T cells, including Tregs, are present in patients with B cell malignancy and
may be an important factor in immune-related disease control.
15

Myeloproliferative neoplasms (MPN), cancer anaemia and supportive care
Gunnar Birgegård, Elisabeth Ejerblad, and Anncarin Svanberg
In MPN and cancer anaemia we are involved in several clinical trials; a phase II study of the effect of the
HDAC-inhibitor Vorinostat, a large European multicentre study for long term follow-up of plateletreducing
therapy in essential thrombocythemia (ET), a 7-year prospective follow-up of ET patients treated
with anagrelide, and a randomised phase II trial investigating the effect of IV iron alone in cancer patients
with functional iron deficiency. As regards supportive care, we have previously shown that cryotherapy
significantly reduces mucositis after high dose chemotherapy, and in two ongoing studies we are
investigating the physiological mucosal effects on oral mucosa and the protective effect of a new saturated
calcium-phosphate solution in addition to cryotherapy during chemotherapy. We are also involved in a
randomised study comparing standard anti-emetic therapy with addition of a new anti-emetic drug, Emend
after high dose chemotherapy.
Acute lymphoblastic leukemia – national studies of toxicity, prognostic factors
and treatment protocols
Helene Hallböök and Bengt Smedmyr
The Swedish Adult Lymphoblastic Leukemia Group (SVALL), chairperson Hallböök, is a working group
with responsibility for national guidelines and studies. During 2010-11 we have evaluated the outcome
after relapse of acute lymphoblastic leukemia (ALL) and the treatment and prognostic factors of
Philadelphia-positive ALL
Clinical and laboratory studies on infectious, hemorrhagic and dermatological
complications in patients treated for hematological malignancies
Honar Cherif, Tobias Svensson, and Martin Höglund
We are conducting several clinical and laboratory studies aiming to improve the diagnosis and management
of these complicationsin patients receiving treatment for hematological cancers.. These studies include for
example: assessing the impact of IgG subgroup deficiency in patients with Chronic Lymphocytic Leukemia
(CLL); conjugated Pneumococcal vaccination in patients with CLL; the use of the thrombopoietin receptor
agonist Eltrombopag in patients with high risk Myelodysplastic syndromes with thrombocytopenia that are
treated with Azacitidine; prospective analysis of dermatological complications in inpatients treated for
hematological malignancies; prospective survey of fungal infections and the use of systemic antifungals;
bacteremia and its related mortality in neutropenic patients; the impact of quinolone prophylaxis on the
risks for developing febrile neutropenia and usage of systemic broad spectrum antibiotics.
Plasma cell disorders
Kristina Carlson, Torbjörn Karlsson and Sara Rosengren
Clinical studies on plasma cell disorders are performed in collaboration with The Nordic Myeloma Study
Group and the Swedish Group for plasma cell disorders. At Uppsala University Hospital clinical trials on
myeloma patients are ongoing in collaboration with e.g. Dept of Radiology. In collaboration with the PETimaging
centre and cardiologic expertise a pilot imaging study of cardiac AL-amyloidosis has recently been
performed and will be published during 2012.
Members of the group during 2011
Gunnar Birgegård, MD, PhD, prof emiritus
Martin Höglund, MD, associate professor
Kristina Carlson, MD, PhD
Elisabeth Ejerblad, MD, PhD
Helene Hallböök, MD, PhD
Torbjörn Karlsson MD, PhD
Bengt Smedmyr, MD, PhD
16
Bengt Simonsson MD PhD, prof emiritus
Ulla Strömberg MD PhD
Caroline Haglund, PhD
Stina Söderlund MD PhD-student
Sara Rosengren, MD
Anna Eriksson, MD, PhD student
Anncarin Svanberg, PhD student

Publications 2009-2011
1. Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, Tidefelt U, Wahlin A,
Hoglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from
the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-87.
2. Wahlin A, Billstrom R, Bjor O, Ahlgren T, Hedenus M, Hoglund M, Lindmark A, Markevarn B,
Nilsson B, Sallerfors B, Brune M. Results of risk-adapted therapy in acute myeloid leukaemia. A longterm
population-based follow-up study. Eur J Haematol. 2009 Aug;83(2):99-107.
3. Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, Hjorth-Hansen H,
Hoglund M, Kovanen P, Laurinolli T, Liesveld J, Paquette R, Pinilla-Ibarz J, Rauhala A, Shah N,
Simonsson B, Sinisalo M, Steegmann JL, Stenke L, Porkka K. Clonal expansion of T/NK-cells during
tyrosine kinase inhibitor dasatinib therapy. Leukemia. 2009;23(8):1398-405.
4. Juliusson G, Antunovic P, Derolf A, Lehmann S, Mollgard L, Stockelberg D, Tidefelt U, Wahlin A,
Hoglund M. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from
the Swedish Acute Leukemia Registry. Blood. 2009;113(18):4179-87.
5. Baccarani M, Cortes J, Pane F, et al Chronic myeloid leukemia: an update of concepts and
management recommendations of European LeukemiaNet. J Clin Oncol. 2009 Dec 10;27(35):6041-
51.
6. Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy.Mustjoki S, Ekblom
M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, Hjorth-Hansen H, Höglund M, Kovanen P,
Laurinolli T, Liesveld J, Paquette R, Pinilla-Ibarz J, Rauhala A, Shah N, Simonsson B, Sinisalo M,
Steegmann JL, Stenke L, Porkka K. Leukemia. 2009;23(8):1398-405.
7. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid
leukemia. Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, Goldman JM,
Müller MC, Radich JP, Rudoltz M, Mone M, Gathmann I, Hughes TP, Larson RA; IRIS Investigators.
Leukemia. 2009 Jun;23(6):1054-61. Epub 2009 Mar 12. Erratum in: Leukemia. 2010 May;24(5):1102.
8. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk,
Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study.
9. Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, Alimena G, Ehrencrona
H, Hjorth-Hansen H, Kairisto V, Levato L, Martinelli G, Nagler A, Lanng Nielsen J, Ozbek U,
Palandri F, Palmieri F, Pane F, Rege-Cambrin G, Russo D, Specchia G, Testoni N, Weiss-Bjerrum O,
Saglio G, Simonsson B. Blood. 2009 May 7;113(19):4497-504.
10. Suboptimal responses in chronic myeloid leukemia: milestones and mechanisms. Porkka K, Mustjoki
S, Simonsson B. Expert Rev Hematol. 2009 Feb;2(1):81-91.
11. Thiele J, Kvasnicka HM, Vardiman JW, Orazi A, Franco V, Gisslinger H, Birgegard G, Griesshammer
M, Tefferi A. Bone marrow fibrosis and diagnosis of essential thrombocythemia. J Clin Oncol. 2009
Dec 1;27(34):e220-1; author reply e222-3.
12. Hoppe A, Persson E, Birgegård G. Medical interns' view of their undergraduate medical education in
Uppsala: an alumnus study with clear attitude differences between women and men. Med Teach. 2009
May;31(5):426-32.
13. Birgegård G. New perspectives in managing myeloproliferative disorders: focus on the patient.
Hematol Oncol. 2009 Jun;27 Suppl 1:5-7.
14. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Kiladjian JJ,
Lengfelder E, McMullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T. Response criteria for
essential thrombocythemia and polycythemia vera: result of a European Leukemia Net consensus
conference. Blood. 2009 May 14;113(20):4829-33.
15. Birgegård G. Long-term management of thrombocytosis in essential thrombocythaemia. Ann
Hematol. 2009 Jan;88(1):1-10.
17

16. Hedenus M, Birgegård G. The role of iron supplementation during epoietin treatment for cancerrelated
anemia. Med Oncol. 2009;26(1):105-15.
17. Hallböök H, Björkholm M, Hägglund H, Smedmyr B. Does granulocyte colony-stimulating factor
improve long-term outcome in adult acute lymphoblastic leukemia?; Swedish Adult ALL Group. Leuk
Lymphoma. 2009 Nov;50(11):1872-4.
18. Kristina Wiberg, Kristina Carlson, Anna Åleskog, Rolf Larsson, Peter Nygren, Elin Lindhagen. In
vitro activity of bortezomib in cultures of patient tumour cells - potential utility in haematological
malignancies. Med Oncol 2009; 26(2):193-201
19. Olsson-Stromberg U, Hermansson M, Lundan T, Ohm AC, Engdahl I, Hoglund M, et al. Molecular
monitoring and mutation analysis of advanced phase CML and Ph+ ALL patients receiving Dasatinib.
Eur J Haematol. 2010 Jul 26.
20. Tina E, Prenkert M, Hoglund M, Paul C, Tidefelt U. Topoisomerase IIalpha expression in acute
myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C. Oncol Rep. 2009
Dec;22(6):1527-31.
21. Haglund C, Aleskog A, Hakansson LD, Hoglund M, Jacobsson S, Larsson R, Lindhagen E. The
FMCA-GM assays, high throughput non-clonogenic alternatives to CFU-GM in preclinical
hematotoxicity testing. Toxicol Lett. 2010 May 4;194(3):102-7.
22. Eriksson A, Hoglund M, Lindhagen E, Aleskog A, Hassan SB, Ekholm C, Fholenhag K, Jensen AJ,
Lothgren A, Scobie M, Larsson R, Parrow V. Identification of AKN-032, a novel 2-aminopyrazine
tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia. Biochem
Pharmacol. 2010 Nov 15;80(10):1507-16.
23. Molecular monitoring and mutation analysis of patients with advanced phase CML and Ph+ ALL
receiving dasatinib. Olsson-Strömberg U, Hermansson M, Lundán T, Ohm AC, Engdahl I, Höglund
M, Simonsson B, Porkka K, Barbany G. Eur J Haematol. 2010 Nov;85(5):399-404.
24. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with Bcell
malignancies. Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Strömberg U,
Loskog AS. Immunology. 2010 Nov;131(3):371-6.
25. Interferon for Treatment of Chronic Myeloid Leukemia. Simonsson B, Hjorth-Hansen H, Bjerrum
OW, Porkka K. Curr Drug Targets. 2010 Dec 14. [Epub ahead of print]
26. Second-generation BCR-ABL kinase inhibitors in CML. Simonsson B, Porkka K, Richter J. N Engl J
Med. 2010 Oct 21;363(17):1673; author reply 1673-5.
27. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia.Saglio G, Kim DW,
Issaragrisil S, le Coutre P, Etienne G, Lobo C, Pasquini R, Clark RE, Hochhaus A, Hughes TP,
Gallagher N, Hoenekopp A, Dong M, Haque A, Larson RA, Kantarjian HM; ENESTnd Investigators.
N Engl J Med. 2010 Jun 17;362(24):2251-9..
28. T regulatory cells control T-cell proliferation partly by the release of soluble CD25 in patients with Bcell
malignancies. Lindqvist CA, Christiansson LH, Simonsson B, Enblad G, Olsson-Strömberg U,
Loskog AS. Immunology. 2010 Nov;131(3):371-6.
29. Svanberg A, Ohrn K, Birgegård G. Oral cryotherapy reduces mucositis and improves nutrition - a
randomised controlled trial. J Clin Nurs. 2010 Aug;19(15-16):2146-51.
30. Birgegård G, Schneider K, Ulfberg J. High incidence of iron depletion and restless leg syndrome
(RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron.
Vox Sang. 2010 Jun 24.
31. Bennett CL, McKoy JM, Henke M, Silver SM, MacDougall IC, Birgegård G, Luminari S, Casadevall
N, Schellekens H, Sartor O, Lai SY, Armitage JO. Reassessments of ESAs for cancer treatment in the
US and Europe. Oncology (Williston Park). 2010 Mar;24(3):260-8.
18

32. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch H, Kiladijan JJ,
Lengfelder E, Mesa R, Mc Mullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T. Aunified
definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and
primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol.
2010 Mar;148(6):961-3.
33. Tobiasson M, Alyass B, Söderlund S, Birgegård G. High prevalence of restless legs syndrome among
patients with polycytemia vera treated with venesectio.Med Oncol. 2010;27(1):105-7.
34. Johansson JE, Remberger M, Lazarevic V, Hallböök H, Wahlin A, Kimby E, Juliusson G, Omar H,
Hägglund H. Allogeneic haematopoietic stem-cell transplantation with reduced intensity conditioning
for advanced stage Hodgkin's lymphoma in Sweden: high incidence of post transplant
lymphoproliferative disorder. Bone Marrow Transplant. 2010 Oct 18.
35. Juliusson G, Karlsson K, Hallböök H Population-based analyses in adult acute lymphoblastic
leukemia.. Blood. 2010 Aug 12;116(6):1011; author reply 1012.
36. Waage A, Gimsing P et al. for the Nordic Myeloma Study Group. Melphalan and prednisone plus
thalidomide or placebo in elderly patients with multiple myeloma. Blood 2010:116(9); 1405-1412.
37. Gimsing P, Carlson K et al. Effect of pamidronate 30 mg versus 90 mg on physicalfunction in patients
with newly diagnosed multiplemyeloma (Nordic Myeloma Study Group): a double-blind, randomised
controlled trial. Lancet Oncol 2010; 11: 973–82
38. Abelsson J, Merup M, Birgegård G, Weisbjerrum O, Brinch L, Brune M, et al. The outcome of allo-
HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplantation. 2011;
39. Björkholm M, Derolf A, Hultcrantz M, Kristinsson S, Ekstrand C, Goldin L, et al. Treatment-related
risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in
myeloproliferative neoplasms. Journal of Clinical Oncology. 2011;29(17):2410-2415.
40. Fernberg P, Edgren G, Adami J, Ingvar Å, Bellocco R, Tufveson G, et al. Time Trends in Risk and
Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients. American
Journal of Transplantation. 2011;11(11):2472-2482.
41. Juliusson G, Karlsson K, Lazarevic V, Wahlin A, Brune M, Antunovic P, et al. Hematopoietic Stem
Cell Transplantation Rates and Long-Term Survival in Acute Myeloid and Lymphoblastic Leukemia :
Real-World Population-Based Data From the Swedish Acute Leukemia Registry 1997-2006. Cancer.
2011;117(18):4238-4246.
42. Nilsson-Ehle H, Birgegård G, Samuelsson J, Antunovic P, Astermark J, Garelius H, et al. Quality of
life, physical function and MRI T2*in elderly low-risk MDS patients treated to a haemoglobin level of
>= 120 g/L with darbepoetin alfa +/- filgrastim or erythrocyte transfusions. European Journal of
Haematology. 2011;87(3):244-252.
43. Larfors G, Höglund M, Cnattingius S. Pregnancy and risk of acute myeloid leukaemia : a case-control
study. European Journal of Haematology. 2011;87(2):169-171.
44. Scherber R, Dueck A, Johansson P, Barbui T, Barosi G, Vannucchi A, et al. The Myeloproliferative
Neoplasm Symptom Assessment Form (MPN-SAF) : International Prospective Validation and
Reliability Trial in 402 patients. Blood. 2011;118(2):401-408.
45. Björkholm M, Ohm L, Eloranta S, Derolf Å, Hultcrantz M, Sjöberg J, et al. Success Story of Targeted
Therapy in Chronic Myeloid Leukemia : A Population-Based Study of Patients Diagnosed in Sweden
From 1973 to 2008. Journal of Clinical Oncology. 2011;29(18):2514-2520.
46. Aapro M, Beguin Y, Birgegård G, Gascon P, Hedenus M, Österborg A. Too-Low Iron Doses and Too
Many Dropouts in Negative Iron Trial?. Journal of Clinical Oncology. 2011;29(17):E525-E526.
47. Barbui T, Barosi G, Birgegård G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-
Negative Classical Myeloproliferative Neoplasms : Critical Concepts and Management
Recommendations From European LeukemiaNet. Journal of Clinical Oncology. 2011;29(6):761-770.
19

48. Haglund C, Aleskog A, Nygren P, Gullbo J, Höglund M, Wickström M, et al. In vitro evaluation of
clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing
normal tissues. Cancer Chemotherapy and Pharmacology. 2011;
49. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, et al. Continuing high early
death rate in acute promyelocytic leukemia : a population-based report from the Swedish Adult Acute
Leukemia Registry. Leukemia. 2011;25(7):1128-1134.
50. Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, et al. Prognostic DNA
methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell
chromatin marks. Blood. 2011;118(20):5573-5582.
51. Johansson J, Apelgren K, Birgegård G, Grydén M, Rügheimer L. Webbaserad pedagogisk
meritportfölj : från idé till verklighet. Högre Utbildning. 2011;1(1):27-37.
52. Juliusson G, Karlsson K, Lazarevic V, et al. Hematopoietic Stem Cell Transplantation Rates and
Long-Term Survival in Acute Myeloid and Lymphoblastic Leukemia : Real-World Population-Based
Data From the Swedish Acute Leukemia Registry 1997-2006. Cancer. 2011;117(18):4238-4246.
53. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete
cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib
treatment : the EUTOS score. Blood. 2011;118(3):686-692.
54. Johansson J, Remberger M, Lazarevic V, Hallböök H, Wahlin A, Kimby E, et al. Allogeneic
haematopoietic stem-cell transplantation with reduced intensity conditioning for advanced stage
Hodgkin's lymphoma in Sweden : high incidence of post transplant lymphoproliferative disorder.
Bone Marrow Transplantation. 2011;46(6):870-875.
55. Simonsson B, Hjorth-Hansen H, Bjerrum O, Porkka K. Interferon alpha for Treatment of Chronic
Myeloid Leukemia. Current Drug Targets. 2011;12(3):420-428.
56. Lindqvist C, Christiansson L, Thörn I, Mangsbo S, Paul-Wetterberg G, Sundström C, et al. Both
CD4(+) FoxP3(+) and CD4(+) FoxP3(-) T cells from patients with B-cell malignancy express
cytolytic markers and kill autologous leukaemic B cells in vitro.. Immunology. 2011;133(3):296-306.
57. Lazarevic V, Hägglund H, Remberger M, Wahlin A, Hallböök H, Juliusson G, et al. Long-term
survival following allogeneic or syngeneic stem cell transplant for follicular lymphoma in Sweden.
Leukemia and Lymphoma. 2011;52(1):69-71.
58. Hehlmann R, Grimwade D, Simonsson B, Apperley J, Baccarani M, Barbui T, et al. The European
LeukemiaNet : achievements and perspectives. Haematologica. 2011;96(1):156-162.
59. Hallböök H, Felth J, Eriksson A, Fryknäs M, Bohlin L, Larsson R, et al. Ex Vivo Activity of Cardiac
Glycosides in Acute Leukaemia. PLoS ONE. 2011;6(1):e15718-.
60. Giebel S, Thomas X, Hallbook H, Geissler K, Boiron J, Huguet F, et al. The prophylactic use of
granulocyte-colony stimulating factor during remission induction is associated with increased
leukaemia-free survival of adults with acute lymphoblastic leukaemia : A joint analysis of five
randomised trials on behalf of the EWALL. European Journal of Cancer. 2011;e-pub dec 22.
61. Lazarevic V, Remberger M, Hägglund H, Hallböök H, Juliusson G, Kimby E, et al. Myeloablative
allogeneic stem cell transplantation for lymphoblastic lymphoma in Sweden : a retrospective study.
American Journal of Hematology. 2011;86(8):709-710.
62. Simonsson B, Gedde-Dahl T, Markevarn B, Remes K, Stentoft J, Almqvist A, et al. Combination of
pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or
intermediate-risk chronic myeloid leukemia. Blood. 2011;118(12):3228-3235.
Dissertations 2011
Caroline Haglund: Integrating Efficacy and Toxicity in Preclinical Anticancer Drug Development:
Methods and Applications.
20

Cancer Pharmacology and Computational Medicine
Rolf Larsson, Mats Gustafsson and Peter Nygren
Cancer Pharmacology and Computational Medicine is a research program that combines areas of
pharmacology, oncology, biomedical engineering, and computational informatics with high throughput
experimental techniques to discover novel and improve existing therapies for cancer and other complex
diseases. We are addressing key issues related to drug resistance and improved multi-compound therapies.
Our multi-disciplinary research is organized it into four mutually reinforcing activities:
I. Drug and multi-compound therapy discovery
This activity is aimed at discovering novel drugs and multi-compound treatments for problems associated
with drug resistance and toxicity in cancer therapy. In-house compound libraries, information-rich model
systems, high-throughput technologies for drug screening, and the most recent methods for systemic
molecular and phenotypic profiling (spectroscopy, arrays, sequencing, and microscopy) are available for
this purpose together with required theory and algorithms for quantitative bioinformatic systems analysis.
Among the several novel assays we have established is a 3D (spheroid) forming assay, and a proximity
ligation-based assay for high content screening of drug effects on signalling pathways. In collaboration
with Stig Linder (Karolinska Institute) we recently screened cultures of ovarian carcinoma and identified a
compound, VLX50, demonstrating strong activity with a high therapeutic window both in vitro and in vivo.
Subsequent studies revealed that VLX 50 was an intracellular iron chelator, inducing cell cycle arrest.
Interestingly, in a subsequent screen for drugs active on 3-D spheroid cultures compared to monolayer, the
most active compound was also an intracellular iron chelator. Thus, this indicates a potentially useful
strategy for treatment of solid tumours
II. Characterization and refinement of drug therapy candidates
Given a promising drug, combination of drugs or treatment protocol, it is important to gain an improved
pharmacological understanding about the properties of the new treatment. For example what systemic
effects does it cause and does it meet basic requirements to be advanced to further preclinical and clinical
testing? For a set of already established drug therapies, are there patient subpopulations that should benefit
from changing the currently employed therapy to others that are more potent with less adverse side effect?
Here we employ modern experimental and bioinformatics tools for addressing this kind of questions while
at the same time developing beyond state-of-the-art alternatives. The main issues of current interest are
determination and prediction of (1) mechanism of action, (2) toxicity and other adverse side effects, (3)
combination activity, and (4) in vivo proof-of-concept. The core of this evaluation program meets
European regulatory requirements for documentation of primary pharmacology prior to clinical phase I
trials in patients but also allow additional analyses.
III. Detection/classification for therapy selection
Although discovery and pharmacological profiling of novel treatment candidates are fundamental for
improved medical treatments, another key issue is to find the most promising treatment for each patient
among the set of treatment protocols available. Ideally, the criteria used for selection of the most promising
treatment should be easy to interpret and allow a deeper understanding of the underlying biochemical
mechanisms involved. To meet these challenges, system wide measurements at the molecular or phenotypic
levels are employed. The resulting measurements are analyzed by means of standard bio-statistical methods
as well as using multivariate machine learning methods in order to obtain successful and easily
interpretable predictors for therapy response. Ideally, the most successful prediction models obtained this
way are easy to interpret in terms of a small subset of all the system wide variables measured (for example
mRNA gene expression levels or morphological changes at the cellular level).
21

IV. Algorithmic biosystems analysis & control
To be able to achieve robust measurements using the many different measurement technologies emerging
for molecular and phenotypic profiling, one needs tailor made algorithms that perform different forms of
low-level instrument bio-signal processing such as noise suppression, as well as, algorithms for systems
analysis that e.g. can give ideas about the underlying biochemical mechanism associated with the disease
and treatment. This requires tailor made analytic tools as well as generic beyond state-of-the-art algorithms
for multivariate and temporal data analysis. In particular, there is a great need for semi-automated
discovery algorithms that can detect and model clinically important multivariate patterns hidden in complex
data sets that may consist of a mixture of standard patient journal information together with different
molecular and phenotypic profiling results of varying quality. Moreover, there is great potential in
interactive closed-loop learning algorithms that are able to propose a set of maximally informative
experiments, analyze the results obtained from the experiments, refine the current models/hypotheses based
on the analysis and propose a new batch of informative experiments for the next iteration in the loop.
For more information, please see;
http://www.medsci.uu.se/forskning/Cancer/Cancerfarmakologi+och+ber%C3%A4kningsmedicin/
Members of the group during 2011
Aftab Obaid, PhD student
Andersson Claes, PhD, researcher
Andersson Gunnar, PhD, post-doc
Bäcklin Christofer, PhD student
Eriksson Anna, MD, PhD student
Freyhult Eva, PhD, post-doc
Fryknäs Mårten, PhD, post-doc
Gullbo Joachim, MD, PhD
Gustafsson Mats, TeknD, professor
Göransson-Kultima Hanna, bioinformatician
Haglund Caroline, PhD student
Hassan Sadia, PhD, post-doc
Haukala Anna, laboratory technician
von Heideman Anne, MD, PhD student
Isaksson Anders, PhD, associate professor
Kultima Kim, PhD, post-doc
Funding
Swedish Cancer Foundation 1000 kSEK
Swedish Strategic Foundation 2400 kSEK
Proactive EU project 900 kSEK
Oncopeptides 350 kSEK
Chemilia 600 kSEK
ALF 1300 kSEK
22
Lannergård Anna K, laboratory technician
Larsson Rolf, MD, professor
Laryea Daniel, PhD, post doc
Lahtinen Sara, PhD student
Leek Christina, laboratory technician
Lenhammar Lena, laboratory technician
Lindhagen Elin, PhD, associate professor
Muhammad Kashif, PhD student
Nordberg, Erika, PhD, post-doc
Nygren Peter, MD, professor
Rasmussen Markus, bioinformatician
Rickardson Linda, PhD, post doc
Rydåker Maria, laboratory technician
Strömbergsson Helena, PhD, post-doc
Winell Henric, PhD student
Åleskog Anna, MD, PhD
Lions 300 kSEK
National Research Council 600 kSEK
Regional Research Council 310 kSEK
Selanders foundation 160 kSEK
Nordiska rådet 500 kSEK

Publications 2009-2011
1. Banduseela VC, Ochala J, Chen YW, Goransson H, Norman H, Radell P, Eriksson LI, Hoffman EP,
Larsson L: Gene expression and muscle fiber function in a porcine ICU model. Physiol Genomics
(2009) 39(3):141-159.
2. Berglund A, Bystrom P, Johansson B, Nygren P, Frodin JE, Pedersen D, Letocha H, Glimelius B: An
explorative randomised phase II study of sequential chemotherapy in advanced upper gastrointestinal
cancer. Med Oncol (2009) 27(1):65-72.
3. Berndtsson M, Beaujouin M, Rickardson L, Havelka AM, Larsson R, Westman J, Liaudet-Coopman
E, Linder S: Induction of the lysosomal apoptosis pathway by inhibitors of the ubiquitin-proteasome
system. Int J Cancer (2009) 124(6):1463-1469.
4. Bjorklund P, Cupisti K, Fryknas M, Isaksson A, Willenberg HS, Akerstrom G, Hellman P, Westin G:
Stathmin as a marker for malignancy in pheochromocytomas. Exp Clin Endocrinol Diabetes (2009)
118(1):27-30.
5. Eriksson M, Hassan S, Larsson R, Linder S, Ramqvist T, Lovborg H, Vikinge T, Figgemeier E,
Muller J, Stetefeld J, Dalianis T et al: Utilization of a right-handed coiled-coil protein from
archaebacterium Staphylothermus marinus as a carrier for cisplatin. Anticancer Res (2009) 29(1):11-
18.
6. Felth J, Rickardson L, Rosen J, Wickstrom M, Fryknas M, Lindskog M, Bohlin L, Gullbo J: Cytotoxic
effects of cardiac glycosides in colon cancer cells, alone and in combination with standard
chemotherapeutic drugs. J Nat Prod (2009) 72(11):1969-1974.
7. Fuchs D, Christofferson R, Stridsberg M, Lindhagen E, Azarbayjani F: Regression of orthotopic
neuroblastoma in mice by targeting the endothelial and tumor cell compartments. J Transl Med (2009)
7:16.
8. Goransson H, Edlund K, Rydaker M, Rasmussen M, Winquist J, Ekman S, Bergqvist M, Thomas A,
Lambe M, Rosenquist R, Holmberg L et al: Quantification of normal cell fraction and copy number
neutral LOH in clinical lung cancer samples using SNP array data. PLoS One (2009) 4(6):e6057.
9. Hansson J, Graf W, Pahlman L, Nygren P, Mahteme H: Postoperative adverse events and long-term
survival after cytoreductive surgery and intraperitoneal chemotherapy. Eur J Surg Oncol (2009)
35(2):202-208.
10. Johansson AS, Pawelzik SC, Larefalk A, Jakobsson PJ, Holmberg D, Lindskog M: Lymphoblastic Tcell
lymphoma in mice is unaffected by Celecoxib as single agent or in combination with
cyclophosphamide. Leuk Lymphoma (2009) 50(7):1198-1203.
11. Kaderi MA, Mansouri M, Zainuddin N, Cahill N, Gunnarsson R, Jansson M, Kimby E, Aleskog A,
Lundin J, Glimelius B, Melbye M et al: Lack of association between the MDM2 promoter
polymorphism SNP309 and clinical outcome in chronic lymphocytic leukemia. Leuk Res (2009)
34(3):335-339.
12. Larsson DE, Hassan S, Larsson R, Oberg K, Granberg D: Combination analyses of anti-cancer drugs
on human neuroendocrine tumor cell lines. Cancer Chemother Pharmacol (2009) 65(1):5-12.
13. Laryea D, Isaksson A, Wright CW, Larsson R, Nygren P: Characterization of the cytotoxic activity of
the indoloquinoline alkaloid cryptolepine in human tumour cell lines and primary cultures of tumour
cells from patients. Invest New Drugs (2009) 27(5):402-411.
14. Lindhagen E, Norberg M, Kanduri M, Tobin G, Saisanen L, Aberg M, Gustafsson MG, Sundstrom C,
Rosenquist R, Aleskog A: In vitro activity of 20 agents in different prognostic subgroups of chronic
lymphocytic leukemia--rolipram and prednisolone active in cells from patients with poor prognosis.
Eur J Haematol (2009) 83(1):22-34.
15. Lonnerholm G, Thorn I, Sundstrom C, Frost BM, Abrahamsson J, Behrendtz M, Heldrup J, Jacobsson
S, Li A, Olofsson T, Porwit A et al: In vitro cellular drug sensitivity at diagnosis is correlated to
23

minimal residual disease at end of induction therapy in childhood acute lymphoblastic leukemia. Leuk
Res (2009) 33(1):46-53.
16. Lovborg H, Burman R, Gullbo J: Structure-activity relationship analysis of cytotoxic
cyanoguanidines: selection of CHS 828 as candidate drug. BMC Res Notes (2009) 2:114.
17. Palmberg E, Johnsen JI, Paulsson J, Gleissman H, Wickstrom M, Edgren M, Ostman A, Kogner P,
Lindskog M: Metronomic scheduling of imatinib abrogates clonogenicity of neuroblastoma cells and
enhances their susceptibility to selected chemotherapeutic drugs in vitro and in vivo. Int J Cancer
(2009) 124(5):1227-1234.
18. Rosén J, Rickardson L, Backlund A, Gullbo J, Bohlin L, Larsson R, Gottfries J: ChemGPS-NP
Mapping of Chemical Compounds for Prediction of Anticancer Mode of Action. QSAR &
Combinatorial Science (2009) 28(4):11.
19. Wensman H, Goransson H, Leuchowius KJ, Stromberg S, Ponten F, Isaksson A, Rutteman GR,
Heldin NE, Pejler G, Hellmen E: Extensive expression of craniofacial related homeobox genes in
canine mammary sarcomas. Breast Cancer Res Treat (2009) 118(2):333-343.
20. Wiberg K, Carlson K, Aleskog A, Larsson R, Nygren P, Lindhagen E: In vitro activity of bortezomib
in cultures of patient tumour cells--potential utility in haematological malignancies. Med Oncol (2009)
26(2):193-201.
21. Wu X, Wanders A, Wardega P, Tinge B, Gedda L, Bergstrom S, Sooman L, Gullbo J, Bergqvist M,
Hesselius P, Lennartsson J et al: Hsp90 is expressed and represents a therapeutic target in human
oesophageal cancer using the inhibitor 17-allylamino-17 demethoxy-geldanamycin. Br J Cancer
(2009) 100(2):334-343.
22. Burman R, Svedlund E, Felth J, Hassan S, Herrmann A, Clark RJ, Craik DJ, Bohlin L, Claeson P,
Goransson U, Gullbo J: Evaluation of toxicity and anti-tumour activity of cycloviolacin O2 in mice.
Biopolymers (2010).
23. Eriksson A, Hoglund M, Lindhagen E, Aleskog A, Hassan SB, Ekholm C, Fholenhag K, Jensen AJ,
Lothgren A, Scobie M, Larsson R et al: Identification of AKN-032, a novel 2-aminopyrazine tyrosine
kinase inhibitor, with significant preclinical activity in acute myeloid leukemia. Biochem Pharmacol
(2010) 80(10):1507-1516.
24. Gustafsson MG, Wallman M, Wickenberg Bolin U, Goransson H, Fryknas M, Andersson CR,
Isaksson A: Improving Bayesian credibility intervals for classifier error rates using maximum entropy
empirical priors. Artif Intell Med (2010) 49(2):93-104.
25. Haglund C, Aleskog A, Hakansson LD, Hoglund M, Jacobsson S, Larsson R, Lindhagen E: The
FMCA-GM assays, high throughput non-clonogenic alternatives to CFU-GM in preclinical
hematotoxicity testing. Toxicol Lett (2010) 194(3):102-107.
26. Halldorsdottir AM, Sander B, Goransson H, Isaksson A, Kimby E, Mansouri M, Rosenquist R,
Ehrencrona H: High-resolution genomic screening in mantle cell lymphoma--specific changes
correlate with genomic complexity, the proliferation signature and survival. Genes Chromosomes
Cancer (2010) 50(2):113-121.
27. Hassan SB, Gali-Muhtasib H, Goransson H, Larsson R: Alpha terpineol: a potential anticancer agent
which acts through suppressing NF-kappaB signalling. Anticancer Res (2010) 30(6):1911-1919.
28. Hu K, Berenjian S, Larsson R, Gullbo J, Nygren P, Lovgren T, Morein B: Nanoparticulate Quillaja
saponin induces apoptosis in human leukemia cell lines with a high therapeutic index. Int J
Nanomedicine (2010) 5:51-62.
29. Kalushkova A, Fryknas M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, Deleu S, Atadja P,
Osterborg A, Nilsson K, Vanderkerken K et al: Polycomb target genes are silenced in multiple
myeloma. PLoS One (2010) 5(7):e11483.
24

30. Kanduri M, Cahill N, Goransson H, Enstrom C, Ryan F, Isaksson A, Rosenquist R: Differential
genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia.
Blood (2010) 115(2):296-305.
31. Laryea D, Gullbo J, Isaksson A, Larsson R, Nygren P: Characterization of the cytotoxic properties of
the benzimidazole fungicides, benomyl and carbendazim, in human tumour cell lines and primary
cultures of patient tumour cells. Anticancer Drugs (2010) 21(1):33-42.
32. Leuchowius KJ, Jarvius M, Wickstrom M, Rickardson L, Landegren U, Larsson R, Soderberg O,
Fryknas M, Jarvius J: High content screening for inhibitors of protein interactions and posttranslational
modifications in primary cells by proximity ligation. Mol Cell Proteomics (2010)
9(1):178-183.
33. Lonnerholm G, Thorn I, Sundstrom C, Frost BM, Flaegstad T, Heyman M, Jonsson OG, Harila-Saari
A, Madsen HO, Porwit A, Schmiegelow K et al: In vitro cellular drug resistance adds prognostic
information to other known risk-factors in childhood acute lymphoblastic leukemia. Leuk Res (2010).
34. Mansouri MR, Sevov M, Aleskog A, Jondal M, Merup M, Sundstrom C, Osorio L, Rosenquist R:
IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia. Eur
J Haematol (2010) 84(2):109-116.
35. Marincevic M, Cahill N, Gunnarsson R, Isaksson A, Mansouri M, Goransson H, Rasmussen M,
Jansson M, Ryan F, Karlsson K, Adami HO et al: High-density screening reveals a different spectrum
of genomic aberrations in chronic lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and
IGHV4-34 B-cell receptors. Haematologica (2010) 95(9):1519-1525.
36. Marincevic M, Mansouri M, Kanduri M, Isaksson A, Goransson H, Smedby KE, Jurlander J, Juliusson
G, Davi F, Stamatopoulos K, Rosenquist R: Distinct gene expression profiles in subsets of chronic
lymphocytic leukemia expressing stereotyped IGHV4-34 B-cell receptors. Haematologica (2010)
95(12):2072-2079.
37. Milani L, Lundmark A, Kiialainen A, Nordlund J, Flaegstad T, Forestier E, Heyman M, Jonmundsson
G, Kanerva J, Schmiegelow K, Soderhall S et al: DNA methylation for subtype classification and
prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia. Blood
(2010) 115(6):1214-1225.
38. Mondal T, Rasmussen M, Pandey GK, Isaksson A, Kanduri C: Characterization of the RNA content of
chromatin. Genome Res (2010) 20(7):899-907.
39. Olsson-Stromberg U, Hermansson M, Lundan T, Ohm AC, Engdahl I, Hoglund M, Simonsson B,
Porkka K, Barbany G: Molecular monitoring and mutation analysis of patients with advanced phase
CML and Ph+ ALL receiving dasatinib. Eur J Haematol (2010) 85(5):399-404.
40. Wickstrom M, Viktorsson K, Lundholm L, Aesoy R, Nygren H, Sooman L, Fryknas M, Vogel LK,
Lewensohn R, Larsson R, Gullbo J: The alkylating prodrug J1 can be activated by aminopeptidase N,
leading to a possible target directed release of melphalan. Biochem Pharmacol (2010) 79(9):1281-
1290.
41. von Heideman A, Berglund A, Larsson R, Nygren P: Safety and efficacy of NAD depleting cancer
drugs: results of a phase I clinical trial of CHS 828 and overview of published data. Cancer Chemother
Pharmacol (2010) 65(6):1165-1172.
42. Isaksson A, Wallman M, Goransson H, Gustafsson MG: Cross-validation and bootstrapping are
unreliable in small sample classification. Pattern Recognition Letters (2008) 29:1960-1965.
43. Andersson C, Gustafsson MG, Strömbergsson H: Quantitative Chemogenomics: Machine-Learning
Models of Protein-Ligand Interaction. Review. Accepted for publication in Current Topics in
Medicinal Chemistry (2011).
44. Kultima K, Nilsson A, Scholz B, Rossbach UL, Fälth M, Andrén P: Development and Evaluation of
Normalization Methods for Label-free Relative Quantification of Endogenous Peptides. Molecular and
Cellular Proteomics (2009) 9(10):285-95.
25

45. Scholz B, Skold K, Kultima K, Fernandez C, Waldemarson S, Savitski MM, Svensson M, Boren M,
Stella R, Andren PE, Zubarev R, James P:Impact of temperature dependent sampling procedures in
proteomics and peptidomics - A characterization of the liver and pancreas post mortem degradome.
Molecular and Cellular Proteomics, in press (2010).
46. Nilsson MF, Danielsson C, Sköld A-C, Johansson A, Blomgren B, Wilson J, Khan KM, Bengtsson E,
Kultima K, Webster WS, Danielsson BR: Improved methodology for identifying the teratogenic
potential in early drug development of hERG channel blocking drugs. Reproductive Toxicology
Apr;29(2):156-63 (2010).
47. Maddah F, Soeria-Atmadja D, Malm P, Gustafsson M, Hammerling U. Interrogating health-related
public databases from a food toxicology perspective : Computational analysis of scoring data. Food
and Chemical Toxicology. 2011;49(11):2830-2840.
48. Fayad W, Rickardson L, Haglund C, Hägg Olofsson M, D'Arcy P, Larsson R, et al. Identification of
Agents that Induce Apoptosis of Multicellular Tumour Spheroids : Enrichment for Mitotic Inhibitors
with Hydrophobic Properties. Chemical Biology and Drug Design. 2011;78(4):547-557.
49. Darmanis S, Nong R, Vänelid J, Siegbahn A, Ericsson O, Fredriksson S, et al. ProteinSeq : highperformance
proteomic analyses by proximity ligation and next generation sequencing. PLoS ONE.
2011;6(9):e25583-.
50. Andersson C, Gustafsson M, Strömbergsson H. Quantitative Chemogenomics : Machine-Learning
Models of Protein-Ligand Interaction. Current Topics in Medicinal Chemistry. 2011;11(15):1978-
1993.
51. Gullbo J, Fryknäs M, Rickardson L, Darcy P, Hägg M, Wickström M, et al. Phenotype-based drug
screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising
strategy for cancer treatment. Biochemical Pharmacology. 2011;82(2):139-147.
52. Alvarsson J, Andersson C, Spjuth O, Larsson R, Wikberg J. Brunn : an open source laboratory
information system for microplates with a graphical plate layout design process. BMC Bioinformatics.
2011;12(1):179-.
53. Wickström M, Larsson R, Nygren P, Gullbo J. Aminopeptidase N (CD13) as a target for cancer
chemotherapy. Cancer Science. 2011;102(3):501-508.
54. Hallböök H, Felth J, Eriksson A, Fryknäs M, Bohlin L, Larsson R, et al. Ex Vivo Activity of Cardiac
Glycosides in Acute Leukaemia. PLoS ONE. 2011;6(1):e15718-.
55. Roggen H, Charnock C, Burman R, Felth J, Larsson R, Bohlin L, et al. Antimicrobial and
antineoplastic activities of Agelasine analogs modified in the purine 2-position. Archiv der Pharmazie.
2011;344(1):50-55.
56. Hassan S, Laryea D, Mahteme H, Felth J, Fryknäs M, Fayad W, et al. Novel activity of acriflavine
against colorectal cancer tumor cells. Cancer Science. 2011;102(12):2206-2213.
57. D'Arcy P, Brnjic S, Olofsson M, Fryknäs M, Lindsten K, De Cesare M, et al. Inhibition of
proteasome deubiquitinating activity as a new cancer therapy. Nature Medicine. 2011;17(12):1636-
1641.
58. Cashin P, Nygren P, Hellman P, Granberg D, Andréasson H, Mahteme H. Appendiceal
adenocarcinoids with peritoneal carcinomatosis treated with cytoreductive surgery and intraperitoneal
chemotherapy : a retrospective study of in vitro drug sensitivity and survival. Clinical colorectal
cancer. 2011;10(2):108-112.
59. Ågren T, Faria V, Engman J, Furmark T, Gustafsson M, Fredrikson M. Effective Connectivity of Fear
Circuitry and Emotion Regulation in Specific Phobia. 66th Annual Meeting of the Society of
Biological Psychiatry, San Francisco, CA, MAY 12-14, 2011. 2011. 69
60. Haglund C, Aleskog A, Nygren P, Gullbo J, Höglund M, Wickström M, et al. In vitro evaluation of
clinical activity and toxicity of anticancer drugs using tumor cells from patients and cells representing
normal tissues. Cancer Chemotherapy and Pharmacology. 2011;
26

61. Xue B, Soeria-Atmadja D, Gustafsson M, Hammerling U, Dunker A, Uversky V. Abundance and
functional roles of intrinsic disorder in allergenic proteins and allergen representative peptides.
Proteins. 2011;79(9):2595-2606.
62. Lundberg M, Thorsen S, Assarsson E, Villablanca A, Tran B, Gee N, et al. Multiplexed
Homogeneous Proximity Ligation Assays for High-throughput Protein Biomarker Research in
Serological Material. Molecular & Cellular Proteomics. 2011;10(4):M110.004978-.
63. Nordlund J, Kiialainen A, Karlberg O, Berglund E, Göransson-Kultima H, Sønderkær M, et al.
Digital gene expression profiling of primary acute lymphoblastic leukemia cells. Leukemia. 2011;dec
16. [Epub ahead of print].
Dissertations 2011
Caroline Haglund: Integrating Efficacy and Toxicity in Preclinical Anticancer Drug Development:
Methods and Applications.
27

Endocrine tumour biology
Britt Skogseid
Our group has chosen a translational research strategy and we focus on clinical and biological aspects of
rare endocrine diseases, such as adrenocortical cancer and neuroendocrine tumours with special emphasis
on the multiple endocrine neoplasia type 1 syndrome (MEN1). During 2010 the group has included two
new PhD students; one MD with a project on adrenocortical carcinoma epidemiology and treatment, and
one molecular biologist with a project on tumourigenesis of the endocrine pancreas.
MEN 1
Multiple endocrine neoplasia type 1 is an autosomal dominant disease caused by a mutation in a tumour
suppressor gene (MEN1). Gene carriers develop multiple tumours of the parathyroids, endocrine pancreas
and pituitary. We have developed biochemical screening programs for early detection of lesions, performed
longitudinal studies of large MEN 1 families, and instituted early interventions allowing unique
possibilities to prospectively observe tumourigenesis in endocrine tissues. The MEN 1 gene was cloned in
1997 and now more than 1300 disease related mutations have been identified, though no obvious genotypephenotype
correlation has yet been revealed. The protein is called menin and is ubiquitously expressed.
Why MEN1 gene inactivation leads to tumour formation only in some endocrine organs is unclear. The
main cause of mortality is the endocrine pancreatic neoplasia. Seemingly, the MEN1 gene is involved in
the endocrine differentiation of the pancreas and may be a haploinsufficient tumour suppressor gene.
Studies on MEN 1
▪ The molecular events in endocrine pancreatic tumours, apart from inactivation of the MEN1 gene, remain
poorly characterized. We study down-stream effects of altered MEN1 gene expression by transfections and
RNA interference using expression microarrays, quantitative PCR and proteomics.
▪ A number of transcription factors are crucial in endocrine pancreatic development and regeneration. Our
hypotheses are that:
1) these factors could be of importance in transformation of the cells,
2) alterations of the expression are regulated by menin, and
3) that the MEN1 gene is a haploinsufficient suppressor in the pancreas.
Immunohistochemistry and quantitative PCR for these factors on human endocrine pancreatic tumours, in
normal and MEN1 human islets, and in islets and tumours from a Men1 germline heterozygous knock-out
mouse model are performed. Also microarray comparing expression in isolated islets of wild type mice to
that of normal sized islets from young mice with heterozygous Men1 gene inactivation has been performed.
This approach has revealed differential regulation of genes involved in apoptosis, chromatin remodelling
and angiogenesis.
▪ The MEN 1 pancreatic endocrine tumours are highly vascularised and previous studies from our group
have demonstrated that several genes known to be involved in the development of tumour vasculature are
modulated by menin. We are further investigating the role of these factors in the development of endocrine
tissue-specific MEN 1 tumours in a naturally occurring tumour model, the Men+/- mouse model of MEN1,
as well as in pancreatic endocrine tumour transplants in which the levels of gene expression for various
angiogenic factors is genetically modulated. For this purpose we use a recently described perfusion-based
transduction protocol for the genetic modification of intact pancreatic islets, which provides a significantly
improved yield of successfully engineered islet-cells preserving the structural and functional integrity of the
islets/tumours.
▪ CGH microarrays on MEN1 tumours of different sizes, and from different patients.
▪ Clinical studies on prospective MEN1 screening from the database of 60 MEN1 families
▪ Outcome following early intervention for endocrine pancreatic tumours using the same clinical material.
28

FIRM-ACT
First international randomized trial on locally advanced and metastatic adrenocortical carcinoma treatment
(FIRM-act). Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. Treatment of ACC has
never been subjected to randomized GCP trials. Uppsala initiated collaboration between ACC specialists in
Europe, USA and Australia in order to reach an agreement on a protocol for an unsponsored academic
phase III survival study. The study, launched in 2004, is a randomized, prospective, controlled, open-label
multicenter, parallel group study.
Eleven countries participate and have included patients: Sweden (study chair Skogseid, data manager
Mikael Björk), Germany, Italy, The Netherlands, France, Canada, USA, Australia, Norway, Austria and
Poland. Our group has designed an electronic CRF, and the data collection is entirely internet based.
www.firm-act.org
The objective of this study is to compare the efficacy of etoposide, doxorubicin and cisplatin plus mitotane
(EDP/M) as first line treatment versus streptozotocin plus mitotane (Sz/M) as first line treatment. In the
beginning of 2010, 304 patients had been enrolled (which actually was ahead of schedule), and further
inclusions were stopped. After 200 observed events (deaths) monitoring and data base cleaning were
performed. Final statistical analysis is currently ongoing, but preliminary data indicate that first line
treatment with EDP/M is beneficial for the patient.
For additional information, please see http://www.medsci.uu.se/endocrine/presentation.htm
Members of the group 2011
Britt Skogseid, professor
Peter Stålberg, MD, assoc. professor
Barbro Eriksson, professor
Mikael Björk, research nurse and system
developer
Andreea Barbu, senior researcher, PhD
Margareta Halin Lejonklou, PhD student
Publications 2009-2011
29
Mårten Santesson, MD, PhD student
Monica Hurtig, research nurse
Daniel Lindholm, MD
Pantelis Antonodimitrakis, MD
Xia Chu, PhD-student
Anette von Malmborg, research engineer
Lillebil Andersson, secretary
1. Welin S, Stridsberg M, Cunningham J, Granberg D, Skogseid B, Öberg K, Eriksson B, Janson ET.
Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut
carcinoid tumors. Neuroendocrinology 2009;89:302-307
2. Tacon LJ, Soon PS, Gill AJ, Chou AS, Clarkson A, Botling J, Stalberg P, Skogseid B, Robinson BG,
Sidhu SB, Clifton-Bligh RJ. The Glucocorticoid Receptor is Overexpressed in Malignant
Adrenocortical Tumors. J Clin Endocrinol Metab. 2009; 94: 4591-9
3. Lopez-Egido JR, Wang Y, Grönberg M, Grimfjärd P, Wang S, Stålberg P, Skogseid B. Differentially
regulated genes in MEN1-transfected BON cells using RT differntial display and oligonucleotide
microarrays. Anticancer Res. 2009 ; 29:1859-66
4. Lejonklou MH, Edfeldt K, JohanssonT, Stålberg P, Skogseid B. Neurogenin 3 and Neurogenic
Differentiation 1 are retained in the cytoplasm of Multiple Endocrine Neoplsia Type 1 islets as well as
pancreatic endocrine tumor cells. Pancreas 2009;38:259-266
5. Johansson T, Westin G, Skogseid B. Identification of Achaete-scute complex-like 1 (ASCL1) taget
genes and evaluation of DKK1 and TPH1 expression in pancreatic endocrine tumors. BMC Cancer.
2009;9:321.

6. Kindmark H, Janson ET, Gustavsson B, Eriksson C, Larsson G, Granberg D, Kozlowacki G, Skogseid
B, Welin S, Oberg K, Eriksson B. Five patients with malignant endocrine tumors treated with imatinib
mesylate (Glivec). Acta Oncol. 2010;49:100-1
7. Lopez JR, Claessen SM, Macville MV, Albrechts JC, Skogseid B, Speel EJ. Spectral karyotypic and
comparative genomic analysis of the endocrine pancreatic tumor cell line BON-1.
Neuroendocrinology. 2010; 91:131-41
8. Lindhe O, Skogseid B. Mitotane effects in a H295R xenograft model of adjuvant treatment of
adrenocortical cancer. Horm Metab Res. 2010;42:725-30
9. Norlén O, Stålberg P, Öberg K, Eriksson J, Hedberg J, Hessman O, et al. Long-Term Results of
Surgery for Small Intestinal Neuroendocrine Tumors at a Tertiary Referral Center. World Journal of
Surgery. 2011;
10. Garske U, Sandström M, Johansson S, Sundin A, Granberg D, Eriksson B, et al. Minor changes in
effective half-life during fractionated 177Lu-Octreotate therapy. Acta Oncologica. 2011;51(1):86-96.
11. Ekeblad S, Lejonklou M, Stålberg P, Skogseid B. Prognostic Relevance of Survivin in Pancreatic
Endocrine Tumors. World Journal of Surgery. 2011;
12. Skogseid IM, Ramm-Pettersen J, Volkmann J, Kerty E, Dietrichs E, Røste GK. Good long-term
efficacy of pallidal stimulation in cervical dystonia: a prospective, observer-blinded study Eur J
Neurol. 2011 Nov 25.
13. Toft M, Lilleeng B, Ramm-Pettersen J, Skogseid IM, Gundersen V, Gerdts R, Pedersen L, Skjelland
M, Røste GK, Dietrichs E. Long-term efficacy and mortality in Parkinson's disease patients treated
with subthalamic stimulation Mov Disord. 2011 Aug 15;26(10):1931-4
Reviews
1. Berruti A, Fassnacht M, Baudin E, Hammer G, Haak H, Leboulleux S, Skogseid B, Allolio B,
Terzolo. Adjuvant therapy in patients with adrenocortical carcinoma: a position of an international
panel. J Clin Oncol. 2010 Aug 10;28(23):e401-2; author reply e403.
30

Biochemical endocrinology
Mats Stridsberg
There are currently two major research areas; the first is focused on diagnostic tools for neuroendocrine
tumours, and the second on Endocrine responses to stress exercise and food intake.
Markers for neuroendocrine tumours and neuroendocrine-related diseases
Mats Stridsberg, Inger Olsson
This project focuses on diagnostic tools for patients with neuroendocrine diseases. These diseases include
patients with malignant tumours, such as carcinoid tumours, endocrine pancreatic tumours,
pheochromocytomas and neuroblastomas. Non-malignant diseases where neuroendocrine properties are of
interest are ischemic coronar disease, cardiac failure and inflammatory bowel disease. A large number of
antibodies against neuroendocrine associated proteins have been raised. These antibodies are used for
developments of radioimmunoassays and Elisas for quantitative measurements in different biological
fluids, mainly plasma and serum. The antibodies are also used in immuno-histochemical applications.
Neuroendocrine proteins of special interest are Chromogranin A, Chromogranin B, Secretogranins,
Secretoneurin, Proconvertases, Somatostatin receptors, Secretin receptors and Synatophysin.
During the last year we have been working with further developments of assays for measurements of
granins, including new and enhanced methods for CgA and CgB and further developments of the assays for
secretogranins. Measurements of granins (CgA and CgB) are still the most important tools for the
management of patients with neuroendocrine tumours. However, also for other diseases measurements of
granins can be used as (new) biomarkers. It has been shown earlier that CgA is a marker for heart failure
and we have shown that CgB also can be used as a biomarker for congestive heart failure. The use of
granins as biomarkers for both tumours and for other diseases will be further evaluated.
Endocrine responses to stress exercise and food intake:
Torbjörn Åkerfeldt, Inger Olsson, Mats Stridsberg
The hormonal responses elicited by nutrition and exercise are an area of interest. Both over-feeding and
starvation involve hormonal responses. This project focuses on improvement and development of
biochemical methods to monitor changes in body composition in relation to food intake and also in relation
to stress and exercise. Hormones of special interest are IGF-1, IGF-binding proteins, Adiponectin,
Obestatin, Leptin, Melatonin, and other peptide hormones.
Members of the group during 2011
Mats Stridsberg, MD, PhD, Assoc. Prof.
Torbjörn Åkerfeldt, MD, PhD student
Inger Olsson, Technician
Funding
ALF
Lions Research Foundation
Publications 2009-2011
1. Portela-Gomes GM, Gayen JR, Grimelius L, Stridsberg M, Mahata SK. The importance of
chromogranin A in the development and function of endocrine pancreas. Regul Pept. 2008 Nov
29;151(1-3):19-25. Erratum in: Regul Pept. 2009;153:93.
31

2. Fuchs D, Christoffersson R, Stridsberg M, Lindhagen E, Azarbayjani F. Regression of orthotopic
neuroblastoma in mice by targeting the endothelial and tumor cell compartments. Journal of
Translational Medicine 2009;7:16
3. Branth S, Hambraeus L, Piehl-Aulin K, Essen-Gustavsson B, Åkerfeldt T, Olsson R, Stridsberg M,
Ronquist G. Metabolic stress-like condition can be induced by prolonged strenuous exercise in
athletes. Ups J Med Sci. 2009;114:12-25.
4. Swenne I, Stridsberg M, Thurfjell B, Rosling A. Triiodothyronine is an indicator of nutritional status
in adolescent girls with eating disorders. Hormone Research. 2009;71:268-275.
5. Alderman JM, Flurkey K, Brooks NL, et al Neuroendocrine inhibition of glucose production and
resistance to cancer in dwarf mice. Exp Gerontol. 2009;44:26-33.
6. Tsolakis AV, Grimelius L, Stridsberg M, Falkmer S, Waldum H, Saras J, Janson ET. Obestatin/ghrelin
cells in normal mucosa and endocrine tumours of the stomach. Eur J Endocrinol. 2009;160:941-949.
7. Welin S, Stridsberg M, Cunningham J, Granberg D, Skogseid B, Öberg KE, Eriksson BK, Janson ET.
Elevated plasma chromogranin A is the first indication of recurrence in radically operated midgut
carcinoid tumors. Neuroendocrinology. 2009;89:302-307.
8. Chen Y, Mahata M, Rao F, et al. Chromogranin A regulates renal function by triggering Weibel-
Palade body exocytosis. J Am Soc Nephrol. 2009;20:1427-1429.
9. Rana BK, Wessel J, Mahboubi V, et al. P. Natural variation within the neuronal nicotinic
acetylcholine receptor cluster on human chromosome 15q24: Influence on heritable autonomic traits
in twin pairs. J Pharmacol Exp Ther. 2009;331:419-28.
10. Zhang K, Rao F, Gayen JR, et al. Autonomic function in hypertension, role of genetic variation at the
catecholamine storage vesicle protein chromogranin B. Circ Cardiovasc Genet. 2009;2:46-56.
11. Grönberg M, Amini RM, Stridsberg M, Janson ET, Saras J. Neuroendocrine markers are expressed in
human mammary glands. Regul Pept 2010; 160:68-74
12. Darnerud PO, Lignell S, Glynn A, Aune M, Törnkvist A, Stridsberg M. Pop levels in breast milk and
maternal serum and thyroid hormone levels in mother-child pairs from Uppsala, Sweden. Environ Int.
2010;36:180-187.
13. Gougeon A, Delangle A, Arouche N, Stridsberg M, Gotteland JP, Loumaye E. Kit ligand and the
somatostatin receptor antagonist BIM-23627, stimulate in vitro resting follicle growth in the neonatal
mouse ovary. Endocrinology. 2010;151:1299-1309.
14. Myrelid A, Frisk P, Stridsberg M, Annerén G, Gustafsson J. Normal growth hormone secretion in
overweight young adults with Down syndrome. Growth Horm IGF Res. 2010;20:174-178.
15. Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic
pain and long-term term opioid treatment. Clin J Pain. 2010; 26:374-380.
16. Fung MM, Salem RM, Mehtani P, et al. Direct vasoactive effects of the chromogranin a (chga)
peptide catestatin in humans in vivo. Clinical and Experimental Hypertension. 2010;32:278-287.
17. Portela-Gomes GM, Grimelius L, Westermark P, Stridsberg M. Somatostatin Receptor Subtypes in
Human Type 2 Diabetic Islets. Pancreas 2010;39:836-842.
18. Rösjö H, Husberg C, Dahl MB, Stridsberg M, Sjaastad I, Finsen AV, Carlson CR, Oie E, Omland T,
Christensen G. Chromogranin B in heart failure: a putative cardiac biomarker expressed in the failing
myocardium. Circ Heart Fail 2010;3:503-511.
19. Mattsson N, Johansson P, Hansson O, et al. Converging pathways of chromogranin and amyloid
metabolism in the brain. J Alzheimers Dis. 2010;20:1039-1049.
20. Hagforsen E, Michaëlsson G, Stridsberg M. Normal and PPP-affected palmoplantar sweat gland
express neuroendocrine markers chromogranins and synaptophsin differently. Arch Dermatol Res.
2010;302:685-693.
32

21. Åkerfeldt T, Helmersson J, Larsson A. Postsurgical inflammatory response is not associated with
increased cystatin C values. Clin Biochem. 2010 September ;43(13-14):1138-40.
22. Portela-Gomes GM, Grimelius L, Wilander E, Stridsberg M. Granin and granin-related peptides in
neuroendocrine tumours. Regul Pept. 2010;165:12-20.
23. Ahlsson F, Diderholm B, Nordén-Lindeberg S, Ewald U, Forslund A, Stridsberg M and Gustafsson J.
Insulin resistance, a link between maternal overweight and fetal macrosomia in non-diabetic
pregnancies. Horm Res Paediatr 2010;74:267274.
24. Portela-Gomes GM, Grimelius L, Stridsberg M. Secretogranin III in human neuroendocrine tumours.
A comparative immunohistochemical study with Chromogranin A and B and secretogranin II. Regul
Pept. 2010;165:30-35.
25. Portela-Gomes GM, Grimelius L, Stridsberg M. Immunohistochemical and Biochemical Studies with
Region-Specific Antibodies to Chromogranins A and B and Secretogranins II and III in
Neuroendocrine Tumors. Cell Mol Neurobiol. 2010;30:1147-1153.
26. Hagforsen E, Stridsberg M, Michaëlsson G. Somatostatin receptors are strongly expressed in
palmoplantar sweat glands and ducts : studies of normal and palmoplantar pustulosis skin. Clinical and
experimental dermatology. 2011;36(5):521-527.
27. Hagforsen E, Michaëlsson G, Stridsberg M. Somatostatin receptors are strongly expresssed in
palmoplantar sweat glands and ducts : studies of normal and palmoplantar pustulosis skin. Clincal and
Experimental Dermatology. 2011;36(5):521-527.
28. Åkerfeldt T, Larsson A. Pentraxin 3 Increase is Much Less Pronounced Than C-Reactive Protein
Increase After Surgical Procedures. Inflammation. 2011 Oct;34(5):367-70.
29. Hudecova M, Holte J, Moby L, Olovsson M, Stridsberg M, Larsson A, et al. Androgen levels, insulin
sensitivity, and early insulin response in women with polycystic ovary syndrome : a long-term followup
study. Fertility and Sterility. 2011;95(3):1146-1148.
30. Georgantzi K, Tsolakis A, Stridsberg M, Jakobson A, Christofferson R, Janson E. Differentiated
expression of somatostatin receptor subtypes in experimental models and clinical neuroblastoma.
Pediatric Blood & Cancer. 2011;56(5):584-589.
31. Danielsson K, Markström A, Stridsberg M, Broman J. Dim light melatonin onset in normal adults and
its relationship with sleep timing and diurnal preference. Biological rhythm research. 2011:1-7.
32. Ludvigsen E, Stridsberg M, Janson E, Sandler S. Altered Expression of Somatostatin Receptors in
Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets
Transplanted to Diabetic NOD Mice In Vivo. Experimental Diabetes Research. 2011;2011:623472.
33

Epidemiology
Epidemiology research is carried out by several individual research groups
working in five different areas; cardiovascular (CV) disease, pulmonary
disorders, osteoporosis, occupational and environmental medicine and
clinical pharmacogenetics. One mutual strategy for these research groups
is to study genetic and environmental risk factors aiming to understand the
pathophysiology of atherosclerosis mediated CV-disorders, osteoporosis,
and chronic respiratory diseases, respectively. Risk factor analysis is also
employed by the environmental medicine group to assess the impact of
occupational and environmental exposures. The common goals for the
research groups are to develop better risk classifications, and to improve
both prevention and treatment strategies for the above mentioned common
disorders.
Cardiovascular epidemiology
Lars Lind
The major uniting aim in the research group is to understand the pathophysiology behind the
atherosclerosis mediated CV disorders myocardial infarction and stroke for an improved risk classification
in the population and improved treatment strategies.
Besides our ongoing studies on established cohorts (see below) we have lately initiated two new, major
projects. The first project, led by Johan Sundström, MetaHealth, is a collaboration network of existing
cohorts in Malmö/Lund and Uppsala designed for individual participant data meta-analyses of uncommon
diseases, for which very large samples are needed. The second project is a new cohort study, the EpiHealth
cohort. The plan is to enrol 300,000 Swedes in the age-groups 45 to 75 years to study the interplay between
genes and life-style factors on the development of common disorders seen in the elderly, such as
myocardial infarction, stroke, bone fractures, dementia, chronic obstructive pulmonary disease, cancer
arthrosis. Data on life-style exposures will be collected by a web-based questionnaire and
serum/plasma/DNA will be biobanked at a visit to a test centre where also physiological measures, such as
blood pressure, lung function, cognitive function, anthropometry and ECG will be recorded
The Prospective Investigation of the Vasculature in Uppsala Seniors
(PIVUS) study
Lars Lind
The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study is a population-based
longitudinal cohort study, started in 2001, of men and women aged 70. A number of cardiovascular
characteristics have been collected, e.g. measurements of intima-media thickness, three different tests of
endothelial function, and a large number of biochemical biomarkers
A reinvestigation of the cohort at age 75 was performed between March 2006 and Sep 2009, and a
reinvestigation at age 80 is about to start. Apart from analyses of classical risk factors, ultrasound of the
carotid arteries and the heart will be performed together with 2 cognitive function tests.
The Uppsala Longitudinal Study of Adult Men (ULSAM)
Johan Sundström, Lars Lind, and Lars Lannfelt (PI)
The ULSAM study was started in 1970, when 2 322 men at the age of 50 participated in a health survey.
The men have thereafter been investigated again at ages 60, 70, 77, 82 and 88 years, respectively. The
focus in the ULSAM cohort is on cardiovascular disease and metabolic links, but several other research
areas have also been explored, such as nutrition, osteoporosis, and dementia. The follow-up time for
morbidity and mortality through national registers is now >40 years. The major research aims in the
ULSAM study are: to investigate the impact of life-time exposures of risk factors using updated covariates
34

on the major CV diseases MI, Stroke and heart failure, to explore new risk factors, and to evaluate the risk
associated with different genotypes on CV outcomes.
The Prospective investigation of Obesity, Energy production and Metabolism
(POEM) longitudinal study
Lars Lind
A randomized sample of more than 1000 individuals selected from the inhabitants of the Uppsala County
aged 50 have been invited for the baseline examination. In addition, by use of a health screening project,
another 300-400 obese middle-aged subjects with a mean age of 50 will be subjected to the same baseline
examination. These subjects will then be examined every 10th year regarding hypertension, obesity,
diabetes and dyslipidemia. The development of CV disorders will be followed throughout life by means of
the Swedish national registers of hospital care and mortality. The first patient was included in the study in
Sep 2010.
Management and outcome of stroke using Riks-Stroke
Anders Terent
Stroke is the most common clinical manifestation of vascular disease in the brain. The onset of symptoms
is sudden and the consequences long-lasting. Bleeding (15%) or infarction in the brain parenchyma (85%)
causes stroke. In Sweden about 30 000 people suffer strokes every year. We perform a cohort study of 105
034 patients, registered in Riks-Stroke (Swedish National Quality Register for Stroke Care) during 2001
through 2005. Cross-linking to the Hospital Discharge and Cause of Death Registers has been done to
achieve data on previous hospitalisations, death dates and causes of death. The objectives are to assess comorbidity,
functionality and drug treatment in stroke patients before and after the stroke. Of particular
interest is the use of anti-thrombotic treatment at onset of acute stroke and at discharge from hospital. Risk
and risk factors for fatal and non-fatal recurrent stroke are analysed.
Members of the group during 2011
Lars Lind, MD, professor
Andreas Terént, MD, professor
Johan Sundström, MD, assoc professor
Kasper Andersen, MD, PhD-student
Anders Holmlund, PhD
Jessika Andersson, MD, PhD-student
Funding
Lars Lind
Swedish Research Council 0.4 MSEK
ALF 2.0 MSEK
Hjärt-Lungfonden 0.4 MSEK
EpiHealth 3.0 MSEK
Publications 2009-2011
35
Jonas Hansson, PhD-student
Gabriel Arefalk, PhD-student
Tomas Cars, PhD-student
Signild Åsberg, MD, PhD-student
Said Mashia, MD, PhD-student
Johan Sundström
Swedish Research Council 0.9 MSEK
ALF 0.2 M SEK
Heart & Lung Foundation
Andreas Terent
0.4 MSEK
AstraZeneca 0.7 MSEK
ALF 0.3 MSEK
1. Ahlstrom, T. et al. Correlation between plasma calcium, parathyroid hormone (PTH) and the
metabolic syndrome (MetS) in a community-based cohort of men and women. Clinical Endocrinology
71, 673-678, (2009).

2. Andersson, J. et al. Echogenecity of the carotid intima-media complex is related to cardiovascular risk
factors, dyslipidemia, oxidative stress and inflammation: the Prospective Investigation of the
Vasculature in Uppsala Seniors (PIVUS) study. Atherosclerosis 204, 612-618, (2009).
3. Andersson, J. et al. The carotid artery plaque size and echogenicity are related to different
cardiovascular risk factors in the elderly: the Prospective Investigation of the Vasculature in Uppsala
Seniors (PIVUS) study. Lipids 44, 397-403, (2009).
4. Andersson, J., Sundstrom, J. & Lind, L. No Differences Regarding Carotid Atherosclerosis between
Isolated Systolic and Combined Hypertension in Elderly Subjects. Journal of Hypertension 27, S93-
S93 (2009).
5. Eggers, K. M., Jaffe, A. S., Lind, L., Venge, P. & Lindahl, B. Value of cardiac troponin I cutoff
concentrations below the 99th percentile for clinical decision-making. Clin Chem 55, 85-92, (2009).
6. Eggers, K. M., Lind, L., Venge, P. & Lindahl, B. Will the universal definition of myocardial infarction
criteria result in an overdiagnosis of myocardial infarction? Am J Cardiol 103, 588-591, (2009).
7. Eggers, K. M., Lindahl, B., Venge, P. & Lind, L. B-Type Natriuretic Peptides and Their Relation to
Cardiovascular Structure and Function in a Population-Based Sample of Subjects Aged 70 Years.
American Journal of Cardiology 103, 1032-1038, (2009).
8. Eggers, K. M., Lindahl, B., Venge, P. & Lind, L. B-Type Natriuretic Peptides in a Population-Based
Sample of Elderly Subjects Are Not Associated With Vascular Pathologies. Journal of the American
College of Cardiology 53, A423-A423 (2009).
9. Engstrom, G., de Verdier, M. G., Dahlback, M., Janson, C. & Lind, L. BP Variability and
Cardiovascular Autonomic Function in Relation to Forced Expiratory Volume A Population-Based
Study. Chest 136, 177-183, (2009).
10. Hagstrom, E. et al. Plasma Parathyroid Hormone and Risk of Congestive Heart Failure in the
Community. Circulation 120, S399-S400 (2009).
11. Hagstrom, E. et al. Plasma parathyroid hormone and the risk of cardiovascular mortality in the
community. Circulation 119, 2765-2771, (2009).
12. Hansen, T. et al. Visceral adipose tissue, adiponectin levels and insulin resistance are related to
atherosclerosis as assessed by whole-body magnetic resonance angiography in an elderly population.
Atherosclerosis 205, 163-167, (2009).
13. Hansen, T. W. et al. Prognostic Value of 24-H Blood Pressure Variability in 7040 Subjects from 6
Populations. Journal of Hypertension 27, S51-S51 (2009).
14. Hansson, J., Lind, L., Hulthe, J. & Sundstrom, J. Relations of serum MMP-9 and TIMP-1 levels to left
ventricular measures and cardiovascular risk factors: a population-based study. Eur J Cardiovasc Prev
Rehabil 16, 297-303, (2009).
15. Holmlund, A., Hedin, M., Pussinen, P. J., Lerner, U. H. & Lind, L. Porphyromonas gingivalis (Pg) a
possible link between impaired oral health and acute myocardial infarction. Int J Cardiol, (2009).
16. Holmlund, A., Holm, G. & Lind, L. Cardiovascular Mortality Is Related to Impaired Oral Health in a
Large Cohort of Subjects Followed for 12 Years. Circulation 119, E338-E338 (2009).
17. Ingelsson, E. et al. Associations of Serum Adiponectin with Skeletal Muscle Morphology and Insulin
Sensitivity. Journal of Clinical Endocrinology & Metabolism 94, 953-957 (2009).
18. Ingelsson, E. & Lind, L. Circulating Retinol-Binding Protein 4 and Subclinical Cardiovascular
Disease in the Elderly. Diabetes Care 32, 733-735, (2009).
19. Ingelsson, E. et al. Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent
cardiovascular disease in elderly. Atherosclerosis 206, 239-244, (2009).
20. Jarhult, S. J., Sundstrom, J. & Lind, L. Brachial artery hyperemic blood flow velocities are related to
carotid atherosclerosis. Clin Physiol Funct Imaging 29, 360-365, (2009).
36

21. Liljedahl, S., Kahan, T., Lind, L. & Arnlov, J. The effects of antihypertensive treatment on the
doppler-derived myocardial performance index in patients with hypertensive left ventricular
hypertrophy: results from the Swedish irbesartan in left ventricular hypertrophy investigation versus
atenolol (SILVHIA). Echocardiography 26, 753-758, (2009).
22. Lind, L. Endothelium-Dependent Vasodilation Is Impaired in Elderly Hypertensive Patients with the
Metabolic Syndrome. Journal of Hypertension 27, S25-S26 (2009).
23. Lind, L., Andersson, J., Hansen, T., Johansson, L. & Ahlstrom, H. Atherosclerosis measured by whole
body magnetic resonance angiography and carotid artery ultrasound is related to arterial compliance,
but not to endothelium-dependent vasodilation - the Prospective Investigation of the Vasculature in
Uppsala Seniors (PIVUS) study. Clin Physiol Funct Imaging 29, (2009).
24. Lind, L., Andersson, J., Larsson, A. & Sandhagen, B. Shear stress in the common carotid artery is
related to both intima-media thickness and echogenecity. Clin Hemorheol Micro 43, 299-308, (2009).
25. Lind, L., Ingelsson, E., Sundstrom, J. & Amlov, J. A. The Impact of Obesity and the Metabolic
Syndrome on the Risk of Cardiovascular Morbidity and Mortality in Middle-Aged Men. Circulation
119, E302-E302 (2009).
26. Lind, L., Larsson, A. & Teerlink, T. L-Arginine is related to endothelium-dependent vasodilation in
resistance and conduit arteries in divergent ways-The Prospective Investigation of the Vasculature in
Uppsala Seniors (PIVUS) study. Atherosclerosis 203, 544-549, (2009).
27. Lind, L., Siegbahn, A., Ingelsson, E., Sundstrom, J. & Amlov, J. A Detailed Cardiovascular
Characterization of Metabolically Healthy Obesity. Circulation 119, E302-E302 (2009).
28. Lind, L. et al. Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction
and disease in the elderly: results from the Prospective Investigation of the Vasculature in Uppsala
Seniors (PIVUS) Study. European Heart Journal 30, 2346-2353, (2009).
29. Lind, L., Zethelius, B., Sundbom, M., Eden Engstrom, B. & Karlsson, F. A. Vasoreactivity is rapidly
improved in obese subjects after gastric bypass surgery. Int J Obes (Lond) 33, 1390-1395, (2009).
30. Lind, P. M., Ingelsson, E., Syvanen, A. C. & Lind, L. A polymorphism in the Ah-receptor gene is
related to hypertension and endothelium-dependent vasodilation. Toxicology Letters 189, S100-S101,
(2009).
31. Mirza, M. A. et al. Relationship between circulating FGF23 and total body atherosclerosis in the
community. Nephrol Dial Transplant 24, 3125-3131, (2009).
32. Mirza, M. A., Larsson, A., Lind, L. & Larsson, T. E. Circulating fibroblast growth factor-23 is
associated with vascular dysfunction in the community. Atherosclerosis 205, 385-390, (2009).
33. Mirza, M. A., Larsson, A., Melhus, H., Lind, L. & Larsson, T. E. Serum intact FGF23 associate with
left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207, 546-
551, (2009).
34. Mirza, M. A. I. et al. Relationship between circulating FGF23 and total body atherosclerosis in the
community. Nephrol Dial Transpl 24, 3125-3131, (2009).
35. Mirza, M. A. I., Larsson, A., Lind, L. & Larsson, T. E. Circulating fibroblast growth factor-23 is
associated with vascular dysfunction in the community. Atherosclerosis 205, 385-390, (2009).
36. Mirza, M. A. I., Larsson, A., Melhus, H., Lind, L. & Larsson, T. E. Serum intact FGF23 associate with
left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207, 546-
551, (2009).
37. Petersson, H. et al. Relationships between serum fatty acid composition and multiple markers of
inflammation and endothelial function in an elderly population. Atherosclerosis 203, 298-303, (2009).
38. Soveri, I. et al. Kidney function and discrimination of cardiovascular risk in middle-aged men. J Intern
Med 266, 406-413, (2009).
37

39. Sundstrom, J. et al. Cardiac troponin-I and risk of heart failure: a community-based cohort study. Eur
Heart J 30, 773-781, (2009).
40. Themudo, R. E. et al. Signal Intensity of Myocardial Scars at Delayed-enhanced MRI. Acta
Radiologica 50, 652-657, (2009).
41. Vasan, R. S. et al. Genetic Variants Associated With Cardiac Structure and Function A Meta-analysis
and Replication of Genome-wide Association Data. Jama-Journal of the American Medical
Association 302, 168-178 (2009).
42. Wiberg, B., Sundstrom, J., Zethelius, B. & Lind, L. Insulin sensitivity measured by the euglycaemic
insulin clamp and proinsulin levels as predictors of stroke in elderly men. Diabetologia 52, 90-96,
(2009).
43. Wikstrom, J., Hansen, T., Johansson, L., Ahlstrom, H. & Lind, L. Lower extremity artery stenosis
distribution in an unselected elderly population and its relation to a reduced ankle-brachial index. J
Vasc Surg 50, 330-334, (2009).
44. Wohlin, M., Sundstrom, J., Andren, B., Larsson, A. & Lind, L. An echolucent carotid artery intimamedia
complex is a new and independent predictor of mortality in an elderly male cohort.
Atherosclerosis 205, 486-491, (2009).
45. Bodén R, Sundström J, Lindström E, Lindström L. Association between symptomatic remission and
functional outcome in first-episode schizophrenia. Schizophr Res. 2009 Feb;107(2-3):232-7.
46. Ingelsson E, Arnlöv J, Sundström J, Risérus U, Michaëlsson K, Byberg L. Relative importance and
conjoint effects of obesity and physical inactivity for the development of insulin resistance. Eur J
Cardiovasc Prev Rehabil. 2009 Feb;16(1):28-33.
47. Neovius M, Sundström J, Rasmussen F. Combined Effects of Overweight and Smoking in Late
Adolescence on Subsequent Mortality: Nationwide Cohort Study. BMJ. 2009 Feb 24;338:b496. doi:
10.1136/bmj.b496.
48. Byberg L, Melhus H, Gedeborg R, Sundstrom J, Ahlbom A, Zethelius B, Berglund L, Wolk A,
Michaëlsson K. Total mortality after changes in leisure time physical activity in 50 year old men: 35
year follow-up of population based cohort. BMJ 2009;338:b688. doi:10.1136/bmj.b688
49. Rönnemaa E, Zethelius B, Sundelöf J, Sundström J, Degerman-Gunnarsson M, Lannfelt L, Berne C,
Kilander L. Glucose metabolism and the risk of Alzheimer's disease and dementia: a population-based
12 year follow-up study in 71-year-old men. Diabetologia. 2009 Aug;52(8):1504-10.
50. Byberg L, Melhus H, Gedeborg R, Sundström J, Ahlbom A, Zethelius B, Berglund LG, Wolk A,
Michaëlsson K. Total mortality after changes in leisure time physical activity in 50 year old men: 35
year follow-up of population based cohort. Br J Sports Med. 2009 Jul;43(7):482.
51. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson
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52. Bodén R, Haenni A, Lindström L, Sundström J. Biochemical risk factors for development of obesity
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53. Asplund K, Jonsson F, Eriksson M, Stegmayr B, Appelros P, Norrving B, Terént A, Asberg KH; Riks-
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54. Terént A, Asplund K, Farahmand B, Henriksson KM, Norrving B, Stegmayr B, Wester PO, Asberg
KH, Asberg S; Riks-Stroke Collaboration. Stroke unit care revisited: who benefits the most? A cohort
study of 105,043 patients in Riks-Stroke, the Swedish Stroke Register. J Neurol Neurosurg Psychiatry.
2009 Aug;80(8):881-7.
38

55. Nilsson G, Holmberg L, Garmo H, Terent A, Blomqvist C. Radiation to supraclavicular and internal
mammary lymph nodes in breast cancer increases the risk of stroke. Br J Cancer. 2009 Mar
10;100(5):811-6.
56. Appelros P, Stegmayr B, Terént A. Sex differences in stroke epidemiology: a systematic review.
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57. Lundström E, Smits A, Terént A, Borg J. Risk factors for stroke-related pain 1 year after first-ever
stroke. Eur J Neurol. 2009 Feb;16(2):188-93.
58. Eriksson M, Glader EL, Norrving B, Terént A, Stegmayr B. Sex differences in stroke care and
outcome in the Swedish national quality register for stroke care. Stroke. 2009 Mar;40(3):909-14.
59. Hergens MP, Lambe M, Pershagen G, Terent A, Ye W. Smokeless tobacco and the risk of stroke.
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61. Arnlov, J., Ingelsson, E., Sundstrom, J. & Lind, L. Response to Letters Regarding Article, "The
Impact of Body Mass Index and the Metabolic Syndrome on the Risk of Cardiovascular Disease and
Death in Middle-Aged Men". Circulation 122, E457-E457, (2010).
62. Arnolov, J., Ingelsson, E., Sundstrom, J. & Lind, L. Impact of Body Mass Index and the Metabolic
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230-U288, (2010).
63. Barbier, C. E., Lind, L., Ahlstrom, H., Larsson, A. & Johansson, L. Apolipoprotein B/A-I ratio related
to visceral but not to subcutaneous adipose tissue in elderly Swedes. Atherosclerosis 211, 656-659,
(2010).
64. Carlsson, L., Lind, L. & Larsson, A. Reference values for 27 clinical chemistry tests in 70-year-old
males and females. Gerontology 56, 259-265 (2010).
65. Dupuis, J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2
diabetes risk. Nat Genet 42, 105-116, (2010).
66. Fan, H. Q. et al. Prognostic value of isolated nocturnal hypertension on ambulatory measurement in
8711 individuals from 10 populations. Journal of Hypertension 28, 2036-2045, (2010).
67. Gkrania-Klotsas, E. et al. Differential White Blood Cell Count and Type 2 Diabetes: Systematic
Review and Meta-Analysis of Cross-Sectional and Prospective Studies. PLoS One 5, (2010).
68. Gustafsson, S., Lind, L., Soderberg, S. & Ingelsson, E. Associations of Circulating Adiponectin with
Measures of Vascular Function and Morphology. Journal of Clinical Endocrinology & Metabolism 95,
2927-2934, (2010).
69. Gustafsson, S. et al. Adiponectin and cardiac geometry and function in elderly: results from two
community-based cohort studies. Eur J Endocrinol 162, 543-550 (2010).
70. Hagstrom, E. et al. Plasma parathyroid hormone and risk of congestive heart failure in the community.
Eur J Heart Fail 12, 1186-1192, (2010).
71. Hallstrom, H. et al. Coffee consumption and CYP1A2 genotype in relation to bone mineral density of
the proximal femur in elderly men and women: a cohort study. Nutr Metab (Lond) 7, 12 (2010).
72. Hansen, T. W. et al. Prognostic Value of Reading-to-Reading Blood Pressure Variability Over 24
Hours in 8938 Subjects From 11 Populations. Hypertension 55, 1049-U1419, (2010).
73. Holmlund, A., Holm, G. & Lind, L. Number of Teeth as a Predictor of Cardiovascular Mortality in a
Cohort of 7,674 Subjects Followed for 12 Years. Journal of Periodontology 81, 870-876 (2010).
74. Hudecova, M., Holte, J., Olovsson, M., Lind, L. & Poromaa, I. S. Endothelial function in patients with
polycystic ovary syndrome: a long-term follow-up study. Fertil Steril 94, 2654-2658, (2010).
39

75. Ingelsson, E. et al. Detailed physiologic characterization reveals diverse mechanisms for novel genetic
Loci regulating glucose and insulin metabolism in humans. Diabetes 59, 1266-1275, (2010).
76. Jobs, E. et al. Serum cathepsin S is associated with serum C-reactive protein and interleukin-6
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77. Kalies, I. et al. Fviia Plasma Levels: Influence of F7, F10 and Epcr (Endothelial Protein C Receptor)
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78. Larsson, T. E. et al. Conjoint Effects of Serum Calcium and Phosphate on Risk of Total,
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79. Lind, L. Arterial stiffness, but not endothelium-dependent vasodilation, is related to a low Ankle-
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80. Naessen, T. et al. Endogenous steroids measured by high-specificity liquid chromatography-tandem
mass spectrometry and prevalent cardiovascular disease in 70-year-old men and women. J Clin
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81. Olafsdottir, I. S. et al. Serum levels of matrix metalloproteinase-9, tissue inhibitors of
metalloproteinase-1 and their ratio are associated with impaired lung function in the elderly: a
population-based study. Respirology 15, 530-535, (2010).
82. Safwenberg, U., Terent, A. & Lind, L. Increased long-term mortality in patients with repeated visits to
the emergency department. Eur J Emerg Med 17, 274-279, (2010).
83. Sakthivel, P. et al. Circulating soluble CTLA-4 is related to inflammatory markers in the 70 year old
population. Scand J Clin Lab Inv 70, 237-243, (2010).
84. Themudo, R. E. et al. Unrecognized myocardial scars detected by delayed-enhanced MRI are
associated with increased levels of NT-proBNP. Coron Artery Dis, (2010).
85. Wiberg, B. et al. Cognitive function and risk of stroke in elderly men. Neurology 74, 379-385, (2010).
86. Bodén R, Sundström J, Lindström E, Wieselgren IM, Lindström L. Five-year outcome of first-episode
psychosis before and after the implementation of a modified assertive community treatment
programme. Soc Psychiatry Psychiatr Epidemiol. 2010 Jun;45(6):665-74.
87. Johansson K, Sundström J, Neovius K, Rössner S, Neovius M. Long-term changes in blood pressure
following orlistat and sibutramine treatment: a meta-analysis. Obes Rev. 2010 Nov;11(11):777-91.
88. Silventoinen K, Sundström J, Tynelius P, Eriksson J, Rasmussen F. Ethnic differences in blood
pressure in young men living in similar environment: a study of international adoptees in Sweden. J
Hypertens. 2010 Jul;28(7):1393-9.
89. Sundelöf J, Sundström J, Hansson O, Eriksdotter-Jönhagen M, Giedraitis V, Larsson A, Degerman-
Gunnarsson M, Ingelsson M, Minthon L, Blennow K, Kilander L, Basun H, Lannfelt L. Cystatin C
Levels are Positively Correlated with both Abeta42 and Tau Levels in Cerebrospinal Fluid in Persons
with Alzheimer's Disease, Mild Cognitive Impairment, and Healthy Controls. J Alzheimers Dis.
2010;21(2):471-8b.
90. Neovius K, Rasmussen F, Sundström J, Neovius M. Forecast of future premature mortality as a result
of trends in obesity and smoking: nationwide cohort simulation study. Eur J Epidemiol. 2010
Oct;25(10):703-9.
91. Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, Berglund L, Arnlöv J,
Hellman P, Blomhoff R, Wolk A, Garmo H, Holmberg L, Melhus H. Plasma vitamin D and mortality
in older men: a community-based prospective cohort study. Am J Clin Nutr. 2010 Oct;92(4):841-8.
92. Velagaleti RS, Gona P, Sundström J, Larson MG, Siwik D, Colucci WS, Benjamin EJ, Vasan RS.
Relations of biomarkers of extracellular matrix remodeling to incident cardiovascular events and
mortality. Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2283-8.
40

93. Sundelöf J, Sundström J, Hansson O, Eriksdotter-Jönhagen M, Giedraitis V, Larsson A, Degerman-
Gunnarsson, Higher Cathepsin B Levels in Plasma in Alzheimer's Disease Compared to Healthy
Controls J Alzheimers Dis. 2010;22(4):1223-30
94. Sundström J. Troponin and heart failure: an early warning system worth listening to? Future Cardiol.
2009 Jul;5(4):321-4.
95. Sundström J. Myocardial biomarkers for prediction of cardiovascular disease. Dis Markers.
2009;26(5-6):235-46.
96. Asberg S, Henriksson KM, Farahmand B, Asplund K, Norrving B, Appelros P, Stegmayr B, Asberg
KH, Terént A. Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529
patients in the Swedish Stroke Register. Stroke. 2010 Jul;41(7):1338-42.
97. Eriksson M, Stecksén A, Glader EL, Norrving B, Appelros P, Hulter Åsberg K,Stegmayr B, Terént A,
Asplund K; Riks-Stroke Collaboration. Discarding heparins as treatment for progressive stroke in
Sweden 2001 to 2008. Stroke. 2010 Nov;41(11):2552-8.
98. Sandset EC, Murray G, Boysen G, Jatuzis D, Kõrv J, Lüders S, Richter PS, Roine RO, Terént A, Thijs
V, Berge E; SCAST Study Group. Angiotensin receptor blockade in acute stroke. The Scandinavian
Candesartan Acute Stroke Trial: rationale, methods and design of a multicentre, randomised- and
placebo-controlled clinical trial (NCT00120003). Int J Stroke. 2010 Oct;5(5):423-7.
99. Asberg S, Henriksson KM, Farahmand B, Asplund K, Norrving B, Appelros P, Stegmayr B, Asberg
KH, Terént A. Ischemic stroke and secondary prevention in clinical practice: a cohort study of 14,529
patients in the Swedish Stroke Register. Stroke. 2010 Jul;41(7):1338-42
100. Appelros P, Jonsson F, Asplund K, Eriksson M, Glader EL, Asberg KH, Norrving B, Stegmayr B,
Terént A; Riks-Stroke Collaboration. Trends in baseline patient characteristics during the years 1995-
2008: observations from Riks-Stroke, the Swedish Stroke Register. Cerebrovasc Dis. 2010;30(2):114-
9
101. Lundström E, Smits A, Terént A, Borg J. Time-course and determinants of spasticity during the first
six months following first-ever stroke. J Rehabil Med. 2010 Apr;42(4):296-301.
102. Eriksson M, Jonsson F, Appelros P, Asberg KH, Norrving B, Stegmayr B, Terént A, Asplund K; Riks-
Stroke Collaboration. Dissemination of thrombolysis for acute ischemic stroke across a nation:
experiences from the Swedish stroke register, 2003 to 2008. Stroke. 2010 Jun;41(6):1115-22.
103. Appelros P, Terént A. [Always hospital admission in TIA and stroke?]. Lakartidningen. 2010 Feb 10-
16;107(6):372.
104. Murray V, Norrving B, Sandercock PA, Terént A, Wardlaw JM, Wester P. The molecular basis of
thrombolysis and its clinical application in stroke. J Intern Med. 2010 Feb;267(2):191-208. Review.
105. Lundström E, Smits A, Borg J, Terént A. Four-fold increase in direct costs of stroke survivors with
spasticity compared with stroke survivors without spasticity: the first year after the event. Stroke. 2010
Feb;41(2):319-24.
106. Appelros P, Stegmayr B, Terént A. A review on sex differences in stroke treatment and outcome. Acta
Neurol Scand. 2010 Jun;121(6):359-69.
107. Henriksson KM, Farahmand B, Johansson S, Asberg S, Terént A, Edvardsson N. Survival after stroke-
-the impact of CHADS2 score and atrial fibrillation. Int J Cardiol. 2010 May 14;141(1):18-23
108. Appelros P, Gunnarsson K, Terént A. Ten-year risk for myocardial infarction in patients with firstever
stroke : a community-based study. Acta Neurologica Scandinavica. 2011;124(6):383-389.
109. Barbier C, Nylander R, Themudo R, Ahlström H, Lind L, Larsson E, et al. Prevalence of
unrecognized myocardial infarction detected with magnetic resonance imaging and its relationship to
cerebral ischemic lesions in both sexes. Journal of the American College of Cardiology.
2011;58(13):1372-1377.
41

110. Ebeling Barbier C, Nylander R, Themudo R, Ahlström H, Lind L, Larsson E, et al. Prevalence of
Unrecognized Myocardial Infarction Detected With Magnetic Resonance Imaging and its Relationship
to Cerebral Ischemic Lesions in Both Sexes. Journal of the American College of Cardiology.
2011;58(13):1372-1377.
111. Debette S, Visvikis-Siest S, Chen M, Ndiaye N, Song C, Destefano A, et al. Identification of cis- and
trans-Acting Genetic Variants Explaining Up to Half the Variation in Circulating Vascular Endothelial
Growth Factor Levels. Circulation Research. 2011;109(5):554-563.
112. Farrokhnia N, Castrén M, Ehrenberg A, Lind L, Oredsson S, Jonsson H, et al. Emergency Department
Triage Scales and Their Components : A Systematic Review of the Scientific Evidence. Scandinavian
Journal of Trauma, Resuscitation and Emergency Medicine. 2011;19:42-.
113. Henriksson K, Farahmand B, Åsberg S, Terént A, Edvardsson N. First-Ever Atrial Fibrillation
Documented After Hemorrhagic or Ischemic Stroke : The Role of the CHADS(2) Score at the Time of
Stroke. Clinical Cardiology. 2011;34(5):309-316.
114. Appelros P, Terént A. Validation of the Swedish inpatient and cause-of-death registers in the context
of stroke. Acta Neurologica Scandinavica. 2011;123(4):289-293.
115. Byberg L, Gedeborg R, Michaëlsson K, Berglund L. Useful Tests of Usefulness of New Risk Factors:
Tools for Assessing Reclassification and Discrimination. Sundström J Scand J Public Healt. 2011
Jun;39(4):439-41
116. Jacobsson J, Sällman Almén M, Benedict C, Hedberg L, Michaëlsson K, Brooks S, et al. Detailed
Analysis of Variants in FTO in Association with Body Composition in a Cohort of 70-Year-Olds
Suggests a Weakened Effect among Elderly. PLoS ONE. 2011;6(5):e20158-.
117. Boggia J, Thijs L, Hansen T, Li Y, Kikuya M, Björklund-Bodegård K, et al. Ambulatory Blood
Pressure Monitoring in 9357 Subjects From 11 Populations Highlights Missed Opportunities for
Cardiovascular Prevention in Women. Hypertension. 2011;57(3):397-405.
118. Hansson J, Vasan R, Ärnlöv J, Ingelsson E, Lind L, Larsson A, et al. Biomarkers of Extracellular
Matrix Metabolism (MMP-9 and TIMP-1) and Risk of Stroke, Myocardial Infarction, and Cause-
Specific Mortality : Cohort Study. PLoS ONE. 2011;6(1):e16185-.
119. Byberg L, Gedeborg R, Cars T, Sundström J, Berglund L, Kilander L, et al. Prediction of fracture risk
in men: A cohort study. Journal of Bone and Mineral Research. 2011;
120. Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Ärnlöv J, et al. Confirmed hypertension
and plasma 25(OH)D concentrations amongst elderly men. Journal of Internal Medicine.
2011;269(2):211-218.
121. Arnlöv J, Sundström J, Ingelsson E, Lind L. Impact of BMI and the metabolic syndrome on the risk of
diabetes in middle-aged men. Diabetes Care. 2011;34(1):61-65.
122. Holmlund A, Hedin M, Pussinen P, Lerner U, Lind L. Porphyromonas gingivalis (Pg) a possible link
between impaired oral health and acute myocardial infarction. International Journal of Cardiology.
2011;148(2):148-153.
123. Arefalk G, Hergens M, Ingelsson E, Arnlöv J, Michaëlsson K, Lind L, et al. Smokeless tobacco (snus)
and risk of heart failure : results from two Swedish cohorts. European Journal of Cardiovascular
Prevention & Rehabilitation. 2011;
124. Debette S, Visvikis-Siest S, Chen M, Ndiaye N, Song C, Destefano A, et al. Identification of cis- and
trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial
growth factor levels. Circulation Research. 2011;109(5):554-563.
125. Ebeling Barbier C, Johansson L, Lind L, Ahlström H, Bjerner T. Several sources of error in estimation
of left ventricular mass with M-mode echocardiography in elderly subjects. Uppsala Journal of
Medical Sciences. 2011;116(4):258-64.
42

126. Bodén R, Lindström L, Rautaharju P, Sundström J. Electrocardiographic signs of autonomic
imbalance in medicated patients with first-episode schizophrenia spectrum disorders : relations to first
treatment discontinuation and five-year remission status. European psychiatry. 2011;
127. Farrohknia N, Castrén M, Ehrenberg A, Lind L, Oredsson S, Jonsson H, et al. Emergency department
triage scales and their components : a systematic review of the scientific evidence.. Scandinavian
journal of trauma, resuscitation and emergency medicine. 2011;19:42-.
128. Asplund K, Åsberg K, Appelros P, Bjarne D, Eriksson M, Johansson Å, et al. The Riks-Stroke story :
building a sustainable national register for quality assessment of stroke care. . 2011;6(2):99-108.
129. Jobs E, Ingelsson E, Risérus U, Nerpin E, Jobs M, Sundström J, et al. Association Between Serum
Cathepsin S and Mortality in Older Adults. Journal of the American Medical Association (JAMA).
2011;306(10):1113-1121.
130. Lee D, Lind P, Jacobs D, Salihovic S, van Bavel B, Lind L. Polychlorinated Biphenyls and
Organochlorine Pesticides in Plasma Predict Development of Type 2 Diabetes in the Elderly. Diabetes
Care. 2011;34(8):1778-1784.
131. Lind P, Lind L. Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis
in the elderly. Atherosclerosis. 2011;218(1):207-213.
132. Oredsson S, Jonsson H, Rognes J, Lind L, Göransson K, Ehrenberg A, et al. A systematic review of
triage-related interventions to improve patient flow in emergency departments. Scandinavian Journal
of Trauma, Resuscitation and Emergency Medicine. 2011;19:43-.
133. Lind L, Siegbahn A, Ingelsson E, Sundström J, Ärnlöv J. A Detailed Cardiovascular Characterization
of Obesity Without the Metabolic Syndrome. Arteriosclerosis, Thrombosis and Vascular Biology.
2011;31(8):E27-U24.
134. Masiha S, Sundström J, Lind L. Left ventricular geometric patterns and adaptations to hemodynamics
are similar in elderly men and women. BMC Cardiovascular Disorders. 2011;11:25-.
135. Sehestedt T, Hansen T, Li Y, Richart T, Boggia J, Kikuya M, et al. Are blood pressure and diabetes
additive or synergistic risk factors? : outcome in 8494 subjects randomly recruited from 10
populations. Hypertension Research. 2011;34(6):714-721.
136. Palming J, Jansson P, Renström F, Johansson A, Johansson L, Karlsson C, et al. Hydrochlorothiazide
Compared to Candesartan Treatment Increases Adipose Tissue Gene Expression and Circulating
Levels of Serum Amyloid A in Hypertensive Patients. Hormone and Metabolic Research.
2011;43(5):319-324.
137. Lind L, Berglund L, Larsson A, Sundström J. Endothelial Function in Resistance and Conduit Arteries
and 5-Year Risk of Cardiovascular Disease. Circulation. 2011;123(14):1545-1551.
138. Nerpin E, Ingelsson E, Risérus U, Sundström J, Larsson A, Jobs E, et al. The combined contribution
of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly
men. Nephrology, Dialysis and Transplantation. 2011;26(9):2820-2827.
139. Sandset E, Bath P, Boysen G, Jatuzis D, Korv J, Lueders S, et al. The angiotensin-receptor blocker
candesartan for treatment of acute stroke (SCAST) : a randomised, placebo-controlled, double-blind
trial. The Lancet. 2011;377(9767):741-750.
140. Nathanson D, Zethelius B, Berne C, Lind L, Andrén B, Ingelsson E, et al. Plasma levels of glucagon
like peptide-1 associate with diastolic function in elderly men. Diabetic Medicine. 2011;28(3):301-
305.
141. Lind L, Siegbahn A, Ingelsson E, Sundström J, Arnlöv J. A detailed cardiovascular characterization of
obesity without the metabolic syndrome. Arteriosclerosis, Thrombosis and Vascular Biology.
2011;31(8):e27-e34.
43

142. Jobs E, Ingelsson E, Risérus U, Nerpin E, Jobs M, Sundström J, et al. Association between serum
cathepsin S and mortality in older adults. Journal of the American Medical Association (JAMA).
2011;306(10):1113-1121.
143. Lind L. Arterial stiffness, but not endothelium-dependent vasodilation, is related to a low Ankle-
Brachial index. Clinical Physiology and Functional Imaging. 2011;31(3):182-187.
144. Mirza M, Alsiö J, Hammarstedt A, Erben R, Michaëlsson K, Tivesten Å, et al. Circulating fibroblast
growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly
individuals. Arteriosclerosis, Thrombosis and Vascular Biology. 2011;31(1):219-227.
145. Rönn M, Lind L, Bavel B, Salihovic S, Michaëlsson K, Lind P. Circulating levels of persistent organic
pollutants associate in divergent ways to fat mass measured by DXA in humans. Chemosphere.
2011;85(3):335-343.
146. Rasmussen M, Sundström M, Kultima H, Botling J, Micke P, Birgisson H, et al. Allele-specific copy
number analysis of tumor samples with aneuploidy and tumor heterogeneity. Genome Biology.
2011;12(10):R108-.
147. Kanoni S, Nettleton J, Hivert M, Ye Z, van Rooij F, Shungin D, et al. Total zinc intake may modify
the glucose-raising effect of a zinc transporter (SLC30A8) variant : a 14-cohort meta-analysis.
Diabetes. 2011;60(9):2407-2416.
148. Strawbridge R, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al. Genome-Wide
Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and
Provides New Insights Into the Pathophysiology of Type 2 Diabetes. Diabetes. 2011;60(10):2624-
2634.
149. Yu K, Hong K, Lee B, Oh M, Cho Y, Koo J, et al. Comparison of 90-day case-fatality after ischemic
stroke between two different stroke outcome registries using propensity score matching analysis. Acta
Neurologica Scandinavica. 2011;123(5):325-331.
150. Sundström J, Neovius M, Tynelius P, Rasmussen F. Association of blood pressure in late adolescence
with subsequent mortality : cohort study of Swedish male conscripts. BMJ. British Medical Journal.
2011;342:d643-.
151. Sundström J, Byberg L, Gedeborg R, Michaëlsson K, Berglund L. Useful tests of usefulness of new
risk factors : Tools for assessing reclassification and discrimination. Scandinavian Journal of Public
Health. 2011;39(4):439-441.
152. Wormser D, Kaptoge S, Di Angelantonio E, Wood A, Pennells L, Thompson A, et al. Separate and
combined associations of body-mass index and abdominal adiposity with cardiovascular disease :
collaborative analysis of 58 prospective studies. The Lancet. 2011;377(9771):1085-1095.
153. Simard J, Arkema E, Sundström A, Geborek P, Saxne T, Baecklund E, et al. Ten years with biologics
: to whom do data on effectiveness and safety apply?. Rhematology Int. 2011;50(1):204-213.
154. Themudo R, Lindahl B, Johansson L, Venge P, Ahlström H, Barbier C, et al. Unrecognized
myocardial scars detected by delayed-enhanced MRI are associated with increased levels of NTproBNP.
Coronary Artery Disease. 2011;22(3):158-164.
155. Strawbridge R, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al. Genome-wide
association identifies nine common variants associated with fasting proinsulin levels and provides new
insights into the pathophysiology of type 2 diabetes. Diabetes. 2011;60(10):2624-2634.
44

Respiratory medicine and allergology
Christer Janson
The research in our group focuses on three principal areas: COPD, asthma and allergy, sleep-disordered
breathing and rehabilitation and physical activity. The group is also involved in projects concerning other
respiratory diseases such as lung cancer and tuberculosis.
Epidemiology of asthma and COPD: risk factors, systemic and local
inflammation and co-morbidity
Christer Jansson
In 2005, four million persons died from chronic respiratory diseases: asthma and chronic obstructive
pulmonary disease (COPD) which makes this one of the globally leading causes of mortality. The
prevalence of asthma and COPD has increased rapidly in most countries and in Sweden one out of every
ten person has asthma and 10% of those above 45 years have COPD. The general aim is to study risk
factors and co-morbidity in asthma and COPD with special emphasis on systemic and local inflammation,
and the analyses are performed using data from several population studies.
During 2008 and 2009 our group coordinated a large epidemiological study in asthma and COPD through
the GA2LEN network. In the study we have now completed a clinical phase were about 1600 subjects were
investigated with allergy testing, spirometry, inflammatory markers etc.
In 2010 we have begun the follow up our large asthma cohort (RHINE II and ECRHS III). The clinical
phase of ECRHS III started in 2011 and will be completed 2012. The MIDAS study includes children and
young adults and is a project done in cooperation with a research group at the Department of Women’s and
Children’s Health, Phadia (Thermo Fisher Scientific) and Aerocrine. In the study we will include 400
asthmatics and 100 controls that will be carefully phenotyped. Participants from the MIDAS and GA2LEN
study are also being included in a genetical project lead by Prof Dumanski at the Department of Genetics
and Pathology which has been sponsored as a pilot project in the Science for Life initiative.
Sleep and Health
Eva Lindberg
About 18% of men and 9% of women suffer from obstructive sleep apnea and every fourth of them display
severe daytime symptoms requiring treatment. Despite that, the knowledge about long-time evolution and
consequences are sparse especially in women. The major aims are to understand the consequences of sleepdisordered
breathing (SDB) to health and to understand the underlying pathophysiology. Our research is
mainly epidemiological in design and we follow two unique population-based cohorts (one male and one
female) prospectively who were investigated for sleep disorders at baseline and followed for health
outcomes. Subsamples have been clinically investigated including polysomnography, blood sampling and
oral glucose tolerance test. During 2011 we have started an unique 10-year follow-up of a communitybased
cohort of women including repeated full-night polysomnography.
In recent years we have focused also on the impact of sleep architecture on metabolism and health. In
addition, during 2010 we started a randomised, controlled trial to study the effect of physical training on
sleep-disordered breathing. In the same clinical cohort we analyse the effect on metabolism and systemic
inflammation when the sleep-disordered breathing is effectively treated.
45

Physical training and physical activity
Margareta Emtner
Focus is on four interrelated themes; to develop valid and reliable measures of physical activity and
capacity, to investigate physical activity and capacity, to investigate physical activity interventions, and to
examine ways to maintain the benefit of rehabilitation long-term.
A major emphasis is on investigating clinically important questions. Despite significant advances in the
prevention and pharmacological management of patients, there continues to be an urgent need to develop
rehabilitation outcomes in order to improve the quality of daily living and reduce emergency room visits
and hospitalizations. Physical inactivity is a tremendous health problem nowadays and interventions aiming
at improving physical activity and capacity are urgent. Current research has three main tracks;
� Physical activity on prescription and behavioural medicine interventions to maintain health
enhancing physical activity
� Measures of physical activity and capacity
� Breathing - identification of breathing pattern and breathing problems and interventions to improve
impaired breathing and its consequences
� To investigate exercise-induced breathing problems in a population of 12-13 year old school
children in Uppsala
We collaborate nationally with the Universities of Gothenburg, Umeå, and Örebro and locally with the
Departments of Women’s and Children’s Health, Surgical Sciences, Otorhinolaryngology and Head &
Neck Surgery, and Neuroscience, Physiotherapy
Members of the group during 2011
Christer Janson, MD, PhD, professor
Eva Lindberg, MD, PhD, professor
Margareta Emtner, PT, PhD, assoc prof
Gunnemar Stålenheim, MD, PhD, assoc prof
Gunnar Boman, MD, PhD, prof emeritus
María Gunnbjörnsdottir, MD, PhD
Inger Dahlén, MD PhD
Mary Kämpe MD, PhD
Inga Sif Olafsdottir MD, PhD
Andrei Malinovschi, MD, PhD
Jenny Theorell Haglöw RN, PhD
Malin Svensson, MD, PhD
Robert Moverare PhD
Rain Jögi, MD, PhD
Harpa Arnardottir PT, PhD
Mats Arne, PT, PhD
Funding
Christer Jansson
Heart and Lung Foundation 700 kSEK
Astma- and Allergy Foundation 200 kSEK
46
Martin Sandelin MD, PhD student
Mirjam Lunggren MD, PhD student
Antonis Patelis MD, PhD student
Carina Hagman PT, PhD student
Guihong Cai, PhD student
Helena Igelström PT, PhD student
Mikael Andersson PT, PhD student
Henrik Johansson PT, PhD student
Kristina Lamberg MD, Clinician
Carl-Axel Karlsson MD, Clinician
Katarina Nisser, RN
Ulrike Spetz-Nyström, RN
Gunilla Hägg, NA
Birgitta Andersson, RN
Gunn-Marie Bodman Lund, secretary
Eva Lindberg
Heart and Lund Foundation 1 360 kSEK
Margareta Emtner
Heart and Lund Foundation 500 kSEK

Publications 2009-2011
1. Valham F, Stegmayr B, Eriksson M, Hagg E, Lindberg E, Franklin KA. Snoring and witnessed sleep
apnea is related to diabetes mellitus in women. Sleep Med 2009; 10:112-7.
2. Kesek, M, Franklin KA, Sahlin C, Lindberg E. Heart rate variability during sleep and sleep apnoea in
a population based study of 387 women. Clin Physiol Funct Imaging. 2009; 29:309-315.
3. Myrdal G, Lamberg K, Lambe M, Stahle E, Wagenius G, Holmberg L. Regional differences in
treatment and outcome in non-small cell lung cancer: a population-based study (Sweden). Lung
Cancer 2009; 63:16-22.
4. Johansson SG, Nopp A, Oman H, Ankerst J, Cardell LO, Gronneberg R, Matsols H, Rudblad S,
Strand V, Stalenheim G. The size of the disease relevant IgE antibody fraction in relation to 'total-IgE'
predicts the efficacy of anti-IgE (Xolair) treatment. Allergy 2009; 64:1472-7.
5. Sahlin C, Franklin KA, Stenlund H, Lindberg E. Sleep in women: Normal values for sleep stages and
position and the effect of age, obesity, sleep apnea, smoking, alcohol and hypertension. Sleep Med
2009; 10:1025-30.
6. Ljung Faxén U, Romanus V, Julander I, Petrini B, Boman G. Multiresistent tuberkulos i Sverige
kräver ökad vaksamhet. Läkartidningen 2009; 106:1895-1997.
7. Hellström K, Vahlberg B, Urell C, Emtner M. Fear of falling, fall-related self-efficacy, anxiety and
depression in individuals with chronic obstructive pulmonary disease. Clinical Rehabilitation 2009;
23: 1136–1144
8. Malinovschi A, Janson C, Högman M, Rolla G, Torén K, Norbäck D, Olin A-C. Both allergic and
non-allergic asthma are associated with increased FENO levels, but only in never-smokers. Allergy
2009; 64:55-61.
9. Skorup P, Rizzo LW. Machado Boman L, Janson C. Asthma management and asthma control in São
Paulo, Brazil and Uppsala, Sweden; a questionnaire-based comparison. Clin Respir J 2009; 3:22-28
10. Högman M, Lafih J, Meriläinen P, Bröms K, Malinovschi A, Janson C . Extended NO analysis in a
healthy subgroup in a random sample population. Clin Physiol Funct Imaging 2009; 29:18-23.
11. Leander M, Cronqvist A, Janson C, Udeenfeldt M, Rask-Andersen A. Health-related quality of life
predicts onset of asthma in a longitudinal population study. Respir Med 2009; 103: 194-200.
12. Macsali F, Gomez Real F, Omenaas E, Bjørge L, Janson C, Franklin KA, Svanes C. Oral
contraception, body mass index and asthma. A cross-sectional Nordic-Baltic population survey. J
Allergy Clin Immunol 2009; 123: 391-397.
13. Malinovschi A, Janson C, Holm L, Nordvall L, Alving K . Basal and induced NO formation in the
pharyngo-oral tract influences estimated alveolar NO levels. J Applied Physiol 2009; 106: 513-519.
14. Gudbjartsson DF, Bjornsdottir U S, et al. Sequence variants affecting eosinophil numbers associate
with asthma and myocardial infarction Nature Genetics 2009; 41: 342-347.
15. Gunnbjörnsdottir MI, Norbäck D, Björnsson E, Soon A, Jarvis D, Jõgi R, Gislason D, Gislason T,
Janson C. Indoor environment in three North European cities in relationship to atopy and respiratory
symptoms. Clin Respir J 2009; 3:85-94..
16. Alimohammadi M, Dubois N, Sköldberg F, et al Pulmonary Autoimmunity as a Feature of
Autoimmune Polyendocrine Syndrome Type 1 and Identification of KCNRG as a Bronchial
Autoantigen. Proc Nat Ac Sci 2009; 106:4396-4401.
17. Modig L, Torén K, Janson C, Järvholm B, Forsberg B. Vehicle exhausts outside the home and onset of
asthma among adults. A prospective cohort study. Eur Respir J 2009; 33: 1258–1264
18. Castro-Giner F, Kogevinas M, Imboden M, de Cid R, Jarvis D, Mächler M, Berger W, Burney P,
Franklin KA, Gonzalez JR, Heinrich J, Janson C, Omenaas E, Pin I, Rochat T, Sunyer J, Wjst M, Antó
J-M, Estivill X, Probst-Hensch NM. Joint effect of obesity and TNFA variability on asthma: two
international cohort studies. Eur Respir J 2009; 33:1003-1009.
47

19. Marcon A, Corsico A, Cazzoletti L, Bugiani M, Accordini S, Almar E, Cerveri I, Gislason D, Gulsvik
A, Janson C, Jarvis D, Martínez-Moratalla J, Pin I, de Marco R. Body mass index, weight gain and
other determinants of lung function decline in adult asthma. J Allergy Clin Immunol 2009;123: 1069-
1074.
20. Leander M, Cronqvist A, Janson C, Uddenfeldt M, Rask-Anderssen A. Non respiratory symptoms and
well being in asthmatics from a general population sample. J Asthma 2009; 46:552-559.
21. Emtner M, Hedin A, Andersson M, Janson C. Impact of patient characteristics, education and
knowledge on emergency room visits in patients with asthma and COPD. BMC Pulmonary Medicine
2009, 9:43.
22. Arne M, Janson C, Janson S, Boman G, Lindqvist U, Berne C, Emtner M. Physical activity and
quality of life in subjects with chronic disease; chronic obstructive pulmonary disease compared with
rheumatoid arthritis and diabetes mellitus. Scand J Prim Health Care 2009; 27:141-147.
23. Thorleifsson SJ, Margretardottir OB, Gudmundsson G,Olafsson I, Benediktsdottir B, Janson C, Buist
AS, Gislason T. Chronic airflow obstruction and markers of systemic inflammation: Results from the
BOLD study in Iceland. Respir Med 2009; 103:1548-1553.
24. Margretardottir OB, Thorleifsson SJ, Gudmundsson G, Olafsson I, Benediktsdottir B, Janson C, Buist
AS, Gislason T. Hypertension, systemic inflammation and body weight in relation to lung function
impairment – an epidemiological study. J COPD 2009; 6:250–255
25. Cerveri I, Corsico AG, Accordini S, Cervio G, Ansaldo E, Grosso A, Niniano R, Tsana Tegomo E,
Antó JM , , Künzli N, Janson C, Sunyer J, Svanes C, Heinrich J, Schouten JP, Wjst M, Pozzi E de
Marco R. What defines airflow obstruction in asthma? Eur Respir J 2009; 34:568-573).
26. Cai G, Bröms K, Janson C, Mälarstig B, Zhuohui Z, Jeong-Lim K, Svärdsudd K, Norbäck D.
Quantitative PCR analysis of fungal DNA in Swedish day care centers and comparison to building
characteristics and allergen levels. Indoor Air 2009; 19:392-400.
27. Engström G, Gerhardsson de Verdier M, Dahlbäck M. Janson C, Lind L. BP variability and
cardiovacular autonomic function in relation to forced expiratory volume. Chest 2009; 136:177-183.
28. Raherison C, Janson C, Jarvis D, Burney P, Cazzoletti L, de Marco R, Neukirch F, Leynaert B-.
Evolution of asthma severity in a cohort of young adults: is there any gender differences?. PLOS One
2009; 4:e7146.
29. de Marco R; Accordini S; Antò JM; Gislason T; Heinrich J; Janson C; Jarvis D; Künzli N; Leynaert B;
Marcon A; Sunyer J; Svanes C; Wjst M; Burney P. Long-term outcomes in mild/moderate COPD in
the European Community Respiratory Health Survey. Am J Respir Crit Care Med 2009; 180:956-961.
30. Ställberg B, Lisspers K, Hasselgren M, Janson C, Johansson G, Svärdsudd K. Asthma control in
primary care. A comparison between 2001 and 2005. Prim Care Respir J 2009 18: 279-286.
31. Castro-Giner F, Künzli N, Jacquemin B, Forsberg B, de Cid R, Sunyer J, Jarvis D, Briggs D, Vienneau
D, Norback D, González JR, Guerra S, Janson C, Antó J-M, Wjst M, Heinrich J, Estivill X, Kogevinas
M. Traffic Related Air Pollution, Oxidative Stress Genes and Asthma (ECHRS). Environ Health Persp
J 2009; 117: 1919-1924.
32. Asarnoj A, Moverare R, Ostblom E, Poorafshar M, Lilja G, Hedlin G, van Hage M, Ahlstedt S,
Wickman M. IgE to peanut allergen components: relation to peanut symptoms and pollen sensitization
in 8-year-olds. Allergy 2010 65:1189-95.
33. Eliason G, Abdel-Halim SM, Piehl-Aulin K, Kadi F. Alterations in the muscle-to-capillary interface in
patients with different degrees of chronic obstructive pulmonary disease. Respir Res 2010, 11:97
34. Bitar MS, Ayed AK, Abdel-Halim SM, Isenovic ER, Al-Mulla F. Inflammation and apoptosis in aortic
tissues of aged type II diabetes: Amelioration with α-lipoic acid through phosphatidylinositol 3kinase/Akt-
dependent mechanism. Life Sci 2010; 86: 844–853.
48

35. Stålenheim G, Blömstrom P, Venemalm L. Chlorhexidine caused anaphylactic reaction. Not only
drugs should be considered in the investigation of allergy, according to a case report. Läkartidningen
2010; 107:37-8.
36. Lindberg E, Nordang L. Therapy-resistant asthma caused by aspirated crayfish claw. Careful
anamnesis and early bronchoscopy would have solved the problem. Läkartidningen. 2010 107:184-5.
37. Kämpe M, Janson C , Stålenheim G, Stolt I, Carlson M. Experimental and seasonal exposure to birch
pollen in allergic rhinitis and allergic asthma with regard to the inflammatory response. Clin Respir J
2010; 4: 37-44.
38. Cazzoletti L, Marcon A, Corsico A, Janson C, Jarvis D, Pin I, Accordini S, Bugiani M, Cerveri I,
Gislason D, Gulsvik A, de Marco R. Asthma severity according to Global Initiative for Asthma and
its determinants. An international study. Int Arch Allergy Immunol 2010;151:70-79.
39. Sundberg R, Torén K, Franklin KA, Gislason T, Omenaas E, Svanes C, Janson C. Asthma in men and
women: treatment adherence, anxiety, and quality of sleep. Respir Med 2010; 104:337-344.
40. Castro-Giner F, de Cid R, Gonzalez JR, Jarvis D, Heinrich J, Janson C, Omenaas ER, Matheson MC,
Pin I, Antó JM, Wjst M, Estivill X, Kogevinas M. Positionally cloned genes and age specific effects in
asthma and atopy: an international population-based cohort study (ECRHS). Thorax 2010; 65:124-
131.
41. Arne M, Lisspers K, Ställberg B, Boman G, Hedenström H, Janson C, Emtner M. How often is
diagnosis of COPD confirmed with spirometry? Respir Med 2010; 104:550-556.
42. Ólafsdóttir IS, Janson C, Lind L, Hulthe J; Gunnbjörnsdóttir M, Sundström J. Serum MMP-9, TIMP-
1 and their ratio is associated with impaired lung function in the elderly - a population-based study.
Respirol 2010; 15:530-535.
43. Uddenfeldt M, Leander M, Lampa E, Janson C.; Norbäck D, Larsson L, Rask-Andersen A High BMI
is related to higher incidence of asthma, while a fish and fruit diet is related to a lower. Respir Med
2010; 104: 972-980
44. Jönsson UB, Douhan-Håkansson L, Jögi R, Janson C, Venge P. Associations of ECP (eosinophil
cationic protein)-gene polymorphisms to allergy, asthma, smoke habits and lung function in two
Estonian and Swedish sub cohorts of the ECRHS II study. BMC Pulm Med 2010; 10:36.
45. Theorell-Haglöw J, Berne C, Janson C., Sahlin C, Lindberg E.Associations between short sleep
duration and central obesity in women. Sleep 2010; 33:593-598.
46. Anto JM, Sunyer J, Basagana X, Garcia-Esteban X, Cerveri I, de Marco R, Heinrich J, Janson C,
Jarvis D, Kogevinas M, Kuenzli N, Leynaert B, Svanes C, Wjst M, Burney P. The causes of newonset
asthma in adults: a population-based international cohort study. Allergy 2010; 65:1021-1030.
47. Leander M, Janson C, Uddenfeldt M, Cronqvist A, Rask-Andersen A. Associations between mortality,
asthma and health-related quality of life in an elderly cohort of Swedes. J Asthma 2010; 47:627-632.
48. Appelberg J, Janson C, Lindberg E, Pavlenko T, Hedenstierna G. Lung aeration during sleep in
patients with obstructive sleep apnoea. . Clin Physiol Funct Imaging 2010; 30:301-307.
49. Gislason T, Guðnason V, Benediktsdottir B, Olafsson I, Aspelund T, Thjodleifsson B, Janson C.
Persistent Chlamydia pneumonia serology is related to a more rapid decline in lung function in women
but not in men. BMC Pulm Med 2010; 10:44.
50. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M,
Lathrop M, Cookson W, GABRIEL Consortium. A Large-Scale, Consortium-Based Genomewide
Association Study of Asthma. New Engl J Med 2010; 363:1211-1221.
51. Benediktsdottir B, Janson C, Lindberg E, Arnardóttir ES, Olafsson I, Cook E, Thorarinsdottir EH,
Gislason T. Prevalence of Restless Legs Syndrome Among Adults in Iceland and Sweden – Lung
function, Comorbidity, Ferritin, Biomarkers and Quality of Life. Sleep Med 2010; 11:1043-1048.
49

52. Rebordosa C, Kogevinas M, Guerra S, Castro-Giner F, Jarvis D, Cazzoletti L, et al. ADRB2
Gly16Arg polymorphism, asthma control and lung function decline. European Respiratory Journal.
2011;38(5):1029-1035.
53. Hallin R, Jansson C, Arnardottir R, Olsson R, Emtner M, Brandt S, et al. Relation between physical
capacity, nutritional status and systemic inflammation in COPD. Clinical Respiratory Journal.
2011;5(3):136-142.
54. Bjerg A, Ekerljung L, Middelveld R, Dahlén S, Forsberg B, Franklin K, et al. Increased Prevalence of
Symptoms of Rhinitis but Not of Asthma between 1990 and 2008 in Swedish Adults : Comparisons of
the ECRHS and GA(2)LEN Surveys. PLoS ONE. 2011;6(2):e16082-.
55. Cai G, Malarstig B, Kumlin A, Johansson I, Janson C, Norbäck D. Fungal DNA and pet allergen
levels in Swedish day care centers and associations with building characteristics. Journal of
Environmental Monitoring. 2011;13(7):2018-2024.
56. de Marco R, Accordini S, Marcon A, Cerveri I, Anto J, Gislason T, et al. Risk Factors for Chronic
Obstructive Pulmonary Disease in a European Cohort of Young Adults. American Journal of
Respiratory and Critical Care Medicine. 2011;183(7):891-897.
57. Fjalldal S, Janson C, Benediktsdottir B, Gudmundsson G, Burney P, Buist A, et al. Smoking, stages
of change and decisional balance in Iceland and Sweden. The Clinical Respiratory Journal.
2011;5(2):76-83.
58. Hagman C, Janson C, Emtner M. Breathing retraining : A five-year follow-up of patients with
dysfunctional breathing. Respiratory Medicine. 2011;105(8):1153-1159.
59. Högman M, Malinovschi A, Norbäck D, Janson C. Added value with extended NO analysis in atopy
and asthma. Clinical Physiology and Functional Imaging. 2011;31(4):294-299.
60. Leander M, Lampa E, Janson C, Svärdsudd K, Uddenfeldt M, Rask-Andersen A. Determinants for a
low health-related quality of life in asthmatics. Uppsala Journal of Medical Sciences. 2011;
61. Macsali F, Real F, Plana E, Sunyer J, Anto J, Dratve J, et al. Early Age at Menarche, Lung Function,
and Adult Asthma. American Journal of Respiratory and Critical Care Medicine. 2011;183(1):8-14.
62. Sundh J, Ställberg B, Lisspers K, Montgomery S, Janson C. Co-morbidity, body mass index and
quality of life in COPD using the clinical COPD questionnaire. COPD: Journal of Chronic Obstructive
Pulmonary Disease. 2011;8(3):173-181.
63. Andersson M, Moberg L, Svantesson U, Sundbom A, Johansson H, Emtner M. Measuring walking
speed in COPD : test-retest reliability of the 30-metre walk test and comparison with the 6-minute
walk test. Primary Care Respiratory Journal. 2011;20(4):434-440.
64. Theorell-Haglöw J, Berne C, Janson C, Lindberg E. The role of obstructive sleep apnea in metabolic
syndrome : A population-based study in women. Sleep Medicine. 2011;12(4):329-334.
65. Wieslander G, Fabjan N, Vogrincic M, Kreft I, Janson C, Spetz-Nyström U, et al. Eating Buckwheat
Cookies Is Associated with the Reduction in Serum Levels of Myeloperoxidase and Cholesterol : A
Double Blind Crossover Study in Day-Care Centre Staffs. Tohoku journal of experimental medicine.
2011;225(2):123-130.
66. Micke P, Edlund K, Holmberg L, et al. Gene copy number aberrations are associated with survival in
histologic subgroups of non-small cell lung cancer. J Thorac Oncol. 2011; 11:1833-40.
67. Movérare R, Ahlstedt S, Bengtsson U, et al. Evaluation of IgE Antibodies to Recombinant Peanut
Allergens in Patients with Reported Reactions to Peanut. Int Arch Allergy Immunol. 2011; 156:282-
290.
68. Ito K, Sjölander S, Sato S, Movérare R, Tanaka A, Söderström L, Borres M, Poorafshar M, Ebisawa
M. IgE to Gly m 5 and Gly m 6 is associated with severe allergic reactions to soybean in Japanese
children. J Allergy Clin Immunol. 2011;128:673-5.
69. Koch A, Bergman B, Holmberg E, Sederholm C, Ek L, Kosieradzki J, Lamberg K, Thaning L,
Ydreborg S-O, Sörenson S. Effects of celecoxib on survival in patients with advanced non-small cell
lung cancer. Eur J Cancer 2011; 47:1546-1555.
50

70. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe - an underestimated disease.
A GA(2) LEN study. Allergy 2011; 66:1216-1223..
71. Malinovschi A, Pizzimenti S, Sciascia S, Heffler E, Badiu I, Rolla G. Exhaled breath condensate
nitrates, but not nitrites or FENO, relate to asthma control. Respir Med 2011; 105:1007-1013.
72. Malinovschi A, Henrohn D, Eriksson A, Lundberg JO, Alving K, and Wikström G, Increased plasma
and salivary nitrite and decreased bronchial contribution to exhaled NO in pulmonary arterial
hypertension. Eur J Clin Invest, 2011: 41:889-897.
73. Urell C, Emtner M, Hedenström H, Tenling A, Breidenskog M, Westerdahl E. Deep breathing
exercises with positive expiratory pressure after cardiac surgery – how many breaths should be
performed? Eur J Cardio Thoracic Surgery 2011; 40: 162-167.
74. Tomassen P, Newson RB, Hoffmans R, et al. Reliability of EP3OS symptom criteria and nasal
endoscopy in the 1 assessment of chronic rhinosinusitis - a GA²LEN study. Allergy 2011; 66:556-561.
75. Everberg H, Brostedt P, Oman H, Bohman S, Movérare R. Affinity Purification of Egg-White
Allergens for Improved Component-Resolved Diagnostics. Int Arch Allergy Immunol. 2011;154:33-
41.
76. Movérare R, Larsson H, Carlsson R, Holmquist I. Mugwort-Sensitized Individuals from North
Europe, South Europe and North America Show Different IgE Reactivity Patterns. Int Arch Allergy
Immunol. 2011; 154: 164-172.
77. Kämpe M, Stolt I, Lampinen M, Janson C, Stålenheim G, Carlson M. Patients with allergic rhinitis
and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen
challenge. Clin Mol Allergy 2011; 9:3
78. Arne, M., Lundin, F., Boman, G., Janson, C., Janson, S., Emtner, M. Factors associated with good
self-rated health and quality of life in subjects with self-reported chronic obstructive pulmonary
disease. International Journal of COPD 2011;6:511-519
Dissertations 2011
Inga Sif Olafsdottir: Inflammatory markers, respiratory diseases, lung function, and associated gender
differences.
51

Metabolic bone disease
Östen Ljunggren
The projects within the research group are based on clinical samples from a specialised osteoporosis
outpatient unit. In that setting individual patients with metabolic bone diseases are investigated. Also
clinical trials and gathering of clinical cohorts are performed. Samples from patients, as well as genetic
analyses and experimental work on human bone cells are conducted at the Centre for clinical and medical
research at Uppsala University. Focus of the research is on three main areas. Male osteoporosis,
osteogenesis imperfecta and phosphate homeostasis.
Male osteoporosis
These investigations are based on the clinical cohort, Mr OS. This is a collaboration between Sweden, US
and Hong Kong. In total 11 000 elderly men are followed prospectively to fracture. In Uppsala 1000 men
are gathered. The baseline sampling of the cohort and 5 year follow up is now completed. Current research
is mostly on regulation of calcium and phosphate, influence of sex hormones and genetic determinants for
fracture.
Osteogenesis Imperfecta
In collaboration with the children’s hospital in Stockholm a cohort of patients with OI is collected. The
mutations causing OI are determined, and at present large amount of clinical data are gathered to
investigate genotype-phenotype interaction in this disease. Also, individual patients with new sorts of
mutations causing defect collagen are investigated. Finally in this project we are investigating the
possibility to use gene silencing to interrupt dominant negative mutations in the genes for collagen type I.
Phosphate homeostasis
In collaboration with nephrologists at Uppsala hospital, hormonal regulation of serum phosphate is
investigated. Focus is on the recently discovered putative hormone FGF-23. Again the research is based on
clinical cases or groups of patients. To date most interest has been on studies in patients with oncogenic
phosphate wasting osteomalacia, and in patient groups with renal impairment.
Members of the group during 2011
Östen Ljunggren, Professor
Hans Mallmin, Professor
Andreas Kindmark, Associate professor
Katarina Lindahl, PhD student
52
Per-Anton Westerberg, PhD student
Hendrik Penno, PhD student
Anna-Lena Johansson, BMA
Publications 2009-2011
1. Kwan T, Grundberg E, Koka V, Ge B, Lam KC, Dias C, Kindmark A, Mallmin H, Ljunggren O,
Rivadeneira F, Estrada K, van Meurs JB, Uitterlinden A, Karlsson M, Ohlsson C, Mellström D,
Nilsson O, Pastinen T, Majewski J. Tissue effect on genetic control of transcript isoform variation.
PLoS Genet. 2009 Aug;5(8)
2. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin
M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C; FREEDOM
Trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J
Med. 2009 Aug 20;361(8):756-65. Erratum in: N Engl J Med. 2009 Nov 5;361(19):1914.
3. Grundberg E, Kwan T, et al. Population genomics in a disease targeted primary cell model. Genome
Res. 2009 Nov;19(11):1942-52.

4. Eastell R, Black DM, et al HORIZON Pivotal Fracture Trial. Effect of once-yearly zoledronic acid
five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol
Metab. 2009 Sep;94(9):3215-25.
5. Atroshi I, Ahlander F, Billsten M, Ahlborg HG, Mellström D, Ohlsson C, Ljunggren O, Karlsson MK.
Low calcaneal bone mineral density and the risk of distal forearm fracture in women and men: a
population-based case-control study. Bone. 2009 Oct;45(4):789-93.
6. Wilson SG, Jones MR, Mullin BH, et al. Common sequence variation in FLNB regulates bone
structure in women in the general population and FLNB mRNA expression in osteoblasts in vitro. J
Bone Miner Res. 2009 Dec;24(12):1989-97.
7. Lindahl K, Rubin CJ, Brändström H, Karlsson MK, Holmberg A, Ohlsson C, Mellström D, Orwoll E,
Mallmin H, Kindmark A, Ljunggren O. Heterozygosity for a coding SNP in COL1A2 confers a lower
BMD and an increased stroke risk. Biochem Biophys Res Commun. 2009 Jul 10;384 (4):501-5.
8. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellström D, Ohlsson C. Low serum
testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009
Jul;94(7):2482-8.
9. Binkley N, Ringe JD, Reed JI, Ljunggren O, Holick MF, Minne HW, Liu M, Lamotta A, West JA,
Santora AC. Alendronate/vitamin D3 70 mg/2800 IU with and without additional 2800 IU vitamin D3
for osteoporosis: results from the 24-week extension of a 15-week randomized, controlled trial. Bone.
2009 Apr;44 (4):639-47.
10. Eriksson AL, Lorentzon M, et al. Genetic variations in sex steroid-related genes as predictors of serum
estrogen levels in men. J Clin Endocrinol Metab. 2009 Mar;94(3):1033-41.
11. Kindblom JM, Ohlsson C, Ljunggren O, Karlsson MK, Tivesten A, Smith U, Mellström D. Plasma
osteocalcin is inversely related to fat mass and plasma glucose in elderly Swedish men. J Bone Miner
Res. 2009 May;24(5):785-91. Erratum in: J Bone Miner Res. 2010 Dec;25(12):2527.
12. Penno H, Nilsson O, Brändström H, Winqvist O, Ljunggren O. Expression of RANK-ligand in
prostate cancer cell lines. Scand J Clin Lab Invest. 2009;69(1):151-5.
13. Ribom EL, Grundberg E, Mallmin H, Ohlsson C, Lorenzon M, Orwoll E, Holmberg AH, Mellström
D, Ljunggren O, Karlsson MK. Estimation of physical performance and measurements of habitual
physical activity may capture men with high risk to fall--data from the Mr Os Sweden cohort. Arch
Gerontol Geriatr. 2009 Jul-Aug;49(1):e72-6.
14. Marsell R, Mirza MA, Mallmin H, Karlsson M, Mellström D, Orwoll E, Ohlsson C, Jonsson KB,
Ljunggren O, Larsson TE. Relation between fibroblast growth factor-23, body weight and bone
mineral density in elderly men. Osteoporos Int. 2009 Jul;20(7):1167-73.
15. Hammarsten J, Damber JE, Karlsson M, Knutson T, Ljunggren O, Ohlsson C, Peeker R, Smith U,
Mellström D. Insulin and free oestradiol are independent risk factors for benign prostatic hyperplasia.
Prostate Cancer Prostatic Dis.2009;12(2):160-5.
16. Movérare-Skrtic S, Svensson J, Karlsson MK, Orwoll E, Ljunggren O, Mellström D, Ohlsson C.
Serum insulin-like growth factor-I concentration is associated withleukocyte telomere length in a
population-based cohort of elderly men. J Clin Endocrinol Metab. 2009 Dec;94(12):5078-84
17. Langdahl BL, Rajzbaum G, Jakob F, Karras D, Ljunggren O, Lems WF,Fahrleitner-Pammer A, Walsh
JB, Barker C, Kutahov A, Marin F. Reduction infracture rate and back pain and increased quality of
life in postmenopausal womentreated with teriparatide: 18-month data from the European Forsteo
Observational Study (EFOS). Calcif Tissue Int. 2009 Dec;85(6):484-93
18. Paternoster L, Lorentzon M, et al. Genome-wide association meta-analysis of cortical bone mineral
density unravels allelic heterogeneity at the RANKL locus and potential pleiotropic effects on bone.
PLoS Genet. 2010 Nov 18;6(11):e1001217.
19. Fahrleitner-Pammer A, Langdahl BL, Marin F, Jakob F, Karras D, Barrett A, Ljunggren O, Walsh JB,
Rajzbaum G, Barker C, Lems WF. Fracture rate and back pain during and after discontinuation of
teriparatide: 36-month data from the EuropeanForsteo Observational Study (EFOS). Osteoporos Int.
2010 Nov 27.
53

20. Ohlsson C, Mellström D, Carlzon D, Orwoll E, Ljunggren O, Karlsson MK,Vandenput L. Older men
with low serum IGF-I have an increased risk of incident fractures: The MrOS Sweden study. J Bone
Miner Res. 2010 Nov 4.
21. Mirza MA, Karlsson MK, Mellström D, Orwoll E, Ohlsson C, Ljunggren O, Larsson TE. Serum
fibroblast growth factor-23 (FGF23) and fracture risk in elderly men. J Bone Miner Res. 2010 Oct 6.
22. Ribom EL, Mellström D, Ljunggren O, Karlsson MK. Population-based reference values of handgrip
strength and functional tests of muscle strength and balance in men aged 70-80 years. Arch Gerontol
Geriatr. 2010 Aug 11.
23. Ohlsson C, Labrie F, Barrett-Connor E, Karlsson MK, Ljunggren O, Vandenput L, Mellström D,
Tivesten A. Low serum levels of dehydroepiandrosterone sulfate predict all-cause and cardiovascular
mortality in elderly Swedish men. J Clin Endocrinol Metab. 2010 Sep;95(9):4406-14.
24. Borgström F, Ström O, Marin F, Kutahov A, Ljunggren O. Cost effectiveness of teriparatide and
PTH(1-84) in the treatment of postmenopausal osteoporosis. J Med Econ. 2010;13(3):381-92.
25. Johansson H, Odén A, Kanis J, McCloskey E, Lorentzon M, Ljunggren O, KarlssonMK, Orwoll E,
Tivesten A, Ohlsson C, Mellström D. Low bone mineral density isassociated with increased mortality
in elderly men: MrOS Sweden. Osteoporos Int. 2010 Jun 29.
26. Meng J, Ohlsson C, Laughlin GA,et al Osteoporotic Fractures in Men (MrOs) Study Group.
Associations of estradiol and testosterone with serum phosphorus in older men: the Osteoporotic
Fractures in Men study. Kidney Int.2010 Aug;78(4):415-22.
27. Westerberg PA, Ljunggren O, Larsson TE, Wadström J, Linde T. Fibroblast growth factor-23 and
mineral metabolism after unilateral nephrectomy. Nephrol Dial Transplant. 2010 Dec;25(12):4068-71.
Epub 2010 Jun 4.
28. Silfverswärd CJ, Penno H, Frost A, Nilsson O, Ljunggren O. Expression ofmarkers of activity in
cultured human osteoblasts: effects of interleukin-4 and interleukin-13. Scand J Clin Lab Invest. 2010
Sep;70(5):338-42.
29. Andersson N, Strandberg L, et al Osteoporotic Fractures in Men MrOS Research Group. A variant
near the interleukin-6 gene is associated with fat mass in Caucasian men. Int J Obes(Lond). 2010
Jun;34(6):1011-9.
30. Vandenput L, Mellström D, Karlsson MK, Orwoll E, Labrie F, Ljunggren O,Ohlsson C. Serum
estradiol is associated with lean mass in elderly Swedish men.Eur J Endocrinol. 2010, 162(4):737-45.
31. Jutberger H, Lorentzon M, et al. Smoking predicts incident fractures in elderly men: Mr OS Sweden. J
Bone Miner Res. 2010 May;25(5):1010-6.
32. Eastell R, Lang T, Boonen S, et al; HORIZON Pivotal Fracture Trial. Effect of once-yearly zoledronic
acid on the spine and hip as measured by quantitative computed tomography: results of the HORIZON
Pivotal Fracture Trial. Osteoporos Int. 2010 Jul;21(7):1277-85.
33. Ohlsson C, Wallaschofski H, Lunetta K, Stolk L, Perry J, Koster A, et al. Genetic Determinants of
Serum Testosterone Concentrations in Men. PLoS Genetics. 2011;7(10):e1002313-.
34. Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson M, et al. High Serum
Testosterone Is Associated With Reduced Risk of Cardiovascular Events in Elderly Men : The MrOS
(Osteoporotic Fractures in Men) Study in Sweden. Journal of the American College of Cardiology.
2011;58(16):1674-1681.
35. Westerberg P, Linde T, Eklöf H, Ljunggren Ö. Repeated venous sampling for determination of a
gradient of fibroblast growth factor 23 for localization of an osteomalacia causing tumor. Acta
Endocrinologica. 2011;7(3):395-403.
36. Fahrleitner-Pammer A, Langdahl B, Marin F, Jakob F, Karras D, Barrett A, et al. Fracture rate and
back pain during and after discontinuation of teriparatide : 36-month data from the European Forsteo
Observational Study (EFOS). Osteoporosis International. 2011;22(10):2709-2719.
54

37. Jamal S, Ljunggren Ö, Stehman-Breen C, Cummings S, McClung M, Goemaere S, et al. Effects of
Denosumab on Fracture and Bone Mineral Density by Level of Kidney Function. Journal of Bone and
Mineral Research. 2011;26(8):1829-1835.
38. Kilpelainen T, Zillikens M, Stancakova A, Finucane F, Ried J, Langenberg C, et al. Genetic variation
near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics.
2011;43(8):753-U58.
39. Siilin H, Ljunggren Ö, Lundgren E. Primary Hyperparathyroidism and Associated Morbidity during
Menopausal Transition : Three Years Follow-up. Acta Endocronologica (Buc). 2011;7(2):249-262.
40. Lindahl K, Barnes A, Fratzl-Zelman N, Whyte M, Hefferan T, Makareeva E, et al. COL1 C-
Propeptide Cleavage Site Mutations Cause High Bone Mass Osteogenesis Imperfecta. Human
Mutation. 2011;32(6):598-609.
41. Johansson H, Odén A, Kanis J, McCloskey E, Lorentzon M, Ljunggren Ö, et al. Low bone mineral
density is associated with increased mortality in elderly men : MrOS Sweden. Osteoporosis
International. 2011;22(5):1411-1418.
42. Ohlsson C, Mellström D, Carlzon D, Orwoll E, Ljunggren Ö, Karlsson M, et al. Older Men With Low
Serum IGF-1 Have an Increased Risk of Incident Fractures : The MrOS Sweden Study. Journal of
Bone and Mineral Research. 2011;26(4):865-872.
43. Mirza M, Alsiö J, Hammarstedt A, Erben R, Michaëlsson K, Tivesten Å, et al. Circulating fibroblast
growth factor-23 is associated with fat mass and dyslipidemia in two independent cohorts of elderly
individuals. Arteriosclerosis, Thrombosis and Vascular Biology. 2011;31(1):219-227.
44. Mirza M, Karlsson M, Mellström D, et al. Serum Fibroblast Growth Factor-23 (FGF-23) and Fracture
Risk in Elderly Men. Journal of Bone and Mineral Research. 2011;26(4):857-864.
45. Ribom E, Mellström D, Ljunggren Ö, Karlsson M. Population-based reference values of handgrip
strength and functional tests of muscle strength and balance in men aged 70-80 years. Elsevier;
Archives of gerontology and geriatrics (Print). 2011;53(2):E114-E117.
46. Ljunggren Ö, Lindahl K, Rubin C, Kindmark A. Allele-Specific Gene Silencing in Osteogenesis
Imperfecta. In: Cartilage and Bone Development and Its Disorders. 2011. p. 85-90. Endocrine
Development, 21.
47. Marsell R, Sisask G, Nilsson Y, Sundgren-Andersson A, Andersson U, Larsson S, et al. GSK-3
inhibition by an orally active small molecule increases bone mass in rats. Bone. 2011;
48. Frisk P, Arvidson J, Ljunggren Ö, Gustafsson J. Decreased bone mineral density in young adults
treated with SCT in childhood: the role of 25-hydroxyvitamin D. Bone Marrow Transplantation. 2011;
49. Kilpeläinen T, Zillikens M, Stančákova A, et al. Genetic variation near IRS1 associates with reduced
adiposity and an impaired metabolic profile. Nature Genetics. 2011;43(8):753-760.
Dissertations during 2011
Hendrik Penno: Involvement of the RANK/RANK-L system in prostate cancer interaction with bone
cells.
55

Clinical Pharmacogenetics and Osteoporosis
Håkan Melhus, Mia Wadelius, Per Hallberg and Gabriellla Scordo
Genetic and dietary risk factors for osteoporosis
Thomas Lind, Annica Jacobson, Håkan Melhus
We aim to identify and study genetic and environmental risk factors that can help us explain why Sweden
and Norway have the world’s highest incidence of osteoporotic fractures, and to develop new treatments
for osteoporosis. We have primarily studied genetic and dietary factors, especially vitamin A and D.
Mechanistic studies on Vitamin A-induced bone toxicity
Thomas Lind, Annica Jacobson, Håkan Melhus
Vitamin A is the only known substance that can induce spontaneous fractures in laboratory animals. We
have previously shown that excessive doses lead to a reduced diameter of the long bones without affecting
the bone mineral density in rodents. To try to clarify the molecular mechanisms behind this vitamin Ainduced
bone toxicity, we have continued these animal studies as well as our studies of the effects in bone
cells in vitro.
Warfarin pharmacogenetics and pharmacometrics
Niclas Eriksson, Anna-Karin Hamberg, Hugo Kohnke, Mia Wadelius
We have worked with warfarin pharmacogenetics for over 10 years, and published one of the first studies
on the vitamin K reductase gene (VKORC1) in 2005. We collaborate with the International Warfarin
Pharmacogenetics Consortium (IWPC) concerning ethnic differences in dose requirements. We have
developed several warfarin dose models and are working with a K-PD model for children. In collaboration
with Malmö and the Sanger Institute (UK) we are doing a GWAS on thrombosis.
Genetic dosing of warfarin and other coumarins
Jenny Thunberg, Maria Röjstad, Hugo Kohnke, Elisabeth Palmcrantz-Graf, Christina Christersson,
Mia Wadelius
We are performing a large EU-funded randomised clinical trial on genetic dosing of coumarins(EU-PACT).
We are using a new rapid point-of-care test to enable genotyping before the start of therapy.
Genetics of serious adverse drug reactions
Pär Hallberg, Håkan Melhus, Mia Wadelius
SWEDEGENE (www.swedegene.se) is a national study of genetic susceptibility to adverse drug reactions
led by our group. We currently have clinical data and DNA from 700 cases and are aiming to collect at
least 4000. Relatively common reactions are genotyped at our department’s SNP&SEQ platform. We
collaborate internationally concerning rare serious reactions, where few cases are found in Sweden. 6900
non-related Swedes with genome-wide data are used as population controls.
Pharmacogenetics of neuropsycodrugs
Gabriella Scordo, Mao Mao
We investigate, by an integrated pharmacokinetic-pharmacodynamic approach, the contribution of allelic
variability in genes coding for proteins involved in drug metabolism, transport and effects to clinical
outcome of the drugs used in the therapy of schizophrenia, depression and Alzheimer’s disease. The aim is
to identify genetic markers of treatment outcome, quantify their predictive value, and evaluate how this
information can be used to design genotype-based dosing schedules for improved pharmacotherapy.
56

Clinical consequences of polymorphisms in xenobiotics metabolising enzymes
Gabriella Scordo
We collaborate in an international, multicenter project that aims to identify and clarify the role of the
genetic polymorphism in the enzymes that metabolize xenobiotics in the susceptibility to develop Multiple
Chemical Sensitivity (MCS), a multi-systemic syndrome characterized by intolerance to environmental
chemicals.
Members of the group during 2011
Håkan Melhus, Professor
Mia Wadelius, MD Ass prof
Pär Hallberg, MD PhD
Gabriella Scordo, MD PhD
Thomas Lind, Researcher
Annica Jacobson Rasmussen, Researcher
Niclas Eriksson, PhD student
Funding 2011
Håkan Melhus:
ALF 670 kSEK
Medical faculty 500 kSEK
Misc funds 150 kSEK
Pär Hallberg:
Swedish Society of Medicine 166 kSEK
57
Anna-Karin Hamberg, PhD student
Mao Mao, PhD student
Hugo Kohnke, Biomedical analyst, MSc
Jenny Thunberg, Research nurse
Maria Röjstad, Research nurse
Elisabeth Palmcrantz-Graf, Clinical project
leader
Mia Wadelius:
Heart and Lung foundation 1200 kSEK
Swedish Research Council 500 kSEK
ALF 400 kSEK
EU FP7 700 kSEK
Gabriella Scordo
Swedish Society of Medicine 166 kSEK
Publications 2009-2011
1. Wagner H, Melhus H, Pedersen N, Michaëlsson K. Heritability of impaired balance: a nationwide
cohort study in twins. Osteoporosis Int 2009; 20:577-83.
2. Wagner H, Melhus H, Gedeborg R, Pedersen NL, Michaëlsson K. Simply Ask Them About Their
Balance--Future Fracture Risk in a Nationwide Cohort Study of Twins.Am J Epidemiol. 2009;
169:143-9.
3. Byberg L, Melhus H, Gedeborg R, Sundström J, Ahlbom A, Zethelius B, Berglund LG, Wolk A,
Michaëlsson K. Total mortality after changes in leisure time physical activity in 50 year old men: 35
year follow-up of population based cohort. BMJ 2009; 338:b688.
4. Ingelsson E, Sundström J, Melhus H, Michaëlssson K, Berne C, Vasan RS, Risérus U, Blomhoff R,
Lind L, Arnlöv J. Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent
cardiovascular disease in elderly. Atherosclerosis 2009 Mar 11.
5. Gillespie U*, Alassaad A*, Henrohn D, Garmo H, Hammarlund-Udenaes M, Toss H, Kettis-Lindblad
Å, Melhus H*, Mörlin C* (*=contributed equally). A comprehensive pharmacist intervention to
reduce morbidity in patients 80 years or older. Arch Int Med 2009;169:894-900.
6. Hagström E, Hellman P, Larsson TE, Ingelsson E, Berglund L, Sundström J, Melhus H, Held C, Lind
L, Michaëlsson K, Ärnlöv J. Plasma parathyroid hormone and the risk of cardiovascular mortality in
the community. Circulation 2009;119-2765-71.

7. Östman B, Michaëlsson K, Helmersson J, Gedeborg R, Melhus H*, Basu S* (*contributed equally).
Oxidative stress and bone mineral density in elderly men: Antioxidant activity of alpha-tocopherol.
Free Radical Bio Med 2009;47:668-73.
8. Mirza M, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 associate with left
ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 2009;207:546-
51.
9. Byberg L, Melhus H, Gedeborg R, Sundström J, Ahlbom A, Zethelius B, Berglund LG, Wolk A,
Michaëlsson K. Total mortality after changes in leisure time physical activity in 50 year old men: 35
year follow-up of population based cohort.Br J Sports Med. 2009;43:482.
10. Sennerby U, Melhus H, Gedeborg R, Byberg L, Garmo H, Ahlbom A, Pedersen NL, Michaëlsson K.
Cardiovascular diseases and risk of hip fracture.JAMA 2009;302:1666-73.
11. Snellman G, Melhus H, Gedeborg R, Olofsson S, Wolk A, Pedersen NL, Michaëlsson K. Seasonal
genetic influence on serum 25-hydroxyvitamin D levels: a twin study.PLoS ONE. 2009;4:e7747.
12. Wadelius M, Chen LY, Lindh JD, Eriksson N, Ghori MRJ, Bumpstead S, Holm L, McGinnis R, Rane
A, Deloukas P. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood
2009 Jan 22;113(4): 784-792.
13. Aomori T, Yamamoto K, Oguchi-Katayama A, et al Rapid SNP detection of the cytochrome P450
(CYP) 2C9 and the vitamin K oxide reductase (VKOR) gene for the warfarin dose adjustment by
SMart-Amplification Process. ClinChem 2009 Apr;55: 804-812.
14. International Warfarin Pharmacogenetics Consortium, Klein TE, Altman RB, et al. Warfarin dosing
using clinical and pharmacogenetic data. N Engl J Med 2009 Feb 19;360:753-64.
15. Takeuchi F, McGinnis R, Bourgeois S, et al. A genome-wide association study confirms VKORC1,
CYP2C9 and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genetics 2009 March
20;5:e1000433.
16. Wadelius M. Pro: Use of Pharmacogenetics in Guiding Treatment with Warfarin. ClinChem 2009
Apr;55(4):709-11.
17. vanSchie RM, Wadelius M, Kamali F, et al. Genotype-guided dosing of coumarin derivatives. The
European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics
2009 Oct;10(10):1687-95.
18. Schwan S, Hallberg P. [Interaction between Saint JohnsWort and alcohol deterrents?].Lakartidningen.
2009 Jul 8-21;106(28-29):1829. Swedish.
19. Schwan S, Hallberg P. [Serotonergic syndrome in combination of linezolid (Zyvixid) and SSRI].
Lakartidningen. 2009 Oct 28-Nov 3;106(44):2856. Swedish.
20. Sundström A, Hallberg P. Data-mining in pharmacovigilance - detecting the unexpected: the role of
index of suspicion of the reporter. Drug Safety 2009;32(5):419-27.
21. Schwan S and Hallberg P. Escitalopram kontra citalopram vid egentlig depression. Läkartidningen
2009 Mar 18-24;106(12):858-61.
22. Schwan S, Hallberg P. SSRIs, bone mineral density, and risk of fractures - a review.
EurNeuropsychopharmacol 2009;19(10):683-92.
23. Schwan S, Hallberg P. Ranking antidepressants. Lancet 2009 May 23;373(9677):1761.
24. Schwan S, Hallberg P. Escitalopram treatment of generalized anxiety disorder in older adults. JAMA
2009 May 20;301(19):1987-8.
25. Günes, A, Melkerson, KI, Scordo, M.G. Dahl, M-L. Association between HTR2C and HTR2A
polymorphisms and metabolic abnormalities in patients treated with olanzapine or clozapine. J Clin
Psychopharmacol 2009; 29: 65-68
58

26. Günes, A, Ozbey, G., et al Influence of genetic polymorphisms, smoking, gender and age on CYP1A2
activity in a Turkish population. Pharmacogenomics 2009; 10: 769-778
27. Mao, M, Matimba, A, Scordo, MG et al. Flavin-containing monooxygenase 3 polymorphisms in 13
ethnic populations from Europe, East Asia and sub-Saharian Africa: frequency and linkage analysis.
Pharmacogenomics 2009; 10: 1447-55
28. Korkina, L, Scordo, MG, Deeva, I, Cesareo, E, De Luca, C. The Chemical Defensive System in the
Pathobiology of Idiopathic Environment-Associated Diseases. Curr Drug Metab 2009; 10: 914-931
29. Hallberg P, Schwan S, Melhus H. Liraglutide for weight loss in obese people. Lancet 2010:375:551.
30. Hallstrom H, Melhus H, Glynn, Lind L, Syvanen AC, Michaelsson K. Coffee consumption and
CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and
women: a cohort study. NutrMetab 2010;7:12.
31. Melhus H, Snellman G,GedeborgR, BybergL, BerglundL, Mallmin H, Hellman P, BlomhoffR,
HagströmE, ÄrnlövJ, Michaëlsson K. Plasma 25-hydroxyvitamin D levels and fracture risk in a
community-based cohort of elderly men in Sweden. J ClinEndocrinolMetab 2010; 95:2637-45.
32. GedeborgR, Thiblin I, BybergL, Melhus H, Lindbäck J, Michaëlsson K. Population density and
mortality among individuals in motor vehicle crashes. InjPrev 2010; 16:302-8.
33. Snellman G, Melhus H, Gedeborg R, Byberg L, Berglund L, Wernroth L, Michaëlsson K.
Determining vitamin D status: a comparison between commercially available assays.PLoS ONE.
2010; 5:e11555.
34. Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, Berglund L, Ärnlöv J,
Hellman P, Blomhoff R, Wolk A, Garmo H, Holmberg L, Melhus H. Plasma vitamin D and mortality
in older men: a community-based prospective cohort study. Am J ClinNutr 2010;92:841-8.
35. Hagström E, Ingelsson E, Sundström J, Hellman P, Larsson TE, Berglund L, Melhus H, Held C,
Michaëlsson K, Lind L, Ärnlöv J. Plasma parathyroid hormone and risk of congestive heart failure in
the community. Eur J Heart Fail 2010; 12:1186-92.
36. Hu L, Lind T, Sundqvist A, Jacobson A, Melhus H. Retinoic acid increases proliferation of human
osteoclast progenitors and inhibits RANKL-stimulated osteoclast differentiation by suppressing
RANK. PLoS ONE 2010 Oct 11;5:e13305.
37. Lind T, Lind PM, Jacobson A, Hu L, Sundqvist A, Risteli J, Yebra-Rodriguez A, Rodriguez-Navarro
A, Andersson G, Melhus H. High dietary intake of retinol leads to bone marrow hypoxia and
diaphysealendosteal mineralization in rats. Bone 2010 Oct 28.
38. Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Arnlöv J, Sundström J, Lind L, Melhus H,
Michaëlsson K, Wolk A. Confirmed hypertension and plasma 25(OH)D concentrations amongst
elderly men. J Intern Med 2010; Oct 29.
39. Bergström MF, Byberg L, Melhus H, Michaëlsson K, Gedeborg R. Extent and consequences of
misclassified injury diagnoses in a national hospital discharge registry. InjPrev 2010, Nov 26.
40. Lenzini P, Wadelius M, Kimmel S, et al. Integration of genetic, clinical, and laboratory data to refine
warfarin dosing. ClinPharmacolTher 2010 May; 87(5):572-8.
41. Lundberg A, Hallberg P. [Meningitis--a very rare adverse effect of lamotrigine treatment].
Lakartidningen. 2010 Aug 11-24;107(32-33):1861-2. Swedish.
42. Hamberg AK, Wadelius M, Lindh JD, Dahl ML, Padrini R, Deloukas P, Rane A, Jonsson EN. A
pharmacometric model describing the relationship between warfarin dose and INR response taking
variations in CYP2C9, VKORC1 and age into account. ClinPharmacolTher 2010 June; 87(6):727-34.
43. Limdi NA, Wadelius M, Cavallari L. et al. on behalf of the IWPC. Warfarin Pharmacogenetics:
VKORC1 genotype as predictive as haplotype across three racial groups. Blood 2010 May
6;115(18):3827-34.
59

44. Glimelius B, Garmo H, Berglund Å, Fredriksson LA, Berglund M, Byström P, Kohnke H, Sørbye H,
Wadelius M. Prediction of irinotecan and 5-FU toxicity and response in patients with advanced
colorectal cancer. Pharmacogenomics J: Epub 2010 Feb 23.
45. Verhoef TI, Redekop WK, Darba J, et al. EU-PACT Group. A systematic review of cost-effectiveness
analyses of pharmacogenetic-guided dosing in treatment with coumarin derivatives.
Pharmacogenomics 2010 Jul;11(7):989-1002.
46. Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P. A signal for an abuse liability for
pregabalin-results from the Swedish spontaneous adverse drug reaction reporting system. Eur J
ClinPharmacol 2010 Sep;66(9):947-53.
47. Smedje H, Schwan S, Hallberg E, Hallberg P. Onset of Kleine-Levin syndrome in association with
isotretinoin treatment. ActaPaediatrica 2010 Jun;99(6):946-8.
48. De Luca,C, Scordo, MG, Cesareo, E et al Biological definition of multiple chemical sensitivity from
redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes.
Toxicol Appl Pharmacol. 2010; 248: 285-292
49. De Luca, C, Scordo, G. et al. Idiophatic environmental intolerances (IEI): from molecular
epidemiology to molecular medicine. Ind J Experiment Biol 2010; 48: 625-635
50. Magliulo L, Dahl ML, Lombardi G, Fallarini S, Villa LM, Biolcati A, Scordo MG. Do CYP3A and
ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?
Eur J Clin Pharmacol. 2010; 67(1):47-54
51. Gokalp O, Gunes A, Cam H, Cure E, Aydin O, Tamer M, et al. Mild hypoglycaemic attacks induced
by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8 polymorphisms in routine clinical
setting. European Journal of Clinical Pharmacology. 2011;67(12):1223-1229.
52. Warensjö E, Byberg L, Melhus H, Gedeborg R, Mallmin H, Wolk A, et al. Dietary calcium intake and
risk of fracture and osteoporosis : prospective longitudinal cohort study. BMJ. British Medical
Journal. 2011;342:d1473-.
53. Michaëlsson K, Byberg L, Ahlbom A, Melhus H, Farahmand B. Risk of Severe Knee and Hip
Osteoarthritis in Relation to Level of Physical Exercise : A Prospective Cohort Study of Long-
Distance Skiers in Sweden. PLOS ONE. 2011;6(3):e18339-.
54. Magliulo L, Dahl M, Lombardi G, Fallarini S, Villa L, Biolcati A, et al. Do CYP3A and ABCB1
genotypes influence the plasma concentration and clinical outcome of donepezil treatment?. European
Journal of Clinical Pharmacology. 2011;67(1):47-54.
55. Byberg L, Gedeborg R, Cars T, Sundström J, Berglund L, Kilander L, et al. Prediction of fracture risk
in men: A cohort study. Journal of Bone and Mineral Research. 2011;dec 20
56. Bergström M, Byberg L, Melhus H, Michaëlsson K, Gedeborg R. Extent and consequences of
misclassified injury diagnoses in a national hospital discharge registry. Injury Prevention.
2011;17(2):108-113.
57. Burgaz A, Byberg L, Rautiainen S, Orsini N, Håkansson N, Ärnlöv J, et al. Confirmed hypertension
and plasma 25(OH)D concentrations amongst elderly men. Journal of Internal Medicine.
2011;269(2):211-218.
58. Berglund L, Berne C, Svärdsudd K, Garmo H, Melhus H, Zethelius B. Seasonal variations of insulin
sensitivity from a euglycemic insulin clamp in elderly men. Uppsala Journal of Medical Sciences.
2011;
59. Hu L, Jonsson K, Andersén H, Edenro A, Bohlooly-Y M, Melhus H, et al. Over-expression of
Adamts1 in mice alters bone mineral density. Journal of Bone and Mineral Metabolism. 2011;
60. Alassaad A, Gillespie U, Bertilsson M, Melhus H, Hammarlund-Udenaes M. Prescription and
transcription errors in multidose-dispensed medications on discharge from hospital : an
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observationaland interventional study. Blackwell Publishing; Journal of Evaluation In Clinical
Practice. 2011;
61. Lind T, Lind M, Jacobson A, Hu L, Sundqvist A, Risteli J, et al. High dietary intake of retinol leads to
bone marrow hypoxia and diaphysealendosteal mineralization in rats. Bone. 2011;48(3):496-506.
62. van Schie RM, Wessels JA, le Cessie S, et al. Loading and maintenance dose algorithms for
phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data. Eur Heart
J 2011 Aug;32(15):1909-17.
63. Howard R, Leathart JBS, French DJ, Krishan E, Kohnke H, Wadelius M, van Schie R, Verhoef T,
Maitland van der Zee AH, Daly AK, Barallon R. Genotyping for CYP2C9 and VKORC1 alleles by a
novel point of care assay with HyBeacon® probes. ClinChimActa 2011 Nov 20;412(23-24):2063-9.
64. AveryPJ, Jorgensen A, HambergAK, WadeliusM, Pirmohamed M, Kamali F; EU-PACT Study Group.
A proposal for an individualized pharmacogenetics-based warfarin dose regimen for patients
commencing anticoagulation therapy. Clin Pharmacol Ther2011 Nov;90(5):701-6.
65. Becquemont L, Alfirevic A, AmstutzU, et al. Practical recommendations for pharmacogenomicsbased
prescription: 2010 ESF-UB Conference on Pharmacogenetics and
Pharmacogenomics.Pharmacogenomics 2011 Jan;12(1):113-24.
66. Johnson JA, Gong L, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium
Guidelines for CYP2C9 and VKORC1 Genotypes and Warfarin Dosing. Clin Pharmacol Ther 2011
Oct;90(4):625-9.
67. Wadelius M, Alfirevic A. Pharmacogenomics and Personalized Medicine: the plunge into nextgeneration
sequencing. Invited review.Genome Medicine 2011;3(12):78
68. Lundberg AM, Hallberg P. [Advantage with rectal drug administration in certain situations, but not
always quicker effect].Lakartidningen. 2011 May 4-10;108(18):992. Swedish.
69. Gökalp O, Gunes A, Cam H, Cure E, Aydın O, Tamer MN, Scordo MG, Dahl ML. Mild
hypoglycaemic attacks induced by sulphonylureas related to CYP2C9, CYP2C19 and CYP2C8
polymorphisms in routine clinical setting. Eur J Clin Pharmacol. 2011; 67(12):1223-9.
61

Occupational and environmental medicine
Eva Vingård
Occupational and environmental medicine is a research area studying the significance of environmental
factors and exposure on human health in a wide context, covering all age groups. The environmental
factors can be from the workplace, the indoor environment, or the outdoor environment. The type of
exposures can be physical, chemical, biological, psychosocial or organisational. The research methodology
mainly includes epidemiological methods, either in specific groups or in the general population, as well as
experimental intervention field studies.
One focus in our research group is health effects of the environment with respect to asthma, ocular and
respiratory symptoms, rhinitis and allergic symptoms. The indoor studies have covered schools, day care
centres, hospitals, dwelling, stables and the cabins in aircraft. Another focus is health and work
environment in health care and education. Studies investigating health, work environment, life style and
socioeconomic factors are conducted. Organisational factors for the good work environment are studied as
well as musculoskeletal and psychiatric disorders in relation to work. Return to work, rehabilitation, causes
for and consequences of sick listing are other focus of research for the group. Another new and promising
area for research is exposure to endocrine disrupting chemicals and the potential progression of major
common diseases like obesity, cardiovascular disease and osteoporosis.
The research at the department is interconnected with the Occupational and Environmental department at
Uppsala Akademiska Hospital serving three county councils (Uppsala, Gävleborg and Dalarna) and many
of the members in the research group have their position at that county council department.
The overall aims of the research group are to;
discover, explore, assess, analyse and report health and risk factors for occupational and environmental
exposures.
develop new methods for research in occupational and environmental medicine
develop and evaluate prevention strategies at work and in the general environment.
Below is a selected list of current research projects, For a more complete list, and more detailed
information, please see http://www.medsci.uu.se/fogrupp/occupmed/occupmedicine.htm.
1. Health and future in the public sector – an investigation of the healthy organisation
2. Hospitalization due to common potentially work related disorders, disability pension and
mortality among native and foreign born residents in Sweden during1990-2008.
3. Lung function and respiratory symptoms in hard metal workers exposed to cobalt.
4. Health and work environment for entrepreneurs and in small scale enterprises.
5. Healthy sustainable houses and energy use
6. Health and safety in surgery of peritoneal carcinogens and treatment with chemotherapy.
7. Asthma, risk factors, prevention and quality of life for the affected person.
8. Horse stable environment, health effects on stable workers and horses and the impact of
horse on community planning.
9. Characterisation, exposure levels and health effects of particles in dwellings.
10. Exposure to endocrine disrupting chemicals and the potential progression of major common
diseases like obesity, cardiovascular disease and osteoporosis.
11. Persistent organic pollutants and CVD from a gender perspective.
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12. Health effects of exposure to Bisphenol A.
13. Experimental early intervention of Swedish Social Insurance Agency to reduce sickness absence at
work.
14. Psychiatric symptoms, psychiatric disorders and its associations with factors in childhood,
sociodemographic factors, life style and work. Follow up of two cohorts; 50000 conscripts
during 40 years and 10 000 inhabitants of Stockholm county.
15. Balanced communication, leadership and health
Funding
Eva Vingård
AFA Insurance 1.9 MSEK
FAS 1.8 MSEK
Ingvar Lundberg
FAS 0.4 MSEK
Dan Norbeck
FORMAS-BIC 600 kSEK
EU (DGSanco) HESEINT 630 kSEK
EU (DGSanco) GERIE 300 kSEK
Members of the group during 2011
Eva Vingård, Professor, MD
Ingvar Lundberg, Professor, MD
Anna Rask Andersen, Professor, MD
Dan Norbäck, Ass professor
Gunilla Wieslander, Ass professor, MD
Robert Wålinder, Ass professor, MD
Monica Lind, Ass professor
Lena Elfman, Ass professor
Malin Josephson, Ass professor
Greta Smedje, Ass professor
Helena Anundi, PhD
Roma Runeson, PhD
63
Karin Engvall
FORMAS 550 kSEK
Monica Lind
FORMAS 2.2 MSEK
Gunilla Wieslander
FORMAS 1.7 MSEK
Margareta Torgén, PhD, MD
Karin Engvall, PhD
Kristina Gunnarsson, PhD
Bo Sahlberg, PhD-student
Magnus Helgesson, PhD-student
Carl Hogstedt, PhD-student
Peter Palm, PhD-student
Monica Rönn, PhD-student
Bo Johansson, PhD-student
Tomas Eriksson, Assistant
Peter Westerholm, Professor emeritus, MD
Publications 2009-2011
1. Lind P.M., Wjheden C, Lundberg R, Alvarez-Lloret P, Sanne AB, Hermsen S.AB:, Rodriques-
Navarro A.B, Larsson S, Rannug A. Short-term exposure to dioxin impairs bone tissue composition in
male Sprague-Dawley rats. Chemospere 2009 May;75(5):680-4.
2. Rehfisch P, Wålinder R. ABC om vibrationsskador. Läkartidningen 2009;11-17;106(7):451
3. Falkenberg A, Nyfjäll M, Bildt C, Vingård E. Precting Sickness Absence-Are Extended Health Checkups
of Any Value? Comparisons of Three Individual Risk Models. J Occup Environ Med.
2009;51(1):104-111.

4. Leineweber, C, Westerlund, H, et al. Covert coping with unfair treatment at work and risk of incident
myocaridal infarction and cardiac death among men: prospective cohort study. J Epidemiol
Community Health 2009 nov 24
5. Leander M, Cronqvist A, Janson C, Uddenfeldt M, Rask-Andersen A. Health-related quality of life
predicts onset of asthma in a longitudinal population study. Respiratory Medicine, 2009; 2:194-200
6. Vingård E, Blomqvist V, Rosenblad A, Lindberg P, Voss M, Alfredsson L, Josephson M. A physical
fitness programme during paid working hours – impact on health and workability among women
working in the social service sector. WORK 2009;34:339-344
7. Gunnbjörnsdóttir MI, Norbäck D, Björnsson E, Soon A, Jarvis D, Jõgi R, Gislason D, Gislason T,
Janson C. Indoor environment in three North European cities in relationship to atopy and respiratory
symptoms. The Clinical Respiratory Journal. 2009; 85-94
8. Alvarez-Lloret, P., Lind, P.M., Nyberg I. and Örberg, J., Rodriguez-Navarro, A.B. Effects of
3,3´,4,4´,5 - pentachlorobiphenyl (PCB126) on vertebral bone mineralization and on thyroxin and
vitamin D levels in Sprague-Dawley rats. Toxicology Letters 2009 June 187(2) 63–68
9. Lind, P. M., Wejheden, C., Lundberg, R., et al. Short-term exposure to dioxin impairs bone tissue
composition in male Sprague-Dawley rats. Chemosphere. 2009 May;75(5):680-4
10. Lind, P.M., Gustafsson, M., Hermsen, S.A.B, Larsson, S., Kyle, C.E., Örberg, J.Rhind, S.M. Exposure
to sewage sludge disrupts bone tissue homeostasis in sheep. Sci Total Environ. 2009 Mar
15;407(7):2200-8.
11. Corriols M, Marin J, Berroteran J, Lozano LM, Lundberg I. Incidence of acute pesticide poisonings in
Nicaragua: a public health concern. Occup Environ Med 2009;66:205-210
12. Stoetzer, Bergman P, Forsell Y, Hallsten L, Johansson G, Lundberg I. Problematic interpersonal
relationships at work and depression: a Swedish prospective cohort study. J Occup Health,
2009;51:144-51
13. Johansson G, Lundberg I. Components of the illness flexibility model as explanations of
socioeconomic differences in sickness absence. Int J Health Services 2009;39:123-38.
14. Hemmingsson T, Melin B, Allebeck P, Lundberg I. Cognitive ability in adolescence and mortality in
middle age: a prospective life course study. J Epidemiol Community Health. 2009;63:697-702
15. Stoetzer U, Ahlberg G, Bergman Peter, Hallsten L, Lundberg I. Working conditions predicting
interpersonal relationship problems at work. Eur J Work Organizational Psychol 2009;18:424-441
16. Wolk K, Mallbris L, Larsson P, Vingård E, Rosenblad A, Ståhle M. Excessive body weight and
smoking associates with a high risk of onset of plaque psoriasis. Acta Derm venerolog
2009;89(5):492-7
17. Elfman L, Riihimäki M, pringle J, Wålinder R. Influence of horse stable environment on human
airways. J Occup Med Toxicol 2009;May 25;4:10
18. Andreasson SN, Anundi H, Sahlberg B, Ericsson CG, Wålinder R, Englund G, Påhlman L, Mahteme
H. Peritonectomy with high voltage electrocautery generates higher levels of ultrafine smoke particles.
Eur J Surg Oncol 2009;106(7):780-4
19. Lund T, Christensen KB, Vaez M, Labriola M, Josephson M, Villadsen E, Voss M. Differences in
sickness absence in Sweden ans Danmark: the cross natioal HAKNAK study. Eur J Public health
2009;19(3) 343-9
20. Skillgate E, Vingård E, Josephson M, Holm LW, Alfredsson L. Is smoking and alkohol consumption
associated with long term sick leave due to unspecific back or neck pain among emplyess in the public
sector? Results of a three year follow-up cohort study. J Rehabil Med 2009;41(7):550-6
21. Lohela M, Björklund C, Vingård E, Hagberg J, Jensen I. Does a change in psychosocial work factors
lead to a change in employee health? J Occup Environ Med 2009;51(2):195-203
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22. Bergström G, Bodin L, Hagberg J, Aronsson G, Josephson M. Sickness presenteeism today, sickness
absenteeism tomorrow? A prosepective study on sickness presenteeism and future sickness
absenteeism. J Occup Environ Med 2009;51(6):629-38
23. Bergström G, Bodin L, Hagberg J, Lindh T, Aronsson G, Josephson M. Does sickness presenteeism
have an impact on futurre general health? Int Arch Occup Environ Health 2009;82(10):1179-90
24. Sieurin L, Josephson M, Vingård E. Positive and negative consequences of sick leave for the
individual, with special focus on part-time sick leave. Scand J Public Health 2009;37(1):50-6
25. Falkenberg A, Nyfjäll M, Bildt C, Vingård E. Predicting sick ness absence – are extended health
check-ups of any value? Comparision of three individual risk models. J Occup Environ Med
2009;51(1):104-11
26. C Leineweber, H Westerlund, T Theorell, M Kivimäki, P Westerholm, L Alfredsson. Covert coping
with unfair treatment at work and risk of incident myocaridal infarction and cardiac death among men:
prospective cohort study. J Epidemiol Community Health 2009 nov 24.
27. Alipour A, Ghaffari M, Shariati B, Jensen I, Vingard E. Four-year incidence of sick leave because of
neck and shoulder pain and its association with work and lifestyle. Spine 2009 Feb 15;34(4):413-8
28. Lindberg P, Josephson M, Alfredsson L, Vingard E. Comparisons between five self-administered
instruments predicting sick leaves in a 4-year follow-up. Int Arch Occup Environ Health. 2009
jan;82(2):227-34.
29. Castro-Giner, F., N. Kunzli, et al. Traffic-related air pollution, oxidative stress genes, and asthma
(ECHRS). Environ Health Perspect. 2009;117(12): 1919-24.
30. Broms, K., D. Norback, et al. Effect of degree of urbanisation on age and sex-specific asthma
prevalence in Swedish preschool children. BMC Public Health 2009; 9: 303.
31. Cai, G. H., K. Broms, et al. Quantitative PCR analysis of fungal DNA in Swedish day care centers and
comparison with building characteristics and allergen levels. Indoor Air 2009;19(5): 392-400.
32. Dharmage, S. C., B. Erbas, et al. "Do childhood respiratory infections continue to influence adult
respiratory morbidity?" Eur Respir J 2009;33(2): 237-44.
33. Engvall, K., M. Hult, et al. A new multiple regression model to identify multi-family houses with a
high prevalence of sick building symptoms "SBS", within the healthy sustainable house study in
Stockholm (3H). Int Arch Occup Environ Health 2009;83(1): 85-94.
34. Lindgren, T., G. Wieslander, et al. Tinnitus among airline pilots: prevalence and effects of age, flight
experience, and other noise. Aviat Space Environ Med 2009;80(2): 112-6.
35. Lindgren, T., G. Wieslander, et al. Hearing status among cabin crew in a Swedish commercial airline
company. Int Arch Occup Environ Health 2009;82(7): 887-92.
36. Malinovschi, A., C. Janson, et al. Both allergic and nonallergic asthma are associated with increased
FE(NO) levels, but only in never-smokers. Allergy 2009;64(1): 55-61.
37. Mirabelli, M. C., M. Olivieri, et al. Inhalation incidents and respiratory health: results from the
European Community Respiratory Health Survey. Am J Ind Med 2009;52(1): 17-24.
38. Mirabelli, M. C., J. P. Zock, et al. Metalworking exposures and persistent skin symptoms in the
ECRHS II and SAPALDIA 2 cohorts. Contact Dermatitis 2009;60(5): 256-63.
39. Norback, D. An update on sick building syndrome. Curr Opin Allergy Clin Immunol 2009;9(1): 55-9.
40. Sahlberg, B., Y. H. Mi, et al. Indoor environment in dwellings, asthma, allergies, and sick building
syndrome in the Swedish population: a longitudinal cohort study from 1989 to 1997. Int Arch Occup
Environ Health 2009;82(10): 1211-8.
41. Sahlberg, B., G. Wieslander, et al. Sick building syndrome (SBS) in relation to domestic exposure in
Sweden - A cohort study from 1991 to 2001. Scand J Public Health.2010 May;38(3):232-8.
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42. Svanes, C., J. Sunyer, et al. Early life origins of chronic obstructive pulmonary disease. Thorax
2009;65(1): 14-20.
43. Zock, J. P., E. Plana, et al. Domestic use of hypochlorite bleach, atopic sensitization, and respiratory
symptoms in adults. J Allergy Clin Immunol 2009;124(4): 731-8 e1.
44. Leander M, Cronqvist A, Janson C, Uddenfeldt M, Rask-Andersen A. Non-respiratory Symptoms and
Well-Being in Asthmatics from a General Population Sample. Journal of Asthma 2009; 46 (6):552-9.
45. Elfman L, Hogstedt C, Engvall K, Lampa E, Lindh H C. Acute Health Effects on Planters of Conifer
Seedings Treated with Insecticides. Ann Occup Hyg 2009 Jun; 53 (4) 383-90.
46. Åkerstedt T, Nordin M, Alfredsson L, Westerholm P, Kecklund G. Sleep and sleepiness: impact of
entering or leaving shitfwork - a prospective study. Chronobiology International, 2010; 27: 987-96
47. Lindgren T. A case of indoor air pollution of ammonia emitted from concrete in a newly built office in
Beijing. Building and Environment 2010, 45 (3), p.596-600.
48. London L, Coggon D, Moretto A, et al. The ethics of humans volunteer studies involving experimental
exposure to pesticides: unanswered dilemmas. Environmental Health 2010; 9:50.
49. Lagerström, M, Josephson M, Arsalani N and Fallahi-Khoshknab M. Striving for balance between
family and work demands among Iranian nurse. Nursing Science Quarterly, 2010;23:162-72.
50. Lind T, Lind PM, Jacobson A, Hu L, Sundqvist A, Risteli J, Yebra-Rodrigues A, Rodriguez-Navarro
A, Andersson G, Melhus H. High dietary intake of retinol leads to bone marrow hypoxia and
diaphyseal endosteal mineralization in rats. Bone 2010; Oct 28.
51. Leander M, Jansson, C Uddenfeldt M, Cronqvist A, Rask-Andersen A. Associations between
mortality, asthma, and health-related quality of life in an elderly cohort of Swedes. J Asthma
2010;47(6):627-32.
52. Holm L, Torgén M, Hansson A-S, et al.. Återgång i arbete efter sjukskrivning för rörelseorganens
sjukdomar och lättare psykisk ohälsa - en systematisk kunskapssammanställning om effekten av
interventioner, rehabilitering och exponeringar på arbetet. Arbete och hälsa nr 2010;44(3)
53. Wahlstedt K, Norbäck D, Wieslander G, Skoglund L, Runeson R. Psychosocial and Ergonomic
Factors and Their Relation to Musculoskeletal Complaints in the Swedish Workforce. International
Journal of Occupational Safety and Ergonomics(JOSE) 2010; Vol. 16, No.3, 311-321.
54. Appelros P, Stegmayr B, Terént A. A review on sex differences in stroke treatment and outcome. Acta
Neurol Scand. 2010 Jun;121(6):359-69.
55. Ernstgård L, Norbäck D, Nordquist T, Wieslander G, Wålinder R, Johanson G. Acute effects of
exposure to 1 mg/m3 of vaporized 2-ethyl-1-hexanol in humans. Indoor Air 2010; 20: 168-175.
56. Henriksson KM, Farahmand B, Johansson S, Asberg S, Terént A, Edvardsson N. Survival after stroke-
-the impact of CHADS2 score and atrial fibrillation. Int J Cardiol. 2010 May 14;141(1):18-23
57. Wieslander G, Kumlin A, Norbäck D. Dampness and 2-Ethyl-1-hexanol in Floor Construction of
Rehabilitation Center: Health Effects in Staff. Archives of Environmental & Occupational Health
2010; Vol 65:No 1
58. Gunnarsson K, Andersson I-M, Rosén G. Systematic Work Environment Management: Experiences
from Implementation in Swedish Small-scale Enterprises. Industrial Health 2010;48:185-196.
59. Uddenfeldt M, Janson C, Lampa E, Leander M, Norbäck D, Larsson L, Rask-Andersen A. High BMI
is related to higher incidence of asthma while a fish and fruit diet is related to a lower - Results from a
long-term follow-up study of three age groups in Sweden. Respiratory Medicine 2010;104: 972-980.
60. Herlin, M, Kalantari F, Stern N, Sand S, Larsson S, Viluksela M, Tuomisto J, Tuomisto J, Tuukkanen
J, Jämsä T, Lind M, Håkansson H. Quantitative characterization of changes in bone geometry, mineral
density and biomechanical properties in two rat strains with different Ah-receptor structures after
long-term exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology.2010 Jun 29;273(1-3):1-11.
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61. Lind M, Öberg D, Larsson s, Kyle C, Örberg J, Rhind S. Pregnant ewes exposed to multiple endocrine
disrupting pollutants through sewage sludge-fertilized pasture show an anti-estrogenic effect in their
trabecular bone Science of the Total Environment 408(2010) 2340-2346.
62. Wahlstedt K, Lindgren T, Norbäck D, Wieslander G, Runeson R Psychosocial Work Environment and
Medical Symptoms among Swedish Commercial Airline Cabin Crew. Am J Ind Med. 2010
Jul;53(7):716-23.
63. Wejheden C, Brunnberg S, Larsson S, Lind M, Andersson G, Hanberg A. Transgenic Mice with a
Constitutively Active Aryl Hydrocarbon Receptor Display a Gn Gender-Specific Bone Phenotype.
Toxicological Sciences 2010;114(1):48-58.
64. Skillgate E, Bohman T, Holm L, Vingård E, Alfresson L. The long-term effects of naprapathic
manual therapy on back and neck pain - Results from a pragmatic randomized controlled trial. BMC
Musculoskeletal Disorders 2010;11:26
65. Arno C. Gutleb, Arvidsson, Örberg Jan, Larsson Sune, Utne Skaare Janneche, Aleksandersen Mona,
Ropstad Erik, Lind Monica. Effects on bone tissue in ewes (Ovies aries) and their foetuses exposed to
PCB 118 and PCB 153. Toxicology Letters 192(2010) 126-133
66. Bergman P, Ahlberg G, Forsell Y, Lundberg I. Non-participation in the second wave of the PART
study on mental disorders and its effects on risk estimates. Int J Soc Psychiatry. 2010;56(2):119-32.
67. Lundin A, Lundberg I, Hallsten L, Ottosson J, Hemmingsson T. Unemployment and mortality - a
longitudinal prospective study on selection and causation in 49 321 Swedish middle aged men. J
Epidemiol Community Health.2010;64(1):22-8.
68. Gunnarsson K, Andersson I, Josephson M. Swedish Entrepreneurs' Use of Occupational Health
Services. AAOHN Journal. 2011;59(10):437-445.
69. Elfman L, Wålinder R. Air quality in Horse Stables, in chemistry, emission Control, Radioactive
Pollution and Indoor Air Quality. In: Air quality in Horse Stables, in chemistry, emission Control,
Radioactive Pollution and Indoor Air Quality. Croatia: InTech; 2011.
70. Arsalani N, Fallahi-Khoshknab M, Ghaffari M, Josephson M, Lagerstrom M. Adaptation of
Questionnaire Measuring Working Conditions and Health Problems Among Iranian Nursing
Personnel. Asian Nursing Research. 2011;5(3):177-182.
71. Hallsten L, Voss M, Stark S, Josephson M, Vingård E. Job burnout and job wornout as risk factors for
long-term sickness absence. Work. 2011;38(2):181-192.
72. Gunnarsson K, Josephson M. Entrepreneurs' Self-reported Health, Social Life, and Strategies for
Maintaining Good Health. Journal of Occupational Health. 2011;53(3):205-213.
73. Hultin H, Hallqvist J, Alexanderson K, Johansson G, Lindholm C, Lundberg I, et al. Work-related
psychosocial events as triggers of sick leave - results from a Swedish case-crossover study. BMC
Public Health. 2011;11:175-.
74. Cai G, Hashim J, Hashim Z, Ali F, Bloom E, Larsson L, et al. Fungal DNA, allergens, mycotoxins and
associations with asthmatic symptoms among pupils in schools from Johor Bahru, Malaysia. Pediatric
Allergy and Immunology. 2011;22(3):290-297.
75. Kim J, Elfman L, Wieslander G, Ferm M, Torén K, Norbäck D. Respiratory Health among Korean
Pupils in Relation to Home, School and Outdoor Environment. Journal of Korean medical science.
2011;26(2):166-173.
76. Gunnarsson K, Andersson I, Josephson M. Entrepreneurs' approach and utilisation of Occupational
Health Service. 2011 Oct;59(10):437-45.
77. Falkstedt D, Lundberg I, Hemmingsson T. Childhood socio-economic position and risk of coronary
heart disease in middle age : a study of 49 321 male conscripts. European Journal of Public Health.
2011;21(6):713-718.
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78. Elfman L, Tooke N, Patring J. Detection of pesticides used in rice cultivation in streams on the island
of Leyte in the Philippines. Agricultural Water Management. 2011;101(1):81-87.
79. Bakolis I, Doekes G, Heinrich J, Zock J, Heederik D, Kogevinas M, et al. Respiratory health and
endotoxin - associations and modification by CD14/-260 genotype. European Respiratory Journal.
2011;
80. Cai G, Mälarstig B, Kumlin A, Johansson I, Janson C, Norbäck D. Fungal DNA and pet allergen
levels in Swedish day care centers and associations with building characteristics. Journal of
Environmental Monitoring. 2011;13(7):2018-2024.
81. Högman M, Malinovschi A, Norbäck D, Janson C. Added value with extended NO analysis in atopy
and asthma. Clinical Physiology and Functional Imaging. 2011;31(4):294-299.
82. Leander M, Lampa E, Janson C, Svärdsudd K, Uddenfeldt M, Rask-Andersen A. Determinants for a
low health-related quality of life in asthmatics. Uppsala Journal of Medical Sciences. 2011; E-pub
83. Lee D, Lind M, Jacobs D, Salihovic S, van Bavel B, Lind L. Polychlorinated Biphenyls and
Organochlorine Pesticides in Plasma Predict Development of Type 2 Diabetes in the Elderly. Diabetes
Care. 2011;34(8):1778-1784.
84. Hong N, Kim K, Lee I, Lind M, Lind L, Jacobs D, et al. The association between obesity and
mortality in the elderly differs by serum concentrations of persistent organic pollutants: a possible
explanation for the obesity paradox. International Journal of Obesity. 2011;
85. Lundin A, Lundberg I, Allebeck P, Hemmingsson T. Psychiatric diagnosis in late adolescence and
long-term risk of suicide and suicide attempt. Acta Psychiatrica Scandinavica. 2011;124(6):454-461.
86. Matheson M, Dharmage S, Abramson M, Walters E, Sunyer J, de Marco R, et al. Early-life risk
factors and incidence of rhinitis : Results from the European Community Respiratory Health Study -
an international population-based cohort study. Journal of Allergy and Clinical Immunology.
2011;128(4):816-823.e5.
87. Norbäck D, Cai G. Fungal DNA in hotel rooms in Europe and Asia-associations with latitude,
precipitation, building data, room characteristics and hotel ranking. Journal of Environmental
Monitoring. 2011;13(10):2895-2903.
88. Norbäck D, Wieslander G, Zhang X, Zhao Z. Respiratory symptoms, perceived air quality and
physiological signs in elementary school pupils in relation to displacement and mixing ventilation
system : an intervention study. Indoor Air. 2011;21(5):427-437.
89. Runeson R, Lindgren T, Wahlstedt K. Sleep Problems and Psychosocial Work Environment Among
Swedish Commercial Pilots. American Journal of Industrial Medicine. 2011;54(7):545-551.
90. Moen B, Norbäck D, Wieslander G, Bakke J, Mageroy N, Granslo J, et al. Can air pollution affect tear
film stability? : a cross-sectional study in the aftermath of an explosion accident. BMC Public Health.
2011;11:235-.
91. Norbäck D, Zock J, Plana E, Heinrich J, Svanes C, Sunyer J, et al. Lung function decline in relation to
mould and dampness in the home : the longitudinal European Community Respiratory Health Survey
ECRHS II. Thorax. 2011;66(5):396-401.
92. Rask-Andersen A. Asthma increase among farmers : a 12-year follow-up. Uppsala Journal of Medical
Sciences. 2011;116(1):60-71.
93. Leineweber C, Westerlund H, Theorell T, Kivimäki M, Westerholm P, Alfredsson L. Covert coping
with unfair treatment at work and risk of incident myocardial infarction and cardiac death among men;
Prospective cohort study. Journal of Epidemiology and Community Health. 2011;65(5):420-425.
94. Merritt A, Emenius G, Elfman L, Smedje G. Measurement of horse allergen (Equ cx) in schools.
ISRN Allergy. 2011;
68

95. Nyberg S, Heikkilä K, Fransson E, Alfredsson L, De Bacquer D, Bjorner J, et al. Job strain in relation
to body mass index : pooled analysis of 160 000 adults from 13 cohort studies. Journal of Internal
Medicine. 2011;
96. Olivieri M, Zock J, Accordini S, Heinrich J, Jarvis D, Künzli N, et al. Risk factors for new-onset cat
sensitization among adults : A population-based international cohort study. Journal of Allergy and
Clinical Immunology. 2011;
97. Rönn M, Lind L, Bavel B, Salihovic S, Michaëlsson K, Lind M. Circulating levels of persistent
organic pollutants associate in divergent ways to fat mass measured by DXA in humans.
Chemosphere. 2011;85(3):335-343.
98. Lind M, Lind L. Circulating levels of bisphenol A and phthalates are related to carotid atherosclerosis
in the elderly. Atherosclerosis. 2011;218(1):207-213.
99. Lind T, Lind M, Jacobson A, Hu L, Sundqvist A, Risteli J, et al. High dietary intake of retinol leads to
bone marrow hypoxia and diaphyseal endosteal mineralization in rats. Bone. 2011;48(3):496-506.
100. Lind PM, van Bavel B, Salihovic S, Lind L. Circulating Levels of Persistent Organic Pollutants
(POPs) and Carotid Atherosclerosis in the Elderly. Environ Health Perspect. 2011 Oct 11;120(1):38-
43.
101. Lind PM, Olsén L, Lind L. Circulating levels of metals are related to carotid atherosclerosis in elderly.
Sci Total Environ. 2011 Dec 15.
102. Olsén L, Lind M, Lind L. Gender differences for associations between circulating levels of metals and
coronary risk in the elderly. International journal of hygiene and environmental health (Print). 2011;
103. Xu F, Zou Z, Yan S, Li F, Kan H, Norbäck D, et al. Fractional Exhaled Nitric Oxide in Relation to
Asthma, Allergic Rhinitis, and Atopic Dermatitis in Chinese Children. Journal of Asthma.
2011;48(10):1001-1006.
104. Smedje G, Lundén M, Gärtner L, Lundgren H, Lindgren T. Hearing status among aircraft maintenance
personnel in a commercial airline company. Noise & Health. 2011;13(54):364-370.
105. Takaoka M, Norbäck D. The Home Environment of Japanese Female University Students :
Association with Respiratory Health and Allergy. Indoor + Built Environment. 2011;20(3):369-376.
106. Wålinder R, Riihimäki M, Bohlin S, Hogstedt C, Nordquist T, Raine A, et al. Installation of
mechanical ventilation in a horse stable : effects on air quality and human and equine airways.
Environmental Health and Preventive Medicine. 2011;16(4):264-272.
107. Solbu K, Daae H, Olsen R, Thorud S, Ellingsen D, Lindgren T, et al. Organophosphates in aircraft
cabin and cockpit air-method development and measurements of contaminants. Journal of
Environmental Monitoring. 2011;13(5):1393-1403.
108. Skoglund L, Josephson M, Wahlstedt K, Lampa E, Norbäck D. Qigong training and effects on stress,
neck-shoulder pain and life quality in a computerised office environment.. Complementary therapies
in clinical practice. 2011;17(1):54-57.
109. Smedje G, Mattsson M, Wålinder R. Comparing mixing and displacement ventilation in classrooms :
pupils' perception and health. Indoor Air. 2011;21(6):454-461.
110. Zhang X, Zhao Z, Nordquist T, Larsson L, Sebastian A, Norback D. A longitudinal study of sick
building syndrome among pupils in relation to microbial components in dust in schools in China.
Science of the Total Environment. 2011;409(24):5253-9.
111. Xu F, Zou Z, Yan S, Li F, Kan H, Norbäck D, et al. Fractional exhaled nitric oxide in relation to
asthma, allergic rhinitis, and atopic dermatitis in Chinese children. Journal of Asthma.
2011;48(10):1001-1006.
112. Chen CM, Thiering E, Doekes G, Zock JP, Bakolis I, Norbäck D, Sunyer J, Villani S, Verlato G,
Täubel M, Jarvis D, heinrich J. Geographic variation and the determinants of domestic endotoxin
levels in mattress dust in Europe. Indoor Air 2011 Sept 12 (epubl ahead of print)
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113. Zhang X, Zhao Z, Nordquist T, Norbäck D. The prevalence and incidence of sick building syndrome
in Chinese pupils in relation to the school environment: a two-year follow-up study. Indoor Air.
2011;21(6):462-471.
114. Runeson Roma, Wahlstedt Kurt, Norbäck D, Pilot Study of Personality Traits Assessed by the
Karolinska Scales of Personality (KSP) in Asthma, Atopy, and Rhinitis. Perceptual and Motor Skills,
2011;113,(3) 1-12
115. Smedje G, Lunden M, Gärtner L, Lundgren H, Lindgren T. Hearing status among aircraft maintenance
personnel in a commercial airline company. Noise & Health. 2011;13(54):364-370.
116. Simoni M, Cai G, Norbäck D, Annesi-Maesano I, Lavaud F, Sigsgaard T, et al. Total viable molds and
fungal DNA in classrooms and association with respiratory health and pulmonary function of
European schoolchildren. Pediatric Allergy and Immunology. 2011;22(8):843-852.
117. Wieslander G, Fabjan N, Vogrincic M, Kreft I, Janson C, Spetz-Nyström U, et al. Eating Buckwheat
Cookies Is Associated with the Reduction in Serum Levels of Myeloperoxidase and Cholesterol : A
Double Blind Crossover Study in Day-Care Centre Staffs. Tohoku journal of experimental medicine.
2011;225(2):123-130.
118. Hong NS, Kim KS, Lee IK, Lind PM, Lind L, Jacobs DR, Lee DH. The association between obesity
and mortality in the elderly differs by serum concentrations of persistent organic pollutants: a possible
explanation for the obesity paradox. Int J Obes (Lond). 2011 Sep 27 (epubl ahead of print).
Dissertations 2011
Anna Falkenberg: Sickness absence, self-rated health and social support. Result from longitudinal study in
Sweden
Leni Skoglund: Qigong as health promoting training in a computerised environment.
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Inflammation and autoimmunity
Inflammation and autoimmunity are important aspects of several diseases
of major importance for morbidity and mortality, including e.g.
cardiovascular diseases, autoimmune diseases, renal diseases,
inflammatory bowel disease and many skin diseases. The long Swedish
tradition of biobanking and the ready access to patient records, together
with the strong clinical and molecular expertise accumulated in Uppsala for
these areas, have resulted in both innovative approaches and several
successful projects. The goals for the independent research groups working
in this area are to develop new biomarkers for disease classification, define
targets for improved diagnostics, create new insights into disease
mechanisms and develop novel therapeutic strategies.
Autoimmunity
Olle Kämpe
Autoimmune disorders account for one third of morbidity and mortality in the Western world. It is thus of
great clinical interest to better understand the underlying factors and develop better diagnostic tools.
Using Addison's disease and Autoimmune Polyendocrine Syndrome type 1 (APS 1) as model disorders, our
research group has improved the diagnostic methods in autoimmune disorders and identified a number of
autoantigens, e.g. 21 hydroxylase in Addison's disease (Winqvist, Lancet 1992), tryptophan hydroxylase in
malabsorption associated with APS-1 (Ekwall, Lancet 1998), SOX10 in vitiligo (Hedstrand, J Biol Chem
2001), TDRD6 in lymphocytic hypophysitis (Bensing, Proc Natl Acad Sci USA 2009), and more recently
NALP5 in hypoparathyroidism (AliMohammadi, N Engl J Med 2008) and KCNRG in a severe form of
lung disease (AliMohammadi, Proc Natl Acad Sci USA 2009).
In recent years, the research has expanded to include epidemiologic investigations of endocrine
autoimmune disorders and genetic studies using the dog and the chicken as tools to better understand
human autoimmune disease.
Olle Kämpe was the principal coordinator of a recently finished EU-project (www.apeced.net) and is the
work-package coordinator of two ongoing EU-projects (www.euradrenal.org and www.eurolupa.org).
Immunological studies of target structures for T- and B-cells using Addison's
disease and APS I as models
Olle Kämpe, Mohammad AliMohammadi, Sophie Bensing, Åsa Hallgren, Håkan Hedstrand, Eva
Landgren, Thomas Nilsson, Filip Sköldberg
a) Identification of a pulmonary autoantigen
b) Identification of autoantigens in uvea and cornea
c) Identification of autoantigens in the kidney
d) Identification of autoantigens in paraneoplastic disorders
Epidemiology of autoimmune polyendocrine syndromes
Olle Kämpe, Sophie Bensing, Sigridur Björnsdottir, Beatrice Kennedy, Tove Fall, Katja Fall, Lena
Brandt, Nancy Pedersen, Paul Blomqvist, Anders Ekbom
a) Continuation of the nation-wide registry and biobank for Addison's disease
b) Risk of prematurity in children of mothers with Addison's disease
c) Risk of fractures in patients with autoimmune Addison's disease
71

d) Heritability between twins of different autoimmune disorders
e) Combining human and canine epidemiology to investigate if there are any relations between diseases in
the dog and in the dog-owner's family
Comparative genomics
Olle Kämpe, Kerstin Ahlgren, Göran Andersson, Leif Andersson, Örjan Carlborg, Lucy Crooks,
Olov Ekwall, Tove Fall, Katarina Sundberg, Åsa Hallgren, Anna Lobell, Hélène Hamlin, Susanne
Kerje, Åke Hedhammar, Kerstin Lindblad-Toh, Anna-Stina Sahlqvist, Katarina Tengvall and
others.
a) Linkage analysis in three chicken models for spontaneous autoimmune disorders, namely the OS-line
for thyroiditis, the Smyth line for vitiligo and the UCD 200-line for scleroderma.
b) GWAS for autoimmune disorders in different breeds of dogs, namely Addison's disease, Canine
diabetes mellitus, and lymphocytic thyroiditis
For more information:
http://www.medsci.uu.se/fogrupp/autoimmun/autoimmun.htm
Members of the group during 2011
Olle Kämpe, MD, PhD, professor
Anna Lobell, PhD, associate professor
Susanne Kerje, PhD
Sophie Bensing, MD, PhD
Mohammad AliMohammadi, MD, PhD
Håkan Hedstrand, MD, PhD
Eva Landgren, MD, PhD
Thomas Nilsson, MD, PhD
Funding
Swedish Research Council 1.6 MSEK
EurAdrenal EU fp7 0.8 MSEK
EuroLUPA EU fp7 0.5 MSEK
72
Åsa Hallgren, first research engineer
Anna-Stina Sahlqvist, PhD-student
Kerstin Ahlgren, PhD-student
Magnus Isacsson, MD, PhD-student
Frida Dahlin, PhD-student
Beatrice Kennedy, MD, PhD-student
Nils Landegren, MD, PhD-student
FORMAS Centers of Excellence 0.7 MSEK
Söderbergs Foundation 1.0 MSEK
ALF 1.8 MSEK
Publications 2009-2011
1. Alimohammadi, M., Dubois, N., Kampe, O. & Carel, J. C. Pulmonary autoimmunity is a feature of
autoimmune polyendocrine syndrome type 1 and is associated with reactivity to the bronchial
autoantigen KCNRG. Hormone Research 2009, 72, 33-34.
2. Alimohammadi, M. Dubois N, et al. Pulmonary autoimmunity as a feature of autoimmune
polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl
Acad Sci USA 2009, 106, 4396-4401.
3. Classen, J. F. et al. Lack of Evidence of Stimulatory Autoantibodies to Platelet-Derived Growth Factor
Receptor in Patients With Systemic Sclerosis. Arthritis Rheum-Us 2009, 60, 1137-1144.
4. Demoulin, J. B., Kampe, O. & Rorsman, F. Scleroderma. New England Journal of Medicine 2009,
361, 826-826.
5. Isaksson, M. et al. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. European
Journal of Immunology 2009, 39, 2925-2935.

6. Kampe, O. Introduction: Autoimmune polyendocrine syndrome type 1 (APS-1): a rare monogenic
disorder as a model to improve understanding of tolerance and autoimmunity. Journal of Internal
Medicine 2009, 265, 511-513.
7. Sahlqvist, A. S. et al. Identification of disease suseptibility genes in Hashimoto's thyroiditis using the
obese strain of chickens as a model. Hormone Research 2009, 72, 215-215.
8. Fetissov SO, Bensing S, Mulder J, et al. Autoantibodies in Autoimmune Polyglandular Syndrome
Type I Patients React with Major Brain Neurotransmitter SystemsJ Comp Neurol 2009; 513: 1-20
9. Bjornsdottir, S. Cnattingius S, Brandt L, Nordenström A, Ekbom A, Kämpe O, Bensing S. Addison's
Disease in Women Is a Risk Factor for an Adverse Pregnancy Outcome. Journal of Clinical
Endocrinology & Metabolism 2010, 95, 5249-5257.
10. Cervato, S. Morlin L, Albergoni MP, et al. AIRE gene mutations and autoantibodies to interferon
omega in patients with chronic hypoparathyroidism without APECED. Clinical Endocrinology 2010,
73, 630-636.
11. Dalin, F. et al. Identification of Retinal Autoantigens in a Young Patient with Osteosarcoma and a
Paraneoplastic Retinitis. Scandinavian Journal of Immunology 2010, 71, PS011.
12. Hallgren, A. et al. Immunoreactivity against kidney collecting ducts in patients with autoimmune
polyendocrine syndrome type 1 and systemic hypertension. Endocrine Journal 2010, 57, S641-S641.
13. Hellstrom, A. R. , Sundström E et al. Sex-linked barring in chickens is controlled by the CDKN2A/B
tumour suppressor locus. Pigment Cell & Melanoma Research 2010, 23, 521-530.
14. Kerje, S. et al. Identification of genes underlying systemic sclerosis in the UCD200 chicken. Clinical
and Experimental Rheumatology 2010, 28, S110-S110.
15. Oftedal, B. E. V., Wolff, A. S. B., Kampe, O. & Husebye, E. Nucleoporin 62, a Novel Autoantigen in
Patients with Autoimmune Polyendocrine Syndrome Type I (APS I). Scandinavian Journal of
Immunology 2010, 71, PS038.
16. Paquette, J. Varin DS, Hamelin CE, Hallgren Å, Kämpe O, Carel JC, Perheentupa J, Deal CL. Risk of
autoimmune diabetes in APECED: association with short alleles of the 5 ' insulin VNTR. Genes and
Immunity 2010, 11, 590-597.
17. Fall T, Wallberg A, Fall N, Ahlgren KM, Hedhammar Å, Hansson-Hamlin H, Lindblad-Toh K,
Andersson G, Kämpe O. Diabetes mellitus in elkhounds is associated with diestrus and pregnancy. J
Veterinary Internal Medicine 2010, 24: 1222-8.
18. Lima K, Abrahamsen T, Wolff A, Husebye E, Alimohammadi M, Kämpe O, et al.
Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome. European Journal of
Endocrinology. 2011;165(2):345-352.
19. Gunnarsson U, Kerje S, Bed'hom B, Sahlqvist A, Ekwall O, Tixier-Boichard M, et al. The Dark
brown plumage color in chickens is caused by an 8.3-kb deletion upstream of SOX10. Pigment Cell &
Melanoma Research. 2011;24(2):268-274.
20. Björnsdottir S, Sääf M, Bensing S, Kämpe O, Michaelsson K, Ludvigsson J. Risk of Hip Fracture in
Addison's Disease: A Population-based Cohort Study. Journal of Internal Medicine. 2011;270(2):187-
195.
21. Smith C, Oscarson M, Rönnblom L, Alimohammadi M, Perheentupa J, Husebye E, et al. TSGA10-A
Target for Autoantibodies in Autoimmune Polyendocrine Syndrome Type 1 and Systemic Lupus
Erythematosus. Scandinavian Journal of Immunology. 2011;73(2):147-153.
22. Ahlgren K, Moretti S, Lundgren B, Karlsson I, Åhlin E, Norling A, et al. Increased IL-17A secretion
in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model.
European Journal of Immunology. 2011;41(1):235-245.
23. Oftedal B, Kämpe O, Meager A, Ahlgren K, Lobell A, Husebye E, et al. Measuring autoantibodies
against IL17F and IL-22 in autoimmune polyendocrine syndrome type I by radioligand binding assay
using fusion proteins. Scandinavian Journal of Immunology. 2011;74(3):327-333.
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Reviews
1. Marta M, Meier UC, Lobell A. Regulation of encephalomyelitis by toll-like receptors. Autoimmun
Rev 2009; 8:506-9.
2. Husebye, E. S., Perheentupa, J., Rautemaa, R. & Kampe, O. Clinical manifestations and management
of patients with autoimmune polyendocrine syndrome type I. Journal of Internal Medicine 265, 514-
529, (2009).
3. Kämpe O. Introduction: Autoimmune polyendocrine syndrome type 1 (APS-1): a rare monogenic
disorder as a model to improve understanding of tolerance and autoimmunity.J Intern Med 2009: 265:
511-13.
4. Husebye ES, Kämpe O. Autoimmune polyendocrine syndrome type I.: Man Immunoendocrinology
2010, George S. Eisenbarth (ed.). Springer Verlag
Dissertations
Kerstin Ahlgren: Immunological Studies using Human and Canine Model Disorders.
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Biological structure and function
Anders Larsson
The researchers within the research group are working within the field of laboratory technology with
independent and collaborative projects. The research group explore several research areas.
Oral immunotherapy with IgY for the prevention of bacterial and viral infections
in humans
Elin Nilsson, Hans Kollberg, Per-Erik Wejåker, Johan Stålberg, Anders Larsson
Cystic fibrosis (CF) is a hereditary life-shortening disorder with repeated respiratory infections and
malnutrition as main clinical manifestations. Chronic lung infections with Pseudomonas aeruginosa (PA)
are major causes of morbidity and mortality. We have shown that we can reduce the number of
pseudomonas infections in CF patients by oral immunotherapy with anti-pseudomonas IgY. The study
includes more than 50.000 daily patient doses and is the world’s largest study with IgY. We have received
an orphan drug designation from EMEA. We also have initiated development of therapies against candida
albicans and ESBL-klebsiella. We have received a grant from Uppsala Bio to conduct a clinical study on
ESBL-carriers in Uppland and an EU grant (EUR 5.35 million over a 4 year period) for a clinical
multicenter study to prevent pseudomonas infections in CF patients.
Serum half-life of pituitary gonadotropins is decreased by sulfonation and
increased by sialylation in women
Leif Wide and Karin Eriksson
The gonadotropins are secreted from the human pituitary as spectra of isoforms with different degrees of
sulfonation and sialylation of the oligosaccharides, modifications suspected to determine their half-lives in
the circulation. We found that the decline in LH and FSH during GnRH receptor blockade is associated
with a decrease in sulfonated and increase in sialylated residues. The results indicate that both sulfonation
and sialylation of the gonadotropins regulate their half-life in the circulation. The rapid disappearance of
LH isoforms with two and three SO3-GalNAc residues suggests their removal by hepatic SO3-GalNAcreceptors
similar to those in rodents. Episodic secretion of spectra of isoforms with different half-lives is
expected to lead to continuous changes in gonadotropin isoform compositions in blood.
Studies of the role of prostasome in fertility and prostate cancer
Göran Ronquist, Lena Carlsson, Gunnar Ronquist, Anders Larsson
We discovered the prostasomes more than 30 years ago and named them. The prostasomes with their
complex membrane architecture have been assigned multifunctional features in the normal reproductive
process. What is more, evidence has accumulated pointing to a role of prostasomes in the propagation of
prostate cancer, based on the findings that also malignant prostate cells are able to produce and export
prostasomes to the extracellular environment. Furthermore, the abilities favouring prostate metastatic
tumour cell survival and motility in an otherwise hostile environment are upregulated in prostasomes
deriving from prostate cancer cells compared to prostasomes from normal secretory prostate cells. We
demonstrated, by using an extremely sensitive and specific method, that prostasomes can function as new
biomarkers for prostate cancer in blood plasma. Hence, our assay seemed to discriminate between blood
samples representing low Gleason scores (indolent prostate cancer) from those representing medium and
high Gleason scores (aggressive prostate cancer).
Studies of cystatin C and inflammation markers
Mats Flodin, Lars-Olof Hansson, Anders Larsson
Estimation of the glomerular filtration rate (eGFR) is essential for the diagnosis and monitoring of patients
with kidney disease and for correct dosage of drugs that are eliminated from the circulation by the kidneys.
Cystatin C has been shown in several studies to be superior to creatinine for estimation of eGFR. We have
shown that cystatin C-estimated GFR has a very good correlation with iohexol-estimated GFR both in
patients with slight and severe kidney disease. Cystatin C also has a low diurnal variability, which
75

facilitates the use of the marker. Cystatin C is also a promising risk marker for cardiovascular morbidity
and mortality and is significantly correlated with HbA1c, diabetes and inflammation in elderly males.
Members of the group during 2011
Anders Larsson, professor/consultant
Lena Carlsson, post doc
Karin Eriksson, laboratory engineer
Mats Flodin, laboratory engineer
Elin Nilsson, post doc
Funding
Impactt, FP7 2 750 kSEK
Uppsala Bio-X 1 500 kSEK
Uppsala Berzelii center 550 kSEK
Swedish Research Council 350 kSEK
76
Peter Ridefelt, associate professor/consultant
Gunnar Ronquist, professor em.
Göran Ronquist, post doc
Ingvar Ryden, post doc
Leif Wide, professor em
Publications 2009-2011
1. Ahlström K, Biber B, Aberg A, Waldenström A, Ronquist G, Abrahamsson P, Strandén P, Johansson
G, Haney MF. Metabolic responses in ischemic myocardium after inhalation of carbon monoxide.
Acta Anaesthesiol Scand. 2009 Sep;53(8):1036-42.
2. Ahlström T, Hagström E, Larsson A, Rudberg C, Lind L, Hellman P. Correlation between plasma
calcium, parathyroid hormone and the metabolic syndrome in a Community-Based Cohort of Men and
Women. Clin Endocrinol (Oxf). 2009 Nov;71(5):673-8.
3. Basu S, Helmersson J, Ärnlöv J, Larsson A. Low dietary intake of b-carotene, a-tocopherol and
ascorbic acid is associated with increased inflammatory and oxidative stress status in a Swedish
cohort. Br J Nutr. 2009 Jun;101(12):1775-82.
4. Bolin, M, Wiberg-Itzel W, Wikström, A-K, Goop M, Larsson A, Olovsson M, Åkerud H.
Angiopoietin-1/Angiopoietin-2 ratio as a predictive biomarker for preeclampsia. Am J Hypertens.
2009;22(8):891-5.
5. Bourlev V, Iljasova N, Adamyan L, Larsson A, Olovsson M. Signs of reduced angiogenic activity
after surgical removal of deeply infiltrating endometriosis. Fertil Steril. 2009 Mar 24.
6. Branth S, Hambraeus L, Piehl-Aulin K, Essén-Gustavsson B, Akerfeldt T, Olsson R, Stridsberg M,
Ronquist G. Metabolic stress-like condition can be induced by prolonged strenuous exercise in
athletes. Ups J Med Sci. 2009;114(1):12-25.
7. Byström P, Björkegren K, Larsson A, Johansson L, Berglund Å. Serum Vitamin B12 and Folate status
among patients with chemotherapy treatment for advanced colorectal cancer. Ups J Med Sci.
2009;114(3):160-4.
8. Carlsson L, Lindman H, Larsson A. Thymidine kinase 1 peptide in serum from patients with breast
cancer. Ups J Med Sci. 2009;114(2):116-20.
9. Carlsson M, Lipcsey M, Larsson A, Tano E, Rubertsson S, Eriksson M, Sjölin J. Inflammatory and
circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic
shock - A model of endotoxin elimination. Crit Care Med. 2009 Apr;37(4):1537-40.
10. Flodin M, Larsson A. Performance evaluation of a particle-enhanced turbidimetric cystatin C assay on
the Abbott Ci8200 analyzer. Clin Biochem. 2009 Jun;42(9):873-6.

11. Gustafsson J, Gunnarsson I, Börjesson O, Pettersson S, Möller S, Fei GZ, Elvin K, Hansson LO,
Lundberg I, Larsson A, Svenungsson E. Predictors of the first arterial event in patients with Systemic
Lupus Erythematosus. Arthritis Research & Therapy 2009, 11:R186 [Epub ahead of print].
12. Kårehed , Wikström A-K, Olsson T, Larsson A, Olovsson M, Åkerud H. Fibrinogen and histidine-rich
glycoprotein in early-onset preeclampsia. Acta Obstet Gynecol Scand. 2010 Jan;89(1):131-139.
13. Lannergard A, Viberg A, Cars O, Sandström M, Larsson A. The time course of the biomarkers serum
amyloid A (SAA), C-reactive protein (CRP), interleukin (IL)-6 and temperature during treatment with
cefuroxime. Scand J Infect Dis. 2009;41(9):663-71.
14. Larsson A. Mikroalbuminuri. Blodtrycket 2009;25(1):17-20.
15. Larsson A. Kreatinin, GFR, Cockcroft-Gault och MDRD. Vad är det egentligen vi mäter? Vaskulär
Medicin, 2009;25(3):127-129.
16. Lind L, Andersson J, Larsson A, Sandhagen B. Shear stress in the common carotid artery is related to
both intima-media thickness and echogenecity. Clin Hemorheol Microcirc. 2009;43(4):299-308.
17. Lind L, Larsson A, Teerlink T. L-arginine is related to endothelium-dependent vasodilation in
resistance and conduit arteries in divergent ways - The Prospective Investigation of the Vasculature in
Uppsala Seniors (PIVUS) study, Atherosclerosis. 2009 Apr;203(2):544-9.
18. Lind L, Wallentin L, Kempf T, Tapken H, Quint A, Lindahl B, Olofsson S, Venge P, Larsson A,
Hulthe J, Elmgren A, Wollert KC. Growth-differentiation factor-15 is an independent marker of
cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the
Vasculature in Uppsala Seniors (PIVUS) Study. Eur Heart J. 2009 Oct;30(19):2346-53.
19. Lipcsey M, Carlsson M, Larsson A, Algotsson L, Eriksson M, Lukinius A, Sjölin J. Effect of a single
dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour
porcine model. Crit Care Med. 2009 Oct;37(10):2782-90.
20. Marklund N, Sihver S, Hovda D, Långström B, Watanabe Y, Ronquist G, Bergström M, Hillered L.
Increased cerebral uptake of [18F]fluoro-deoxyglucose but not [1-14C]glucose early following
traumatic brain injury in rats. J Neurotrauma. 2009 Aug;26(8):1281-93.
21. Mindemark M, Larsson A. Long-term effects of an education program on the optimal use of clinical
chemistry testing in primary health care. Scand J Clin Lab Invest. 2009;69(4):481-6.
22. Mirza MA, Larsson A, Lind L, Larsson TE. Circulating fibroblast growth factor-23 is associated with
vascular dysfunction in the community. Atherosclerosis. 2009;67(2):560-67.
23. Mirza MA, Hansen T, Johansson L, Ahlström H, Larsson A, Lind L, Larsson TE. Relation between
circulating FGF23 and total body atherosclerosis in the community. Nephrol Dial Transplant. 2009
Oct;24(10):3125-31.
24. Mirza MA, Larsson A, Melhus H, Lind L, Larsson TE. Serum intact FGF23 Associate with Left
Ventricular Mass, Hypertrophy and Geometry in an Elderly Population. Atherosclerosis. 2009
Dec;207(2):546-51.
25. Rafik Hamad R, Larsson A, Pernow J, Bremme K, Eriksson MJ. Assessment of left ventricular
structure and function in preeclampsia by echocardiography and cardiovascular biomarkers. J
Hypertens. 2009 Nov;27(11):2257-64.
26. Ronquist G, Frithz G, Wang YH, Lindeborg T. Captopril may reduce biochemical (prostate specific
antigen) failure following radical prostatectomy for clinically localized prostate cancer. Scand J Urol
Nephrol 2009;43(1):32-36.
27. Ronquist G, Carlsson L, Ronquist G, Larsson A. Human Prostasomes Contain Chromosomal DNA,
Prostate. 2009 May 15;69(7):737-43.
28. Said Ahmed D, Larsson A, Hillered L, Wande B, Ryden I. Quantitative determination of cerebrospinal
fluid bilirubin on a high throughput chemistry analyzer. Clinical Laboratory. 2009;55(7-8):283-288.
77

29. Skalkidou A, Sylvén SM, Papadopoulos FC, Olovsson M, Larsson A, Sundström-Poromaa I. Risk of
postpartum depression in association with serum leptin and interleukin-6 levels at delivery: a nested
case-control study within the UPPSAT cohort. Psychoneuroendocrinology 2009;34:1329-1337.
30. Sköldenberg EG, Larsson A, Jakobson A, Hedborg F, Kogner P, Christofferson RH, Azarbayjani F.
The angiogenic growth factors HGF and VEGF in serum and plasma from neuroblastoma patients.
Anticancer Res. 2009;Aug;29(8):3311-9.
31. Sundelöf J, Larsson A, Rönnemaa E, Degerman-Gunnarsson M, Helmersson J, Basun H, Kilander L,
Lannfelt L, Basu S. Systemic Tocopherols and F2-isoprostanes and the Risk of Alzheimer´s disease,
Dementia and Mild Cognitive Impairment: A Prospective Population-Based Study. J Alzheimers Dis.
2009;18(1):71-8.
32. Sundelöf J, Larsson A, Rönnemaa E, Degerman-Gunnarsson M, Helmersson J, Basun H, Kilander L,
Lannfelt L, Basu S. Systemic inflammation and the Risk of Alzheimer´s disease, Dementia and Mild
Cognitive Impairment: A Prospective Population-Based Study. J Alzheimers Dis. 2009;18(1):79-87.
33. Waldenström A, Haney M, Biber B, Kavianipour M, Moritz T, Strandén P, Wikström G, Ronquist G.
Ischaemic preconditioning relates to decreasing levels of extracellular adenosine that may be energymetabolically
useful in myocardium at risk; an experimental study in the pig. Acta Physiol (Oxf) 2009
Dec 18. Epub ahead of print.
34. Wide L, Eriksson K, Sluss PM, Hall JE. Serum half-life of pituitary gonadotropins is decreased by
sulfonation and increased by sialylation in women. J Clin Endocrinol Metab. 2009 Mar;94(3):958-64.
35. Wikström A-K, Larsson A, Åkerud H, Olovsson M. Increased circulating levels of the antiangiogenic
factor endostatin in early-onset but not late-onset preeclampsia. Reprod Sci. 2009 Oct;16(10):995-
1000.
36. Wohlin M, Sundström J, Andrén B, Larsson A, Lind L. An echolucent carotid artery intima-media
complex is a new and independent predictor of mortality in an elderly male cohort. Atherosclerosis.
2009 Aug;205(2):486-91.
37. Xu, S., Zhao, L., Larsson, A. and Venge, P. Purification and characterization of a novel phospholipase
B (PBL) from human neutrophils. FEBS J. 2009 Jan;276(1):175-86.
38. Åberg AM, Ronquist G, Haney M, Waldenstrom A. Effects of some modulators on purine nucleoside
phosphorylase activity in myocardial tissue. Scand J Clin Lab Invest. 2009 Nov 23. [Epub ahead of
print]
39. Åkerud H, Ronquist G, Wiberg-Itzel E. Lactate distribution in culture medium of human myometrial
biopsies incubated under different conditions. Am J Physiol Endocrinol Metab. 2009
Dec;297(6):E1414-9.
40. Carlsson L, Lind L, Larsson A. Reference values for 27 clinical chemistry tests in 70 year old males
and females. Gerontology. 2010;56(3):259-65.
41. Wide L, Eriksson K, Sluss PM, Hall JE. The Common Genetic Variant of Luteinizing Hormone Has a
Longer Serum Half-Life than the Wild Type in Heterozygous Women. J Clin Endocrinol Metab. 2010
Jan;95(1):383-9
42. Lipcsey M, Olovsson M, Larsson E, Einarsson R, Qadhr GA, Sjölin J, Larsson A. The Brain Is a
Source of S100B Increase During Endotoxemia in the Pig. Anesth Analg. 2010 Jan;110(1):174-180.
43. Sahlén G, Nilsson O, Larsson A, Carlsson L, Norlén BJ, Ronquist G. Secretions from Seminal
Vesicles lack characteristic Markers for Prostasomes. 2010 May;115(2):107-12.
44. Ahlström K, Biber B, Aberg AM, Abrahamsson P, Johansson G, Ronquist G, Waldenström A, Haney
MF. Exogenous carbon monoxide does not affect cell membrane energy availability assessed by
sarcolemmal calcium fluxes during myocardial ischaemia-reperfusion in the pig. Eur J Anaesthesiol.
2010 Aug 31. [Epub ahead of print]
78

45. Andersson A, Ronquist G. Lessons from the recent Journal Citation Report figures. Ups J Med Sci.
2010 Aug;115(3):161-2.
46. Babiker AA, Magnusson PU, Ronquist G, Nilsson B, Ekdahl KN. Mapping pro- and antiangiogenic
factors on the surface of prostasomes of normal and malignant cell origin. Prostate. 2010 Jun
1;70(8):834-47.
47. Barbier CE, Lind L, Ahlström H, Larsson A, Johansson L.Apolipoprotein B/A-I ratio related to
visceral but not to subcutaneous adipose tissue in elderly Swedes. Atherosclerosis. 2010
Aug;211(2):656-9.
48. Berglund Å, Nygren P, Byström P, Johansson B, Larsson A, Einarsson R, Glimelius B. The clinical
utility of tumour marker measurements in advanced upper gastrointestinal cancer. Oncology Reports,
2010;24:1645-52.
49. Bourlev V, Iljasova N, Adamyan L, Larsson A, Olovsson M. Signs of reduced angiogenic activity
after surgical removal of deeply infiltrating endometriosis. Fertil Steril. 2010 Jun;94(1):52-7. Lipcsey
M, Olovsson M, Larsson E, Einarsson R, Qadhr GA, Sjölin J, Larsson A. The Brain Is a Source of
S100B Increase During Endotoxemia in the Pig. Anesth Analg. 2010 Jan;110(1):174-180.
50. Carlsson L, Lind L, Larsson A. Reference values for 27 clinical chemistry tests in 70 year old males
and females. Gerontology. 2010;56(3):259-65.
51. Carlsson L, Ronquist G, Ronquist G, Egberg N, Eliasson R, Larsson A. Association of cystatin C to
prostasomes in human seminal plasma. Int J Androl. 2010 Jun 28. [Epub ahead of print].
52. Dahlin A, Wetterhall M, Caldwell K, Larsson A, Bergquist J, Hillered L, Hjort K. Methodological
aspects on microdialysis protein sampling and quantification in biological fluids – An in vitro study on
human ventricular CSF. Anal Chem. 2010 Jun 1;82(11):4376-85.
53. Degerman Gunnarsson M, Lindau M, Wall A, Blennow K, Darreh-Shori T, Nordberg A, Larsson A,
Lannfelt L, Basun H, Kilander L. PET Pittsburgh Compound-B (PIB) and Alzheimer biomarkers: a
one-year follow-up study. Dement Geriatr Cogn Disord. 2010 Mar 20;29(3):204-212.
54. Jobs E, Risérus U, Ingelsson E, Helmersson J, Nerpin E, Jobs M, Sundström J, Lind L, Larsson A,
Basu S, Ärnlöv J. Serum Cathepsin S is independently associated with serum C-reactive protein and
interleukin-6 in elderly men. J Clin Endocrinol Metab. 2010 Sep;95(9):4460-4.
55. Kenan N, Larsson A, Axelsson O, Helander A, Changes in transferrin glycosylation during pregnancy
may lead to false-positive results on carbohydrate-deficient transferrin (CDT) results when testing for
riskful alcohol consumption. Clin Chim Acta. 2010 Sep 23. [Epub ahead of print].
56. Kårehed , Wikström A-K, Olsson T, Larsson A, Olovsson M, Åkerud H. Fibrinogen and histidine-rich
glycoprotein in early-onset preeclampsia. Acta Obstet Gynecol Scand. 2010 Jan;89(1):131-139.
57. Larsson A, Palm M, Hansson L-O, Axelsson O. Cystatin C and Modification of Diet in Renal Disease
(MDRD) estimated glomerular filtration rate differ during normal pregnancy. Acta Obstet Gynecol
Scand. 2010 Jul;89(7):939-44.
58. Larsson A, Palm M, Helmersson J, Axelsson O. Pentraxin 3 values during normal pregnancy.
Inflammation. 2010 Sep 18. [Epub ahead of print].
59. Lipcsey M, Furubring M, Rubertsson S, Larsson A. The majority of Swedish intensive care patients
have reduced glomerular filtration rate measured by Cystatin C. Ups J Med Sci. 2010 Nov 11. [Epub
ahead of print]
60. Mindemark M, Larsson A. Longitudinal trends in laboratory test utilisation at a large tertiary care
university hospital in Sweden. Ups J Med Sci. 2010 Nov 11.
61. Mindemark M, Wernroth L, Larsson A.Costly regional variations in primary health care test
utilization in Sweden. Scand J Clin Lab Invest. 2010 Apr 19;70(3):164-70.
62. Ndjole AM, Bodolea C, Nilsen T, Gordh T, Flodin M, Larsson A. Determination of cerebrospinal
fluid cystatin C on Architect ci8200. J Immunol Methods. 2010 Aug 31;360(1-2):84-8.
79

63. Ridefelt P, Larsson A, Rehman, J, Axelsson J. Influences of sleep and the circadian rhythm on ironstatus
indices. Clin Biochem. 2010 Nov;43(16-17):1323-8.
64. Ronquist G, Larsson A, Ronquist G, Carlsson L. Proteomic analysis of prostate cancer metastasis –
derived prostasomes. Anticancer Res. 2010 Feb;30(2):285-90.
65. Sahlén G, Nilsson O, Larsson A, Carlsson L, Norlén BJ, Ronquist G. Biochemical and Ultrastructural
Findings in Secretions from Seminal Vesicles lack characteristic Markers for Prostasomes. Ups J Med
Sci. 2010 May;115(2):107-12.
66. Sundelöf J, Sundström J, Hansson O, Eriksdotter-Jönhagen M, Giedraitis V, Larsson A, Degerman-
Gunnarsson M, Ingelsson M, Minthon L, Blennow K, Kilander L, Basun H, Lannfelt L. Cystatin C
levels are positively correlated with both Abeta42 and Tau Levels in CSF in Persons with Alzheimer’s
Disease, Mild Cognitive Impairment, and Healthy Controls. J Alzheimers Dis. 2010 Jan 1;21(2):471-
8.
67. Sundelöf J, Sundström J, Hansson O, Eriksdotter-Jönhagen M, Giedraitis V, Larsson A, Degerman-
Gunnarsson M, Ingelsson M, Minthon L, Blennow K, Kilander L, Basun H, Lannfelt L. Higher
Cathepsin B Levels in Plasma in Alzheimer´s Disease Compared to Healthy Controls. J Alzheimers
Dis. 2010;22(4):1223-30.
68. Waldenström A, Haney M, Biber B, Kavianipour M, Moritz T, Strandén P, Wikström G, Ronquist G.
Ischaemic preconditioning is related to decreasing levels of extracellular adenosine that may be
metabolically useful in the at-risk myocardium: an experimental study in the pig. Acta Physiol (Oxf).
2010 May;199(1):1-9.
69. Wide L, Naessén T, Eriksson K. Effects of 17beta-oestradiol and norethisterone acetate on sulfonation
and sialylation of gonadotrophins in post-menopausal women. Ups J Med Sci. 2010 May;115(2):97-
106.
70. Wide L, Eriksson K, Sluss PM, Hall JE. The common genetic variant of luteinizing hormone has a
longer serum half-life than the wild type in heterozygous women. J Clin Endocrinol Metab. 2010
Jan;95(1):383-9.
71. Åberg AM, Ahlström K, Abrahamsson P, Waldenström A, Ronquist G, Hauck P, Johansson G, Biber
B, Haney M. Ischaemic pre-conditioning means an increased adenosine metabolism with decreased
glycolytic flow in ischaemic pig myocardium. Acta Anaesthesiol Scand. 2010 Nov;54(10):1257-64.
72. Åberg AM, Ronquist G, Haney M, Waldenstrom A.Effects of some modulators on purine nucleoside
phosphorylase activity in myocardial tissue. Scand J Clin Lab Invest. 2010 Feb;70(1):8-14.
73. Åkerfeldt T, Helmersson J, Larsson A. Postsurgical inflammatory response is not associated with
increased cystatin C values. Clin Biochem. 2010 September ;43(13-14):1138-40.
74. Åkerfeldt T, Larsson A. Pentraxin 3 increase is much less pronounced than CRP increase after surgical
procedures. Inflammation. 2010 Aug 6. [Epub ahead of print]
75. Ahlström K, Biber B, Åberg AM, Abrahamsson P, Johansson G, Ronquist G, Waldenström A, Haney
MF. Exogenous carbon monoxide does not affect cell membrane energy availability assessed by
sarcolemmal calcium fluxes during myocardial ischaemia-reperfusion in the pig. Eur J Anaesthesiol.
2011 May;28(5):356-62.
76. Arinell K, Christensen K, Blanc S, Larsson A, Fröbert O. Effect of prolonged standardized bed rest on
cystatin C and other markers of cardiovascular risk. BMC Physiol. 2011 Dec 9;11(1):17.
77. Basu S, Zethelius B, Helmersson J, Berne C, Larsson A, Ärnlöv J. Cytokine-mediated inflammation is
independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a
community-based cohort of elderly men. Int J Clin Exp Med 2011;4(2):164-168.
78. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Sundström Poromaa I. Androgen levels,
insulin sensitivity, and early insulin response in women with polycystic ovary syndrome: a long-term
follow-up study. Fertil Steril. 2011 Mar 1;95(3):1146-8.
80

79. Carlsson L, Ronquist KG, Ronquist G, Egberg N, Eliasson R, Larsson A. Association of cystatin C to
prostasomes in human seminal plasma. Int J Androl. 2011 Aug;34(4):363-8.
80. Hansson J, Vasan RS, Ärnlöv J, Ingelsson E, Lind L, Larsson A, Michaelsson K, Sundström J.
Biomarkers of Extracellular Matrix Metabolism (MMP-9 and TIMP-1) and Risk of Stroke,
Myocardial Infarction, and Cause-Specific Mortality: Cohort Study. PLoS ONE, 2011;6(1):e16185.
81. Hansson LO, Flodin M, Larsson A, Althaus H, Blirup-Jensen S, Schmidt C, Zeger I, Lindström V,
Grubb A. The first harmonization step on cystatin C, with the aim to introduce the first ERM-
DA471/IFCC cystatin C calibrator and one worldwide company-independent EGFR equation. Clin
Chem Lab Med. 2011;49:557.
82. Hudecova M, Holte J, Olovsson M, Stridsberg M, Larsson A, Berglund L, Berne C, Sundström
Poromaa I. Prevalence of the metabolic syndrome in women with a previous diagnosis of polycystic
ovary syndrome - a long term follow-up. Fertil Steril. 2011 Nov;96(5):1271-4.
83. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Sundström Poromaa I. Androgen levels,
insulin sensitivity, and early insulin response in women with polycystic ovary syndrome: a long-term
follow-up study. Fertil Steril. 2011 Mar 1;95(3):1146-8.
84. Hudecova M, Holte J, Olovsson M, Stridsberg M, Larsson A, Berglund L, Berne C, Sundström
Poromaa I. Diabetes and impaired glucose tolerance in patients with polycystic ovary syndrome - a
long term follow-up. Hum Reprod. 2011 Jun;26(6):1462-8.
85. Jobs E, Ingelsson E, Risérus U, Nerpin E, Jobs M, Sundström J, Basu S, Larsson A, Lind L, Ärnlöv J.
Serum cathepsin S and the risk for mortality. JAMA. 2011 Sep 14;306(10):1113-21.
86. Kenan N, Larsson A, Axelsson O, Helander A, Changes in transferrin glycosylation during pregnancy
may lead to false-positive results on carbohydrate-deficient transferrin (CDT) results when testing for
riskful alcohol consumption. Clin Chim Acta. 2011 Jan 14;412(1-2):129-33.
87. Larsson A. What can we learn from studies on regional differences in the use of laboratory tests? Ups
J Med Sci. 2011 Nov;116(4):225-6.
88. Larsson A. Creatinine and cystatin C. There is a lack of studies that compare endogenous and
exogenous GFR markers in ICU patients. Ups J Med Sci. 2011 Aug;116(3):223. IF 0.73.
89. Larsson A, Palm M, Helmersson J, Axelsson O. Pentraxin 3 values during normal pregnancy.
Inflammation. 2011;34(5):448-51.
90. Larsson A, Hansson L-O, Flodin M, Katz R, Shlipak M. Calibration of the Siemens cystatin C
immunoassay has changed over time. Clin Chem. 2011 May;57(5):777-8.
91. Lind L, Berglund L, Larsson A, Sundström J. Endothelial Function in Resistance and Conduit Arteries
and 5-year Risk of Cardiovascular Disease. Circulation. 2011 Apr 12;123(14):1545-51.
92. Lipcsey M, Furubring M, Rubertsson S, Larsson A. The majority of Swedish intensive care patients
have reduced glomerular filtration rate measured by Cystatin C. Ups J Med Sci. 2011 Mar;116(1):39-
46.
93. Miles EA, Noakes PS, Kremmyda LS, Vlachava M, Diaper ND, Rosenlund G, Urwin H, Yaqoob P,
Rossary A, Farges MC, Vasson MP, Liaset B, Frøyland L, Helmersson J, Basu S, Garcia E, Olza J,
Mesa MD, Aguilera CM, Gil A, Robinson SM, Inskip HM, Godfrey KM, Calder PC. The Salmon in
Pregnancy Study: study design, subject characteristics, maternal fish and marine n-3 fatty acid intake,
and marine n-3 fatty acid status in maternal and umbilical cord blood. Am J Clin Nutr. 2011 Dec;94(6
Suppl):1986S-1992S.
94. Mindemark M, Larsson A. Longitudinal trends in laboratory test utilisation at a large tertiary care
university hospital in Sweden. Ups J Med Sci. 2011 Mar;116(1):34-8.
95. Mindemark M, Larsson A. Ruling out IBD: Estimation of the possible economic effects of preendoscopic
screening with F-calprotectin. Clin Biochem. 2011 Oct 26. [Epub ahead of print]
81

96. Nerpin E, Ingelsson E, Risérus U, Ingelsson E. Sundström J, Larsson A, Jobs E, Jobs M, Hallan S,
Zethelius B, Berglund L, Basu S, Ärnlov J. The combined contribution of albuminuria and glomerular
filtration rate to the prediction of cardiovascular mortality in the community. Nephrol Dial Transplant.
2011 Sep;26(9):2820-7.
97. Nitsch D, Sandling J, Byberg L, Larsson A, Tuvemo T, Syvänen AC, Koupil I, Leon DA. Foetal,
developmental and parental influences on childhood cystatin C in a non-clinical population sample of
children. The Uppsala Family Study. Am J Kidney Dis. 2011;57(6):863-872.
98. Nylander M, Ramström S, Osman A, Åklint E, Larsson A, Lindahl TL. The role of thrombin receptors
PAR1 and PAR4 for PAI-1 storage, synthesis and secretion by human platelets. Thromb Res. 2012 Jan
25. [Epub ahead of print]
99. Palm M, Basu S, Larsson A, Wernroth L, Åkerud H, Axelsson O. A longitudinal study of plasma
levels of Soluble fms-like tyrosine kinase 1 (sFlt1), Placental growth factor (PlGF), sFlt1:PlGF ratio
and Vascular endothelial growth factor (VEGF-A) in normal pregnancy. Acta Obstet Gynecol Scand.
2011 Nov;90(11):1244-51.
100. Ridefelt P, Axelsson J, Larsson A. Diurnal variability of calcium during normal sleep and after an
acute shift of sleep. Clin Chem Lab Med. 2011 Sep 29. [Epub ahead of print].
101. Ronquist G. Prostasomes are mediators of intercellular communication: from basic research to clinical
implications. J Intern Med. 2011 Nov 24.
102. Ronquist KG, Larsson A, Ronquist G, Isaksson A, Hreinsson J, Carlsson L, Stavreus-Evers A.
Prostasomal DNA characterization and transfer into human sperm. Mol Reprod Dev. 2011
Jul;78(7):467-76.
103. Ryden I, Lind L, Larsson A. Reference values for 75-year-old males and females for thirty frequently
used laboratory markers. Ups J Med Sci. 2012 Feb 3. [Epub ahead of print]
104. Shlipak MG, Weekley CC, Li Y, Hansson L-O, Larsson A, Whooley M. Comparison of
Cardiovascular Prognosis by Three Serum Cystatin C Methods in the Heart and Soul Study. Clin
Chem. 2011 May;57(5):737-45.
105. Tavoosidana G, Ronquist G, Darmanis S, Carlsson L, Wu D, Conze T, Ek P, Semjonow A, Eltze E,
Larsson A, Landegren U, Kamali-Moghaddam M. Prostasomes assessed in human blood plasma are
biomarkers predicting Gleason score in prostatectomy specimens. Proc Natl Acad Sci U S A. 2011
May 24;108(21):8809-14.
106. Tegler LT, Nonglaton G, Büttner F, Caldwell K, Christopeit T, Danielson UH, Fromell K, Gossas T,
Larsson A, Longati P, Norberg T, Ramapanicker R, Rydberg J, Baltzer L. Powerful Protein Binders
from Designed Polypeptides and Small Organic Molecules-A General Concept for Protein
Recognition. Angew Chem Int Ed Engl. 2011 Feb 18;50(8):1823-7.
107. Åkerfeldt T, Larsson A. Pentraxin 3 increase is much less pronounced than CRP increase after surgical
procedures. Inflammation. 2011;34(5):367-70.
108. Åkerfeldt T, Larsson A. Postsurgical inflammation is associated with increased cathepsin B and
decreased cathepsin S concentrations in the circulation. Scand J Clin Lab Invest. 2011 May;71(3):203-
7.
82

Coagulation and Inflammation Science
Agneta Siegbahn
Cells within arteriosclerotic tissue express high levels of tissue factor (TF), the principal activator of blood
coagulation. Uncontrolled activation of the coagulation process following plaque rupture with assembly of
the TF/FVIIa complex on cellular surfaces leads to fast thrombus formation eventually with a total
occlusion of the vessel and myocardial infarction. Circulating procoagulant cellular aggregates and
microparticles contribute to the systemic responses in this syndrome. TF/FVIIa also supports several noncoagulant
functions, including cell migration, apoptosis and inflammation by activation of intracellular
pathways. The molecular mechanisms leading to activation of these path-ways and the biological
significance remain elusive. Our research focuses on characterization of TF expression and procoagulant
activity, and signalling mechanisms to find ways for pharmacological interventions and possible defects in
signalling as a mechanism of cardiovascular disease. The research group is furthermore engaged in
genomic and proteomic analyses and functional studies in a number of global clinical trials in acute
coronary syndromes and arterial fibrillation using the new generation of antithrombotic and antiplatelet
drugs. The underlying theme of our research is thus the integrated approach from molecular basic science
to patients treatment, ultimately personalized.
TF expression and procoagulant activity
Individual variations of TF expression and activity in monocytes have been established, but still little is
known of cellular and genetic factors regulating the magnitudes of TF expression and activity. We
identified the novel 5466 A>G SNP in the TF gene, coding for increased TF expression and activity in
monocytes. This SNP was subsequently shown to be associated with myocardial infarct and cardiovascular
death in acute coronary syndrome. Very recently, thrombin formation following vascular injury and
thrombin-lowering effect of statins in patients with CAD were found to be genetically determined by the
TF 5466A>G polymorphism. We are continuing our studies how the tissue factor gene is regulated on the
molecular level. The ultimate goal being to identify novel mechanisms, genetic, epigenetic and
microRNAs, governing tissue factor gene regulation.
Microparticles; methods and biological functions
Upon activation platelets, leukocytes and endothelial cells form MPs. Circulating platelet MPs have been
found in inflammatory diseases and are related to the severity of disease. We have during the year
developed a new flow cytometry method to calculate the amount of MPs with different cellular origin in
whole blood. The new method is superior to earlier used methods, and is now implemented in a number of
new clinical studies in patients with CAD and pulmonary arterial hypertension. Characterization of the
biological effects induced by purified platelet MPs upon interaction with a number of human cells and
whether new antiplatelet/antithrombotic drugs can interfere with this interaction are a subject of our
ongoing experimental studies.
TF non-coagulant, signalling roles
The TF-induced signalling events eventually changes cell fate and behaviour, rendering cells and tissues
pro-migratory, resistant to apoptosis and proliferative. This experimental work is paralleled by clinical
observations of increased TF expression in conditions such as metastatic cancers and the atherosclerotic
plaque, where cell survival, migration and proliferation are paramount to the pathological process. We
recently reported that TF/FVIIa induces the transactivation of the PDGFRβ, and thereby identified a new
signalling pathway involved in cell migration. We continue to investigate how TF interacts with PDGFRβ
and other growth factor receptors. We hypothesize that several of the non-haemostatic functions of TF are
dependent on growth factor activity and aim to clarify what role growth factor receptor signalling play in
these functions of TF.
During the year we have also focused on I) connections between TF cytoplasmic domain and the
cytoskeleton and II) mechanism involved in TF-dependent antiapoptotic effects. Using a peptide
83

microarray we have characterized the interaction of TF with the actin-crosslinking protein Filamin A, and
shown for the first time that TF-signalling reduces activation of caspase-8 through a reduction of the “death
associated protein kinase 1 (DAPK1).
Identification of biomarkers in atherothromboembolic diseases
We have established individual responses to drug treatment with an oral thrombin inhibitor (DTI) and that
treatment can be monitored in ACS by measurements of biomarkers, such as D-dimer. We now report a
persistent elevation of platelet activity in a myocardial infarction population after the cessation of the acute
antithrombotic treatment and that the addition of an oral DTI diminishes the platelet activity. In contrast,
long-term treatment with a DTI increased several markers of inflammation.
Biobanks from international prospective clinical trials have been established at the UCR-laboratory during
the last 2 years. DNA and plasma samples from patient materials (including around 70.000 patients) in
acute and chronic CAD and AF have been accumulated from a large number of trials, e.g. PLATO - on new
P2Y12 inhibitor ticagrelor in ACS (n=18000), and ARISTOTLE - on new oral factor Xa inhibitor apixaban
in AF (n=18000). We have been actively involved in the design of the substudy programs of biomarkers,
genome wide association studies and the analyses of the plasma samples, performed at the UCR-laboratory
and to translate candidate genes and proteins into functional studies. Based on these studies we will
establish sensitive and rapid tests for clinical purposes.
Collaborations with several groups within the SciLife laboratory have started during the year. Plasma
samples from our well-characterized patients with CAD are used in a new plasma proteomic multiplex
assay and with Professor Ulf Landegren using proximity ligation assay. The purpose is to identify new
biomarkers and establish methods with higher sensitivity to be used in the understanding of
pathophysiologic mechanisms, diagnosis and for estimation of prognosis and treatment efficacy in these
diseases.
Members of the group during 2011
Agneta Siegbahn, Professor, MD, PhD
Dariush Mokhtari, PhD
Mikael Åberg, PhD
Christina Christersson, MD, PhD
Lena Kask, PhD
Funding
Agneta Siegbahn
Heart and Lung Foundation: 2.2 MSEK
Swedish research council: 1.4 MSEK
ALF grant: 800 kSEK
Industrial grants 500 kSEK
Christina Christersson
ALF grant: 100 kSEK
Local funds: 110 kSEK
84
Jenny Alfredsson, PhD
Åsa Thulin, PhD
Oskar Eriksson,PhD-student
Helena Vretman, Research engineer
Dariush Mokhtari
Linné foundation: 100 kSEK
SSMF: 100 kSEK
The Swedish Society of Medicine:120 kSEK
Byggmästare Engkvist stiftelse 700 kSEK
Mikael Åberg
Selander foundation: 110 kSEk

Publications 2009-2011
1. Varenhorst C, James S, Erlinge D,. Braun OÖ, Brandt JT,. Winters KJ,. Jakubowski JA, Olofsson S,
Wallentin L, Siegbahn A. Assessment of P2Y12 inhibition with the point-of-care device VerifyNow
P2Y12 in patients treated with prasugrel or clopidogrel co-administered with aspirin. Am Heart
J.2009 Mar;157(3):562e1-9.
2. Varenhorst C, James S, Erlinge D, Brandt JT, Braun OÖ, Man M, Siegbahn A, Walker J, Wallentin L,
Winters KJ, Close SL. Genetic variation of CYP2C19 affects both pharmacokinetic and
pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary
artery disease. Eur Heart J. 2009 Jul;30(14):1744-52.
3. Alström U, Granath F, Oldgren J, Ståhle E, Tydén H, Siegbahn A. Platelet inhibition assessed with
VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery.Thromb Res.
2009 Nov;124(5):572-7.
4. Thulin A, Ringvall M, Dimberg A, Kårehed K, Väisänen T, Väisänen MR, Hamad O, Wang J,
Bjerkvig R, Nilsson B, Pihlajaniemi T, Akerud H, Pietras K, Jahnen-Dechent W, Siegbahn A, Olsson
AK. Activated platelets provide a functional microenvironment for the antiangiogenic fragment of
histidine-rich glycoprotein. Mol Cancer Res. 2009 Nov;7(11):1792-802.
5. Darmanis S, Yuan Nong R, Hammond M, Gu J, Alderborn A, Vänelid J, Siegbahn A, Gustafsdottir S,
Ericsson O, Landegren U, Kamali-Moghaddam M. Sensitive plasma protein analysis by microparticlebased
proximity ligation assays.Mol Cell Proteomics. 2010 Feb;9(2):327-35.
6. Eggers KM, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Jantzen F, Peter T, Allhoff T, Siegbahn
A, Venge P, Wollert KC, Wallentin L. Growth-differentiation factor-15 for long-term risk prediction
in patients stabilized after an episode of non-ST-segment-elevation acute coronary syndrome.Circ
Cardiovasc Genet. 2010 Feb 1;3(1):88-96.
7. Christersson C, Johnell M, Siegbahn A. The influence of direct thrombin inhibitors on the formation
of platelet-leukocyte aggregates and tissue factor expression. Thromb Res. 2010 Oct;126(4):e327-33.
8. Uronen RL, Lundmark P, Orho-Melander M, Jauhiainen M, Larsson K, Siegbahn A, Wallentin L,
Zethelius B, Melander O, Syvänen AC, Ikonen E. Niemann-Pick C1 modulates hepatic triglyceride
metabolism and its genetic variation contributes to serum triglyceride levels. Arterioscler Thromb
Vasc Biol. 2010 Aug;30(8):1614-20.
9. Åberg M, Johnell M, Wickström M, Siegbahn A. Tissue Factor/ FVIIa prevents the extrinsic pathway
of apoptosis by regulation of the tumor suppressor Death-Associated Protein Kinase 1 (DAPK1).
Thromb Res. 2010 Dec 16.
10. Christina Christersson, Jonas Oldgren, Lars Wallentin, Agneta Siegbahn. Treatment with an Oral
Direct Thrombin Inhibitor Diminishes Platelet Activity but Increases Markers of Inflammation in
Patients with Myocardial Infarction. J Intern Med. 2011, Jan 22. Ringvall M, Thulin Å, Lei Z, Jahnen-
Dechent W, Siegbahn A and Olsson A-K. Enhanced platelet activation mediates the accelerated
angiogenic switch in HRG-deficient mice. PLOS 1, 2011, Jan 17;6(1):e14526
11. Oldgren J, Budaj A, Granger C, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in
patients with acute coronary syndromes on dual antiplatelet therapy : a randomized, double-blind,
phase II trial. European Heart Journal. 2011;32(22):2781-2789.
12. Darmanis S, Nong R, Vänelid J, Siegbahn A, Ericsson O, Fredriksson S, et al. ProteinSeq : highperformance
proteomic analyses by proximity ligation and next generation sequencing. PLoS ONE.
2011;6(9):e25583-.
13. Lind L, Siegbahn A, Ingelsson E, Sundström J, Arnlöv J. A detailed cardiovascular characterization of
obesity without the metabolic syndrome. Arteriosclerosis, Thrombosis and Vascular Biology.
2011;31(8):e27-e34.
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14. Åberg M, Johnell M, Wickström M, Siegbahn A. Tissue Factor/ FVIIa prevents the extrinsic pathway
of apoptosis by regulation of the tumor suppressor Death-Associated Protein Kinase 1 (DAPK1).
Thrombosis Research. 2011;127(2):141-148.
15. Varenhorst C, Koul S, Erlinge D, Lagerqvist B, Siegbahn A, Wallentin L, et al. Relationship between
Clopidogrel-Induced Platelet P2Y12 Inhibition and Stent Thrombosis or Myocardial Infarction after
Percutaneous Coronary Intervention : A Case-Control Study. American Heart Journal.
2011;162(2):363-371.
16. Ringvall M, Thulin Å, Zhang L, Cedervall J, Tsuchida-Straeten N, Jahnen-Dechent W, et al.
Enhanced Platelet Activation Mediates the Accelerated Angiogenic Switch in Mice Lacking Histidine-
Rich Glycoprotein. PLoS ONE. 2011;6(1):e14526-.
17. Christersson C, Oldgren J, Wallentin L, Siegbahn A. Treatment with an Oral Direct Thrombin
Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with
Myocardial Infarction.. Journal of Internal Medicine. 2011;270(3):215-223.
Reviews and bookchapters
1. Wallentin L., Lindahl B., Siegbahn A. Unstable coronary artery disease. International Textbook of
Cardiology. Mosby International Limited, London, England. Third edition (major revision from
second edition). 2009; 367-387.
2. Siegbahn A. Pathogenesis of acute coronary syndromes; coagulation and fibrinolysis, mechanisms of
thrombus formation. In Akut kranskärlssjukdom. ( Major revision of previous chapter). Ed. Wallentin
L. Fjärde upplagan. CASAB 2010.
3. Patrono C, Andreotti F, Arnesen H, Badimon L, Baigent C, Collet J, et al. Antiplatelet agents for the
treatment and prevention of atherothrombosis. European Heart Journal. 2011; 32(23): 2922-32.
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Dermatology and Venereology
Anders Vahlquist
Our research embraces several projects related to the biology and treatment of skin diseases, especially
keratinisation disorders. Epithelial differentiation is a complex process, which can be modulated by vitamin
A and its analogs (retinoids), also used therapeutically in keratinizing disorders. We try to identify new
gene mutations and pathogenetic mechanisms underlying several types of congenital keratinizing disorders,
such as ichthyosis and epidermolysis bullosa (EB). The skin barrier failure in these disorders, as well as in
atopic dermatitis, is studied aiming at finding new therapies.
The inflammatory process in psoriasis and palmo-plantar pustulosis (PPP) is investigated in vivo and in
vitro. Experimental models have been established to discover new strategies for treating psoriasis based on
inhibition of EGF signalling. Clinical characteristics and serologic markers are also studied in autoimmune
disorders of the skin. The treatment of hyperhidrosis using botulinum toxin is also being developed.
During 2011 we have focused on the following projects;
Etiologies and new therapies for monogenetic epidermal diseases
Hans Törmä, Marie Virtanen, Berit Berne, Anders Vahlquist
New keratin mutations underlying various epidermolytic skin disorders are continuously searched for.
Immortalized cells from epidermolytic ichthyosis (EI) and EB patients have been established and
characterized in our lab. These cells are now used for screening of chemical libraries in the search novel
therapies using automated fluorescence microscopy. Compounds affecting keratin filament structure will be
tested in cell and organotypic cultures in vitro.
Using transgene mouse models for epidermolytic disorders (collaboration with Irwin McLean et al,
Dundee), we explore the effects of substances that in our cell culture experiments on keratinocytes have
shown the most promising results as stabilizers (chaperons) of mutated cytoskeleton. Provided these animal
experiments continue to show promising results on inducible EB/EI and no toxicity is observed, then a next
step will be to plan phase I trials in humans.
In other projects, the genetic causes of autosomal recessive congenital ichthyosis (ARCI) other rare
keratinisation disorders, which are currently diagnosed at the Genodermatosis Centre in Uppsala (a national
referral centre), are investigated. This has already resulted in new knowledge about the pathoetiology of
these diseases. The analyses are performed within the framework of a EU-sponsored network (GeneSkin).
In order to find new targets for treatment of ARCI and hyperkeratinisation, the interplay between known
ARCI-associated gene products is studied in patients´ skin and in siRNA knock-down keratinocytes
exposed to retinoids and other drug candidates.
The skin barrier function and mRNA expression profile is examined in vivo after topical application of
moisturizers with various compositions in patients with mutations in profilaggrin (atopic dermatitis and
ichthyosis vulgaris) or steroid sulfatase (X-linked ichthyosis). Huge differences in the expression of barrier
repair genes have been noted between the two types of ichthyosis, which may explain an association
between dermatitis and ichthyosis in the former case.
HER deregulation in psoriatic skin
Ola Rollman, Hans Törmä
Psoriatic skin displays chronic inflammation and hyperplasia associated with incomplete maturation of
epithelial cells. The initiating and driving forces in this disease are not fully understood although several
hallmarks of psoriatic skin suggest that aberrant cell signalling via human epidermal growth factor
receptors (HERs) may add to the characteristic phenotype. Gene and protein expression of HER members
and their ligands are investigated in diseased vs. normal skin using PCR, proximity ligation, Western blot
and IHC assays. These studies have shown that HER1-ligands are overexpressed while HER4 is markedly
87

downregulated in psoriatic plaques. Ongoing research focuses at more detailed mapping of epidermal
HER4 as potential target for antipsoriatic therapy.
Pathogenic mechanisms in palmo-plantar pustulosis
Eva Hagforsen
Palmo-plantar pustulosis (PPP) is a complex autoimmune disease precipated by smoking. PPP is
characterized by redness, scaling and pustules on the palms / soles. The disease mainly affects women who
smoke and are very resistant to treatment. Immunohistochemical studies are performed to understand the
inflammation in PPP, which mainly affects the outer portion of the sweat ducts (the acrosyringium).
Members of the group during 2011
Anders Vahlquist, MD, PhD, Professor
Hans Törmä, PhD, Associate professor
Berit Berne, MD, PhD, Professor
Eva Hagforsen, PhD, Researcher
Ola Rollman, MD, PhD, Associate professor
Carl Swartling, MD, PhD
Marie Virtanen, MD, PhD
Funding
Foundation of Ichthyosis and Related Skin Types 500 kSEK
Welander & Finsen funds (total) 925 kSEK
Psoriasis Foundation 150 kSEK
ALF (Vahlquist, Berne, Rollman) 1100 kSEK
Other funds 700 kSEK
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Anders Strand, MD, PhD
Mats Berg, MD, PhD
Hao Li, PhD-student
Torborg Hoppe, MD, PhD-student
Mattias Karlqvist, MD, PhD-student
Inger Pihl-Lundin, Research engineer
Mikael Lindberg, PhD, researcher
Publications 2009-2011
1. Pavez-Loriè E, Cools M, Borgers M, Wouters L, Shroot B, Hagforsen E, Törmä E, Vahlquist A.
Topical treatment with CYP26 inhibitor talarozole (R115866) dose dependently alters the expression
of retinoid-regulated genes in normal human epidermis. Br J Dermatol; 160: 26-36, 2009.
2. Pavez-Loriè E, Gånemo A, Borgers M, Wouters L, Blockhuys S, Van de Plassche L, Törmä H,
Vahlquist A. Expression of retinoid-regulated genes in lamellar ichthyosis vs. healthy control
epidermis: changes after oral treatment with Liarozole. Acta Derm Venereol; 89:12-20, 2009.
3. Gånemo A, Jagell S, Vahlquist A. Sjögren-Larsson Syndrome: A study of clinical symptoms and
dermatological treatment in 34 Swedish patients. Acta Derm Venereol; 89: 68-73, 2009.
4. Chamcheu JC, Pavez Loriè E, Akgul B, Bannbers E, Virtanen M, Gammon L, Moustakas A, Navsaria
H, Vahlquist A, Törmä H. Characterization of immortalized human epidermolysis bullosa simplex
(KRT5) cell lines: Trimethylamine N-oxide protects the keratin cytoskeleton against disruptive stress
conditions. J Derm Sci; 53: 198-206, 2009.
5. Pavez Loriè E, Li H, Vahlquist A, Törmä H. The involvement of cytochrome P450 (CYP) 26 in the
metabolism of retinoic acid in human epidermal epidermal keratinocytes. Biochim Biophys Acta
(Lipids); 1791:220-8, 2009.
6. Pavez-Loriè E, Chamcheu JC, Vahlquist A, Törmä H. Both all-trans retinoic acid and cytochrome
(CYP) 26 inhibitors affect the expression of vitamin A metabolising enzymes and retinoid biomarkers
in human organotypic epidermis. Arch Derm Research; 301: 475-85, 2009.

7. Klar J, Schweiger M, Zimmerman R, Zechner R, Li H, Törmä H, Vahlquist A, Bouadjar B, Dahl N,
Fischer J. Mutations in the fatty acid transport protein 4 gene cause the ichthyosis prematurity
syndrome. Am J Human Genet; 85:248-53, 2009.
8. Buraczewska I, Berne B, Lindberg M, Lodén M, Törmä H. Long-term treatment with moisturizers
affects the mRNA levels of genes involved in keratinocyte differentiation and desquamation. Arch
Dermatol Res; 301.175-81, 2009.
9. Wirén K, Nohlgård C, Nyberg F, Holm L, Svensson M, Johannesson A, Wallberg P, Berne B, Edlund
F, Lodén M. Treatment with a barrier-strengthening moisturizing cream delays relapse of atopic
dermatitis. A prospective and randomized controlled clinical trial. JEADV 23:1267-72, 2009.
10. Buraczewska I, Berne B, Lindberg M, Lodén M, Törmä H. Moisturizers change the mRNA expression
of enzymes synthesizing skin barrier lipids. Arch Dermatol Res; 301:587-9422, 2009.
11. Törmä H, Berne B. Sodium lauryl sulfate alters the mRNA expression of lipid-metabolizing enzymes
and PPAR-signaling in normal human skin in vivo. Exp Dermatol; 18:1010-5, 2009.
12. Skoog T, Elomaa O, Pasonen-Seppänen SM, Forsberg S, Ahokas K, Jeskanen L, Pärssinen J, Tiala I,
Rollman O, Lohi J, Saarialho-Kere U. Matrix metalloproteinase-21 expression is associated with
keratinocyte differentiation and upregulated by retinoic acid in HaCaT cells. J Invest Dermatol.
129:119-30, 2009
13. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, Haavik J, Husebye
ES, Gustafsson J, Rorsman F, Meloni A, Janson C, Vialettes B, Kajosaari M, Egner W, Sargur R,
Pontén F, Amoura Z, Grimfeld A, De Luca F, Betterle C, Perheentupa J, Kämpe O, Carel JC.
Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and
identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci; 106:4396-401, 2009.
14. Forsberg, Sofi (2009) Human epidermal growth factor receptors and biological effect of HER-directed
molecules on skin epithelialization. Digital comprehensive Summaries of Uppsala Dissertations from
the Faculty of Medicine 424, Department of Medical Sciences Uppsala University, Uppsala, pp.
62.2010
15. Chamcheu JC, Virtanen M, Navsaria H, Bowden PE, Vahlquist A, Törmä H Epidermolysis bullosa
simplex due to KRT5 mutations: mutation-related differences in cellular fragility and the protective
effects of trimethylamine N-oxide in cultured primary keratinocytes. Br J Dermatol; 162:980–989,
2010.
16. Dahlqvist, J, Klar, J, Tiwari, N, Schuster, J, Törmä, H, Pujol, R, van Steensel, M, Brinkhuijzen, T,
Gijezen, L, Chaves, A, Tadini, G, Vahlquist, A, Dahl, N. A single-nucleotide deletion in the POMP 5’
UTR causes a transcriptional switch and altered epidermal proteasome distribution in KLICK
genodermatosis. Am J Hum Genet 86, 596-603, 2010.
17. Karlsson T, Vahlquist A, Törmä H. Keratinocyte differentiation induced by calcium, phorbol ester or
interferon-gamma elicits distinct changes in the retinoid signalling pathways. J Dermatol Sci; 57:207-
213, 2010.
18. Ocaya P, Gidlöf A, Olofsson P, Törmä H, Sirsjö A. The CYP26 inhibitor R115866 increases retinoid
signalling in rat intimal smooth muscle cells. J Vasc Res; 48:23-30, 2010.
19. Sonkoly, E, Wei, T, Pavez Lorie, E, Suzuki, H, Kato, M, Törmä, H, Ståhle, M, Pivarcsi, A. Protein
kinase C-dependent upregulation of miR-203 induces the differentiation of human keratinocytes. J
Invest Dermatol; 130, 124-134, 2010.
20. Virtanen M, Sirsjö A, Vahlquist A, Törmä H. Keratins 2e and 4/13 in reconstituted human skin are
reciprocally regulated by retinoids, acting via the nuclear receptor RAR . Exp Dermatol; 19:674–681,
2010.
21. Oji V, Tadini G, Akiyama M, et al. Revised nomenclature and classification of inherited ichthyoses.
Results of the First Ichthyosis Consensus Conference in Sorèze 2009. J Am Acad Dermatol; 63, 607-
641, 2010.
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22. Vahlquist A, Bygum A, Gånemo A, Virtanen M, Hellström-Pigg M, Strauss G, et al. Genotypic and
clinical spectrum of self-improving collodion ichthyosis: ALOX12B, ALOXE3, and TGM1 mutations
in Scandinavian patients. J Invest Dermatol 130:438-443, 2010.
23. Vahlquist, A. Pleomorphic ichthyosis: proposed name for a heterogeneous group of congenital
ichthyoses with phenotypic shifting and mild residual scaling. Acta Derm Venereol. 90, 454-460,
2010.
24. Vahlquist, A. and Tasanen, K. Epidermolysis bullosa care in Scandinavia. Dermatol Clin; 28, 425-
427, 2010.
25. Forsberg, S. and Rollman, O. Re-epithelialization from human skin explant cultures is promoted by
ligand-activated HER3 receptor. J Dermatol Sci; 59, 7-15, 2010.
26. Swartling, C., Karlqvist, M., Hymnelius, K., Weis, J. and Vahlquist, A. Botulinum toxin in the
treatment of sweat-worsened foot problems in patients with epidermolysis bullosa and pachyonychia
congenita. Br J Dermatol; 163:1072-6, 2010.
27. Hagforsen E, Michaëlsson G, Stridsberg M. Normal and PPP-affected palmoplantar sweat gland
express neuroendocrine markers chromogranins and synaptophysin differently. Arch Dermatol Res;
302: 685-93, 2010.
28. Hagforsen, E., Hedstrand, H., Nyberg, F. and Michaëlsson, G. Novel findings of Langerhans cells and
interleukin-17 expression in relation to the acrosyringium and pustule in palmoplantar pustulosis. Br J
Dermatol. 163, 572-579, 2010.
29. Chamcheu, Jean Christopher. Disease-causing keratin mutations and cytoskeletal dysfunction in
human skin. In vitro models and new pharmacological strategies for treating epidermolytic
genodermatosis. Digital comprehensive Summaries of Uppsala Dissertations from the Faculty of
Medicine 564, Medical Sciences/Dermatology Uppsala University, Uppsala, pp. 85, 2010.
30. Murakami M, Hagforsen E, Morhenn V, Ishida-Yamamoto A, Iizuka H. Patients with palmoplantar
pustulosis have increased IL-17 and IL-22 levels both in the lesion and serum. Exp Dermatol.
2011;20:845-847.
31. Hagforsen E, Michaëlsson G, Stridsberg M. Somatostatin receptors are strongly expresssed in
palmoplantar sweat glands and ducts: studies of normal and palmoplantar pustulosis skin. Clin Exp
Dermatol. 2011;36:521-527.
32. Berg M, Lindberg M. Possible gender differences in the quality of life and choice of therapy in acne. J
Eur Acad DermatolVenereol. 2011;25:969-972.
33. Kuhn A, Wozniacka A, Szepietowski J, Glaeser R, Lehmann P, Haust M, et al. Photoprovocation in
Cutaneous Lupus Erythematosus : A Multicenter Study Evaluating a Standardized Protocol. J Invest
Dermatol. 2011;131:1622-1630.
34. Gustavsson I, Sanner K, Lindell M, Strand A, Olovsson M, Wikström I, et al. Type-specific detection
of high-risk human papillomavirus (HPV) in self-sampled cervicovaginal cells applied to FTA elute
cartridge. J Clin Virol. 2011;51:255-258.
35. Chamcheu J, Navsaria H, Pihl-Lundin I, Liovic M, Vahlquist A, Törmä H. Chemical Chaperones
Protect Epidermolysis Bullosa Simplex Keratinocytes from Heat Stress-Induced Keratin Aggregation :
Involvement of Heat Shock Proteins and MAP Kinases. J Invest Dermatol. 2011;131:1684-1691.
36. Rajpopat S, Moss C, Mellerio J, Vahlquist A, Gånemo A, Hellström-Pigg M, et al. Harlequin
Ichthyosis A Review of Clinical and Molecular Findings in 45 Cases. Arch Dermatol.
2011;147(6):681-686.
37. Winge M, Hoppe T, Liedén A, Nordenskjöld M, Vahlquist A, Wahlgren C, et al. Novel point
mutation in the STS gene in a patient with X-linked recessive ichthyosis. J Dermatol Sci.
2011;63(1):62-64.
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38. Wiegell S, Fabricius S, Stender I, Berne B, Kroon S, Andersen B, et al. A randomized, multicentre
study of directed daylight exposure times of 11/2 vs. 21/2 h in daylight-mediated photodynamic
therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and
scalp. Br J Dermatol. 2011;164:1083-1090.
39. Wilson N, Hansen C, Cardenas Perez M, Vahlquist A, Schwartz M, Smith F. Homozygosity of
dominant missense mutations in keratin 17 leads to alopecia in addition to severe pachyonychia
congenita. J Invest Dermatol. 2011;131(Suppl.1):S67-S67.
40. Ocaya P, Elmabsout A, Olofsson P, Törmä H, Gidlöf A, Sirsjö A. CYP26B1 Plays a Major Role in the
Regulation of All-trans-Retinoic Acid Metabolism and Signaling in Human Aortic Smooth Muscle
Cells. J Vascular Res. 2011;48(1):23-30.
41. Törmä H. Regulation of keratin expression by retinoids. Dermato-endocrinology. 2011;3:136-140.
42. Chamcheu J, Pihl-Lundin I, Eteti Mouyobo C, Gester T, Virtanen M, Moustakas A, et al.
Immortalized keratinocytes derived from patients with epidermolytic ichthyosis reproduce the disease
phenotype : A useful in vitro model for testing new treatments. Br J Dermatol. 2011;164:263-272.
43. Winge M, Hoppe T, Berne B, Vahlquist A, Nordenskjöld M, Bradley M, et al. Filaggrin genotype
determines functional and molecular alterations in skin of patients with atopic dermatitis and
ichthyosis vulgaris. PLoS ONE. 2011;6(12):e28254-.
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Gastroenterology and hepatology
Per M. Hellström
Research in gastroenterology and hepatology is focused on inflammatory reactions in the gastrointestinal
tract and liver. From a patient registry, special attention is given to inflammatory bowel disease (IBD;
Crohn’s disease, ulcerative colitis) and microscopic colitides (collagenous colitis, lymphocytic colitis) as
well as inflammatory liver disease and anemia as complications of disease. Etiopathogenic perspectives of
disease are covered through studies on the commensal mikroflora, the environmental pollutant bisphenol A,
cytomelgovirus and eosinophilic granulocyte invasion in IBD. Different biomarkers of inflammation are
studied and evaluated as regards their usefulness as predictors of disease progression. Special attention is
given to the biomarkers nitric oxide (NO), tumour necrosis factor (TNF), interleukin-1beta (IL-1�), and
interferon gamma, as well as interleukin-2 and interleukin-17, metalloproteinases and CXCL2; all of which
indicative of an inflammatory process. In addition, regulatory gut peptide functions are studied in IBD as
compared to irritable bowel syndrome (IBS). In IBD, markers of eosinophil granulocyte activity as
indicated by different CD markers, eosinophil cationic protein and eosinophil protein X are studied in
relation the inflammatory processes as mirrored by fecal calprotectin, myeloperoxidase, tryptase and Creactive
protein (CRP). Parallel research programs with their basis in epidemiology, biochemistry,
immunology and physiology are conjoined to focus on mechanisms underlying IBD and secondary
inflammatory reactions primarily in the liver, causing primary sclerosing cholangitis. The composite work
includes epidemiological, experimental, and clinical studies aiming at delineating events at the molecular
and subcellular level leading to relevant clinical research of disease, and identifying diagnostic and
predictive markers of gastrointestinal and liver disease.
The aim is to build a gastroenterological research facility with modern immunoassay and molecular biology
based analytical detection systems branching into:
� Clinical research unit for academic and industry-sponsored clinical trials
� Gastroenterology lab unit with basic chemistry and physiology for clinical and
investigational studies of pathophysiology in gastrointestinal disease
Select projects
1. Epidemiology of IBD and microscopic colitides and complications of disease
2. Environmental pollutants in etiology of IBD
3. Genes encoding inflammatory marker proteins in IBD
4. Cytomegalovirus and commensal gut microflora as pathogen in IBD
5. Nitric oxide, nitrite and nitrate as cytoprotectives in the gut
6. Pathogenic mechanisms in microscopic colitis
7. Eosinophilic granulocyte activation, macrophage infiltration and apoptosis in IBD.
8. Gastrointestinal permeability (“leaky gut”) and endotoxemia in IBD and IBS
9. Early diagnostic and predictive markers in IBD with primary sclerosing cholangitis
10. Regulatory neuropeptides and hormones in pathophysiology and inflammation
11. Fecal inflammatory markers for diagnosis and monitoring of bowel graft-vs-host disease in allogenic
bone marrow transplant
12. Treatment of chronic hepatitis B and C and their complications
13. Diagnosis and treatment of portal hypertension using transjugular intrahepatic portosystemic shunt
(TIPSS)
14. Diagnostic markers of hepatorenal syndrome in liver cirrhosis
92

Members of the group during 2011
Per M. Hellström , MD, PhD, professor
Marie Carlson, MD, PhD, associate prof
Fredrik Rorsman, MD, PhD, associate prof
Anders Rönnblom, MD, PhD, associate prof
Per Sangfelt, MD, PhD, associate prof
Mari Thörn, MD, PhD
Michael Wagner, MD, PhD
Maria Lampinen, PhD
Christer Peterson, PhD
Dominic-Luc Webb, PhD
Funding
Per M. Hellström
Swedish Research Council 1500 kSEK
NovoNordisk fund 1500 kSEK
Gastroenterological Research 1000 kSEK
Bengt Ihre fund 250 kSEK
ALF 288 kSEK
Marie Carlson
ALF 500 kSEK
Bengt Ihre fund 200 kSEK
The Cooperation fund 200 kSEK
93
Michael Wagner, MD, PhD
Johan Vessby, MD
Marie Backman, PhD-student
Kristin Blom, PhD-student
Linda Gillberg, PhD-student
Inger Gustafsson, research nurse
Catarina Lundell Lövgren, research nurse
Pernilla Quarfordt, BMA
Ingrid Stolt, BMA
Fredrik Rorsman
ALF 305 kSEK
Anders Rönnblom
ALF 128 kSEK
Per Sangfelt
ALF 120 kSEK
Mari Thörn
Svenska Läkaresällskapet 135 kSEK
Publications 2009-2011
1. Rajani R, Melin T, Björnsson E, Broomé U, Sangfelt P, et al. Budd-Chiari syndrome in Sweden:
epidemiology, clinical characteristics and survival - an 18-year experience. Liver Int 2009;29:253-9.
2. Classen J-F, Rorsman F, Lennartsson J, Rorsman C, et al. Lack of evidence of stimulatory
autoantibodies to platelet-derived growth factor receptor in patients with systemic sclerosis. Arthritis
Rheum 2009;60:1137-44.
3. Alimohammadi M, Dubois N, et al Pulmonary autoimmunity as a novel component of autoimmune
polyendocrine syndrome type I and the identification of KCNRG as a bronchial autoantigen. Proc Natl
Acad Sci U S A 2009;106:4396-401.
4. Franck-Larsson K, Graf W, Rönnblom A. Lower gastrointestinal symptoms and quality of life in
patients with systemic sclerosis: a population-based study. Eur J Gastroenterol Hepatol 2009;21:176-
82.
5. Werner M, Almer S, Prytz H, Lindgren S, Wallerstedt S, Björnsson E, Bergquist A, Sandberg-Gertzén
H, Hultcrantz R, Sangfelt P, Weiland O, Danielsson A. Hepatic and extrahepatic malignancies in
autoimmune hepatitis. A long-term follow-up in 473 Swedish patients. J Hepatol 2009;50:388-93.
6. Lagging M, Wejstål R, Uhnoo I,et al. Swedish Consensus Group. Treatment of hepatitis C virus
infection: updated Swedish Consensus recommendations. Scand J Infect Dis 2009;41:389-402.

7. Kämpe M, Janson C, Stolt I, Stålenheim G, Carlson M. Experimental and seasonal exposure to birch
pollen in patients with allergic rhinitis and allergic asthma with regard to the inflammatory response.
Clin Respiratory J 2010;4:37-44.
8. McGovern D PB, Daly MJ, Törkvist L, et al. Genome-wide association identifies 28 ulcerative colitis
susceptibility loci. Nature genetics 2010;42:332-7.
9. Törkvist L, Halfvarson J, Ong R, Lördal M, et al. Analysis of 39 Crohn’s disease risk loci in Swedish
inflammatory bowel disease patients. Inflamm Bowel Dis 2010;6:907-9.
10. Wagner M, Lampinen M, Sangfelt P, Agnarsdottir M, Carlson M. Budesonide treatment of patients
with collagenous colitis restores normal eosinophil and T-cell activity in the colon. Inflamm Bowel
Dis 2010;16:1118-26.
11. Rajani R, Björnsson E, Bergquist A, Danielsson A, Gustavsson A, Grip O, Melin T, Sangfelt P,
Wallerstedt S, Almer S. The epidemiology and clinical features of portal vein thrombosis: a
multicentre study. Aliment Pharmacol Ther 2010;32:1154-62.
12. Werner M, Wallerstedt S, Lindgren S, et al Characteristics and long-term outcome of patients with
autoimmune hepatitis related to the initial treatment response. Scand J Gastroenterol 2010;45:457-67.
13. Rönnblom A, Samuelsson SM, Ekbom A. Ulcerative colitis in the county of Uppsala 1945-2007:
incidence and clinical characteristics. J Crohns Colitis 2010;4:532-6.
14. Eloranta ML, Franck-Larsson K, Lövgren T, Kalamajski S, Rönnblom A, Rubin K, Alm GV,
Rönnblom L. Type I interferon system activation and association with disease manifestations in
systemic sclerosis. Ann Rheum Dis 2010;69:1396-402.
15. Stål P, Befrits R, Rönnblom A, Danielsson A, Suhr O, Ståhlberg D, Brinkberg Lapidus A, Löfberg R.
Clinical trial: the safety and short-term efficacy of recombinant cholera toxin B subunit in the
treatment of active Crohn's disease. Aliment Pharmacol Ther 2010;31:387-95.
16. Lundgren BA, Rorsman F, Portela-Gomes GM, et al Identification of complement C3 as an
autoantigen in inflammatory bowel disease. Eur J Gastroenterol Hepatol 2010;22:429-36.
17. Ardesjö B, Portela-Gomes GM, Rorsman F, Grimelius L, Ekwall O. Identification of a novel staining
pattern of bile duct epithelial cells in primary sclerosing cholangitis. Inflamm Bowel Dis 2010;16:305-
11.
18. Witte AB, Grybäck P, Jacobsson H, Näslund E, Hellström PM, et alInvolvement of endogenous
glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine secretion. Scand J
Gastroenterol 2010 Nov 30. [Epub ahead of print]
19. Hellström PM. Glucagon-like peptide-1 gastrointestinal regulatory role in metabolism and motility.
Vitam Horm 2010;84:319-29.
20. Gustavsson A, Järnerot G, Hertervig E, et al. Clinical trial: colectomy after rescue therapy in
ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study. Aliment
Pharmacol Ther 2010;32:984-9.
21. Edholm T, Degerblad M, Grybäck P, Hilsted L, Holst JJ, Jacobsson H, Efendic S, Schmidt PT,
Hellström PM. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and
insulin-glucose homeostasis. Neurogastroenterol Motil 2010;22:1191-200.
22. Ejskjaer N, Dimcevski G, Wo J, Hellström PM, et al. Safety and efficacy of ghrelin agonist TZP-101
in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study.
Neurogastroenterol Motil 2010;22:1069-e281.
23. Falkén Y, Hellström PM, Sanger GJ, et al. Actions of prolonged ghrelin infusion on gastrointestinal
transit and glucose homeostasis in humans. Neurogastroenterol Motil 2010;22:e192-200.
24. Ehrsson YT, Hellström PM, Brismar K, Sharp L, Langius-Eklöf A, Laurell G. Explorative study on
the predictive value of systematic inflammatory and metabolic markers on weight loss in head and
neck cancer patients undergoing radiotherapy. Support Care Cancer 2010;18:1385-91.
25. Lönnkvist MH, Theodorsson E, Holst M, Ljung T, Hellström PM. Blood chemistry markers for
evaluation of inflammatory activity in Crohn's disease during infliximab therapy. Scand J
Gastroenterol. 2011 Apr;46(4):420-7
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26. Hellström PM, Webb D. Irritable Bowel syndrome: Principles and novel treatment options. Drugs of
the future. 2011;36(9):669-675.
27. Naessen S, Carlström K, Holst J, Hellström PM, Hirschberg A. Women with bulimia nervosa exhibit
attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a
meal. American Journal of Clinical Nutrition. 2011;94(4):967-972.
28. Lönnkvist M, Theodorsson E, Holst M, Ljung T, Hellström PM. Blood chemistry markers for
evaluation of inflammatory activity in Crohn's disease during infliximab therapy. Scandinavian
Journal of Gastroenterology. 2011;46(4):420-427.
29. Witte A, Gryback P, Jacobsson H, Naslund E, Hellström PM, Holst J, et al. Involvement of
endogenous glucagon-like peptide-1 in regulation of gastric motility and pancreatic endocrine
secretion. Scandinavian Journal of Gastroenterology. 2011;46(4):428-435.
30. Wagner M, Peterson C, Stolt I, Sangfelt P, Agnarsdóttir M, Lampinen M, et al. Fecal eosinophil
cationic protein as a marker of active disease and treatment outcome in collagenous colitis : A pilot
study. Scandinavian Journal of Gastroenterology. 2011;46(7-8):849-854.
31. Hellström PM, Saito Y, Bytzer P, Tack J, Mueller-Lissner S, Chang L. Characteristics of Acute Pain
Attacks in Patients With Irritable Bowel Syndrome Meeting Rome III Criteria. American Journal of
Gastroenterology. 2011;106(7):1299-1307.
32. Falkén Y, Hellström PM, Holst J, Näslund E. Changes in Glucose Homeostasis after Roux-en-Y
Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery : Role of
Gut Peptides. Journal of Clinical Endocrinology and Metabolism. 2011;96(7):2227-2235.
33. Wallon C, Persborn M, Jönsson M, Wang A, Phan V, Lampinen M, et al. Eosinophils Express
Muscarinic Receptors and Corticotropin-Releasing Factor to Disrupt the Mucosal Barrier in Ulcerative
Colitis. Gastroenterology. 2011;140(5):1597-1607.
34. Wo J, Ejskjaer N, Hellström PM, Malik R, Pezzullo J, et al. Randomised clinical trial : ghrelin agonist
TZP-101 relieves gastroparesis associated with severe nausea and vomiting - randomised clinical
study subset data. Alimentary Pharmacology and Therapeutics. 2011;33(6):679-688.
35. Hellström PM. GLP-1 playing the role of a gut regulatory compound. Acta Physiologica.
2011;201(1):151-156.
36. Carlson M, Venge P, Lampinen M. C3b-induced eosinophil degranulation involves PI3-kinases and is
inhibited by protein kinase C activity. Acta Pathologica, Microbiologica et Immunologica
Scandinavica (APMIS). 2011;119(2):119-126.
37. Ahlgren K, Moretti S, Lundgren B, Karlsson I, Åhlin E, Norling A, et al. Increased IL-17A secretion
in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model.
European Journal of Immunology. 2011;41(1):235-245.
38. Nybacka A, Carlstrom K, Stahle A, et al. Randomized comparison of the influence of dietary
management and/or physical exercise on ovarian function and metabolic parameters in overweight
women with polycystic ovary syndrome. Fertility and Sterility. 2011;96(6):1508-1513.
39. Kämpe M, Stolt I, Lampinen M, Janson C, Stålenheim G, Carlson M. Patients with allergic rhinitis
and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen
challenge. Clin Mol Allergy. 2011 Jan 21;9(1):3
40. Wagner M, Peterson C, Stolt I, Sangfelt P, Agnarsdóttir M, Lampinen M, et al. Fecal eosinophil
cationic protein as a marker of active disease and treatment outcome in collagenous colitis : A pilot
study. Scandinavian Journal of Gastroenterology. 2011;46(7-8):849-854.
41. Pedersen C, Alsiö Å, Lagging M, Langeland N, Färkkilä M, Buhl M, et al. Ribavirin plasma
concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C
virus genotype 2/3 infection. Journal of Viral Hepatitis. 2011;18(4):245-251.
42. Torkzad MR, Ullberg U, Nyström N, Blomqvist L, Hellström P, Fagerberg UL. Manifestations of
small bowel disease in pediatric Crohn's disease on magnetic resonance enterography. Inflamm Bowel
Dis. 2012 Mar;18(3):520-8.
43. Hellström PM. Ulimorelin, TZP-101. Drug Future 2011;12:899-907.
95

Molecular Medicine
Ann-Christine Syvänen
The research group in Molecular Medicine is interested in methods for large-scale genomic analyses and
applies them to human diseases, with a focus on pediatric leukemia and autoimmune diseases. The group
headed by professor Ann-Christine Syvänen was established in 1998 at Uppsala University Hospital with
the aim to introduce modern molecular methods into clinical research. Since its start the group has worked
towards this goal by creating close collaborations with clinical scientists at the hospital and by hosting the
SNP&SEQ Technology Platform in Uppsala that offers large- scale SNP genotyping and second generation
sequencing services to academic researchers in Sweden and other countries.
Epigenetic biomarkers for acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer in the Western world.
Although there has recently been great progress in treatment protocols for ALL, about 20% of the patients
do not respond to drug treatment for unknown reasons. The aim of the research project on ALL in the
Molecular Medicine group is to identify genetic and epigenetic signatures that may be used as biomarkers
to improve stratification of the ALL patients into groups for alternative treatment protocols. In these studies
a unique collection of bone marrow and blood samples from children with ALL that have been collected in
the Nordic countries by the Nordic Society for Paediatric Oncology (NOPHO) are being analyzed. The
project involves a close collaboration between the Molecular Medicine group and pediatric oncologists at
the Children’s University Hospital in Uppsala. In addition to the identification of biomarkers for patient
stratification, the Molecular Medicine group also strives to elucidate the functional roles of epigenetic
modifications of DNA and histones in the transformation of normal blood progenitor cells into leukemic
cells. The project is funded by the Swedish Foundation for Strategic Research (SSF), the Cancer
Foundation and the Pediatric Cancer Foundation.
From genes to function in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is regarded as the prototype for autoimmune disease because it
involves most immune cell types and can affect all organs of the human body. SLE has a strong heritable
component. There are 40 confirmed genetic risk loci for SLE that have been identified by genome-wide
association studies and consequent follow up studies. By analysis of a collection of well characterized
Swedish patients with SLE, the Molecular Medicine group has contributed to the identification of 13 of
these loci. Via a national network for SLE research with participants from most University Hospitals in
Sweden, a large number of Swedish patients with SLE that have been carefully investigated by clinicians
can be included in genetic studies of SLE. The genes at the SLE-associated loci belong to the type I
interferon (IFN), B-cell and T-cell signaling pathways. Several of the risk genes for SLE also confer risk
for other autoimmune disease. To identify the actual functional, disease-causing alleles in the risk loci for
SLE, the Molecular Medicine group uses new technology for second generation DNA sequencing in
combination with functional analysis of fractionated human blood cells. The project involves a close
collaboration with the research group in Rheumatology and the Rheumatology Clinic at Uppsala University
Hospital. The project is funded by the Knut and Alice Wallenberg Foundation, the Swedish Research
Council for Medicine & Health (VR MH) and the Swedish Research Council for Science &Technology
(VR NT).
Large collaborative projects
The Molecular Medicine group participates in collaborative projects, in which its competence in genomic
technology is combined with the capacity of the SNP&SEQ Technology Platform for large-scale SNP
genotyping and second generation sequencing. In the EU FP7 “Engage” project the group performs
genome-wide analysis of DNA methylation in samples from European twin cohorts. As partner of the EU
FP7 “Geuvadis” consortium the Molecular Medicine group and the SNP&SEQ Technology Platform work
together with 11 major sequencing and genotyping centers across Europe to define best laboratory practices
96

for second generation transcriptome and exome sequencing. The Molecular Medicine group is part of the
EU FP7 “European Sequencing and Genotyping Infrastructure (ESGI) ” to which it contributes by
laboratory protocols and bioinformatics tools for allele-specific gene expression, while the SNP&SEQ
Platform offers transnational access to SNP genotyping and second generation DNA sequencing. In
addition to the European Commission, technology development activities in the Molecular Medicine group
are funded by the Swedish Research Council for Science & Technology (VR NT).
For more information see www.molmed.medsci.uu.se
Members of the group during 2011
Ann-Christine Syvänen, PhD, professor
Eva Berglund, PhD, post doc,
Per Wahlberg, PhD, post doc
Jonas Carlsson, PhD, post doc
Johanna Sandling, PhD, post doc
Mathias Brännvall, PhD, project coordinator
Per Lundmark, PhD student
Jessica Nordlund, PhD student,
97
Lillebil Andersson, admin assistant
Chuan Wang, PhD student,
Mårten Lindqvist, PhD student
Anders Lundmark, research engineer
Elin Övernäs, PhD, research engineer
Sofia Nordman,PhD research engineer
Behrooz Torabi, project student
Funding
Swedish Research Concil for Science and Technology (VR NT) 1.3 Mkr
Swedish Research Concil for Medicine and Health (VR MH) 1.2 Mkr
Swedish Foundation for Strategic Research (SSF) (3 groups) 4.0 Mkr
The Knut and Alice Wallenberg Foundation (KAW) (2 groups) 4.8 Mkr
Swedish Foundation for Cancer Research 0.7 Mkr
Swedish Foundation for Pediatric Cancer Research 0.5 Mkr
European Commission, FP7 2.8 Mkr
Publications 2009-2011
1. Eriksson AL, Lorentzon M, Vandenput L, Labrie F, Lindersson M, Syvänen A-C, Orwoll ES,
Cummings SR, Zmuda JM, Ljunggren O, Karlsson MK, Mellström D, Ohlsson C. Genetic variations
in sex steroid-related genes as predictors of serum estrogen levels in men. J Clin Endocrinol Metab
3:1033-41, 2009
2. Gateva V, Sandling JK, Hom G et al. A large-scale replication study identifies TNIP1, PRDM1,
JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nature Genetics 11:1228-
33, 2009
3. Ghotbi R, Gomez A, Milani L, Tybring G, Syvänen A-C, Bertilsson L, Ingelman-Sundberg M, Aklillu
E. Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human
livers. Pharmacogenomics J 3:208-17, 2009
4. Giedraitis V, Kilander L, Degerman-Gunnarsson M, Sundelöf J, Axelsson T, Syvänen A-C, Lannfelt
L, Glaser A. Genetic analysis of Alzheimer's disease in the Uppsala Longitudinal Study of Adult Men.
Dement Geriatr Cogn Disord 1:59-68, 2009
5. Li JB, Gao Y, Aach J, Zhang K, Kryukov GV, Xie B, Ahlford A, Yoon JK, Rosenbaum AM, Zaranek
AW, LeProust E, Sunyaev SR, Church GM. Multiplex padlock targeted sequencing reveals human
hypermutable CpG variations. Genome Res. 19:1606-15, 2009

6. McEvoy BP, Montgomery GW, McRae AF, Ripatti S, Perola M, Spector TD, Cherkas L, Ahmadi KR,
Boomsma D, Willemsen G, Hottenga JJ, Pedersen NL, Magnusson PK, Kyvik KO, Christensen K,
Kaprio J, Heikkilä K, Palotie A, Widen E, Muilu J, Syvänen A-C, Liljedahl U, Hardiman O, Cronin S,
Peltonen L, Martin NG, Visscher PM. Geographical structure and differential natural selection among
North European populations. Genome Res 19:804-14, 2009
7. Milani L, Lundmark A, Nordlund J, Kiialainen A, Flaegstad T, Jonmundsson G, Kanerva J,
Schmiegelow K, Gunderson KL, Lönnerholm G, and Syvänen A-C. Allele-specific gene expression
patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation.
Genome Res .1:1-11, 2009
8. Newton-Cheh C, Johnson T, Gateva Vet al Genome-wide association study identifies eight loci
associated with blood pressure. Nat Genet 41:666-676, 2009
9. Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C, Padyukov L, Truedsson L,
Alm G, Eloranta ML, Jonsson R, Rönnblom L, Syvänen AC. Additive effects of the major risk alleles
of IRF5 and STAT4 in primary Sjögren's syndrome. Genes Immun. 1:68-76, 2009
10. Rönn A-C, Andrés O, López-Giráldez F, Johnsson-Glans C, Verschoor EJ, Domingo-Roura X,
Bruford MW, A.-C. Syvänen A-C, M. Bosch M. First generation microarray-system for identification
of primate species subject to bushmeat trade. Endang Species Res. June 19, 2009
11. Wade CM, Giulotto E, Sigurdsson S, et al Genome sequence, comparative analysis, and population
genetics of the domestic horse. Science. 5954:865-7, 2009
12. Wahlberg P, Carlborg O, Foglio M, Tordoir X, Syvänen AC, Lathrop M, Gut IG, Siegel PB,
Andersson L. Genetic analysis of an F(2) intercross between two chicken lines divergently selected for
body-weight. BMC Genomics. 10:248, 2009
13. Ahlford A, Kjeldsen B, Reimers J, Lundmark A, Romani M, Wolff A, Syvänen A-C, Brivio M. Dried
reagents for multiplex genotyping by tag-array minisequencing to be used in microfluidic devices.
Analyst 135:2377-85, 2010
14. Dupuis J, Langenberg C, Prokopenko I et al. New genetic loci implicated in fasting glucose
homeostasis and their impact on type 2 diabetes risk. Nat Genet. 42:105-16, 2010
15. Edvardsen H, Brunsvig PF, Solvang H, Tsalenko A, Andersen A, Syvänen A-C, Yakhini Z, Børresen-
Dale AL, Olsen H, Aamdal S, Kristensen VN. SNPs in genes coding for ROS metabolism and
signalling in association with docetaxel clearance. Pharmacogenomics J. 2010 Feb 16. [Epub ahead of
print]
16. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm G,
Syvänen A-C, Rönnblom L, Barnes BJ. Genetic variants and disease-associated factors contribute to
enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus
erythematosus. Arthritis Rheum. 62:562-73, 2010.
17. Folkersen L, Hooft FV, et al. Association of Genetic Risk Variants With Expression of Proximal
Genes Identifies Novel Susceptibility Genes for Cardiovascular Disease. Circ Cardiovasc Genet.
3:365-373, 2010
18. Hellquist A, Sandling JK, Zucchelli M, Koskenmies S, Julkunen H, D'Amato M, Garnier S, Syvänen
A-C, Kere J. Variation in STAT4 is associated with systemic lupus erythematosus (SLE) in a Finnish
family cohort. Ann Rheum Dis. 69:883-6, 2010.
19. Hällström H, Melhus H, Glynn A, Lind L, Syvänen A-C, Michaelsson K. Coffee consumption and
CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and
women: a cohort study. Nutr Metab (Lond)7:12, 2010
20. Heid IM, Jackson AU, Randall JC, et al Meta-analysis identifies 13 new loci associated with waist-hip
ratio and reveals sexual dimorphism in the genetic basis of fat distribution. Nat Genet. 2010 42:949-
60.
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21. Ikram MK, Xueling S, Jensen RA, et al. Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence
the microcirculation in vivo. PLoS Genet.(2010) 6:e1001184.
22. Ingelsson E, Langenberg C, Hivert MF, et al; on behalf of the MAGIC investigators. Detailed
physiologic characterization reveals diverse mechanisms for novel genetic loci regulating glucose and
insulin metabolism in humans. Diabetes 59:1266-1275, 2010
23. Milani L, Lundmark A, et al DNA methylation for subtype classification and prediction of treatment
outcome in patients with childhood acute lymphoblastic leukemia. Blood 115:1214-25, 2010.
24. Saxena R, Hivert MF, Langenberg C, et al. Genetic variation in GIPR influences the glucose and
insulin responses to an oral glucose challenge. Nat Genet. 42:142-8, 2010.
25. Sandling, J. K., Garnier, S et al. A candidate gene study of the type I interferon pathway implicates
IKBKE and IL8 as risk loci for SLE. Eur J Hum Genet. Dec 22. [Epub ahead of print], 2010
26. Svenungsson E, Gustafsson J, et al. A STAT4 risk allele is associated with ischemic cerebrovascular
events and antiphospholipid antibodies in Systemic Lupus Erythematosus. Ann Rheum Dis 69:834-40,
2010.
27. Tabara Y, Kohara K, Kita Y et al. Common variants in the ATP2B1 gene are associated with
susceptibility to hypertension: the Japanese Millennium Genome Project. Hypertension 56:973-80,
2010
28. Uronen RL, Lundmark P, Orho-Melander M,et al C1 modulates hepatic triglyceride metabolism and
its genetic variation contributes to serum triglyceride levels. Arterioscler Thromb Vasc Biol. 30:1614-
20, 2010.
29. Vuong MT, Gunnarsson I, Lundberg S, Svenungsson E, Wramner L, Fernström A, Syvänen A-C, Do
LT, Jacobson SH, Padyukov L. Genetic risk factors in lupus nephritis and IgA nephropathy--no
support of an overlap. PLoS One 5:e10559, 2010.
30. Popov S, Silveira A, Wågsäter D, Takemori H, Oguro R, Matsumoto S, et al. Salt-inducible kinase 1
influences Na+,K+-ATPase activity in vascular smooth muscle cells and associates with variations in
blood pressure. Journal of Hypertension. 2011;29(12):2395-2403.
31. Cunninghame Graham D, Morris D, Bhangale T, Criswell L, Syvänen A, Rönnblom L, et al.
Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus. PLoS
genetics. 2011;7(10):e1002341-.
32. Wang C, Kokkonen H, Sandling J, Johansson M, Seddighzadeh M, Padyukov L, et al. Preferential
Association of Interferon Regulatory Factor 5 Gene Variants with Seronegative Rheumatoid Arthritis
in 2 Swedish Case-Control Studies. Journal of Rheumatology. 2011;38(10):2130-2132.
33. Strawbridge R, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al. Genome-Wide
Association Identifies Nine Common Variants Associated With Fasting Proinsulin Levels and
Provides New Insights Into the Pathophysiology of Type 2 Diabetes. Diabetes. 2011;60 (10):2624-
2634.
34. Sawcer S, Hellenthal G, Pirinen M, Spencer C, Patsopoulos N, Moutsianas L, et al. Genetic risk and a
primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature.
2011;476(7359):214-219.
35. Nitsch D, Sandling J, Byberg L, Larsson A, Tuvemo T, Syvänen A, et al. Fetal, Developmental, and
Parental Influences on Cystatin C in Childhood : The Uppsala Family Study. American Journal of
Kidney Diseases. 2011;57(6):863-872.
36. Peden J, Hopewell J, Saleheen D, Chambers J, Hager J, Soranzo N, et al. A genome-wide association
study in Europeans and South Asians identifies five new loci for coronary artery disease. Nature
Genetics. 2011;43(4):339-344.
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37. Kiialainen A, Karlberg O, Ahlford A, Sigurdsson S, Lindblad-Toh K, Syvänen A. Performance of
Microarray and Liquid Based Capture Methods for Target Enrichment for Massively Parallel
Sequencing and SNP Discovery. PLoS ONE. 2011;6(2):e16486-.
38. Kanoni S, Nettleton J, Hivert M, Ye Z, van Rooij F, Shungin D, et al. Total zinc intake may modify
the glucose-raising effect of a zinc transporter (SLC30A8) variant : a 14-cohort meta-analysis.
Diabetes. 2011;60(9):2407-2416.
39. Kilpeläinen T, Zillikens M, Stančákova A, Finucane F, Ried J, Langenberg C, et al. Genetic variation
near IRS1 associates with reduced adiposity and an impaired metabolic profile. Nature Genetics.
2011;43(8):753-760.
40. Strawbridge R, Dupuis J, Prokopenko I, Barker A, et al. Genome-wide association identifies nine
common variants associated with fasting proinsulin levels and provides new insights into the
pathophysiology of type 2 diabetes. Diabetes. 2011;60(10):2624-2634.
41. Sandling J, Garnier S, Sigurdsson S, Wang C, Nordmark G, Gunnarsson I, et al. A candidate gene
study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE. European
Journal of Human Genetics. 2011;19(4):479-484.
42. Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, et al. Association of
EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes
and Immunity. 2011;12(2):100-109.
43. Berglund E, Kiialainen A, Syvänen A. Next generation sequencing technologies and applications for
human Genetic History and Forensics. Investigative Genetics. 2011;2(1):23-.
44. Sovio U, Mook-Kanamori D, Warrington N, Lawrence R, Briollais L, Palmer C, et al. Association
between Common Variation at the FTO Locus and Changes in Body Mass Index from Infancy to Late
Childhood: The Complex Nature of Genetic Association through Growth and Development. .
2011;7(2):e1001307-.
45. Boeger C, Chen M, Tin A, Olden M, Koettgen A, de Boer I, et al. CUBN Is a Gene Locus for
Albuminuria. Journal of the American Society of Nephrology. 2011;22(3):555-570.
46. Nordlund J, Kiialainen A, Karlberg O, Berglund E, Göransson-Kultima H, Sønderkær M, et al. Digital
gene expression profiling of primary acute lymphoblastic leukemia cells. Leukemia. 2011; Dec 16
[Epub ahead of print]
47. Wang C, Kokkonen H, Sandling J, Johansson M, Seddighzadeh M, Padyukov L, et al. Preferential
association of interferon regulatory factor 5 gene variants with seronegative rheumatoid arthritis in 2
Swedish case-control studies. Journal of Rheumatology. 2011;38(10):2130-2132.
Dissertations 2011
Per Lundmark: Genetic and genomic analysis of DNA sequence variation
100

Renal Medicine
Bengt Fellström
The overall objective of the research is to investigate means and methods for prevention of renal failure,
and treatment of complications in renal failure. Our research program involves studies on cardio-vascular
complications in chronic kidney disease and renal transplantation, studies on FGF-23 in renal failure,
clinical studies on chronic kidney disease and haemodialysis as well as studies on new biomarkers for renal
failure. Recently we have also finalized new approaches with regard to pathogenesis and treatment of IgA
nephropathy, and commenced new joint venture with the research group in Nanotechnology and Functional
Surfaces. A substantial research grant has been approved for development of a new generation of dialysers
and new devices for extracorporeal blood treatment. It is our firm belief that the outcome of this research
will lead to an improved medical and social rehabilitation of patients with renal failure.
Cardio Vascular Complications in Chronic Kidney Disease and Renal
Transplantation
Bengt Fellström, Hans Furuland, Inga Soveri, Eva Carlsson, Hilde Kloster, Nektarios Karefyllakis,
Mattias Tejde
Cardiovascular disease (CVD) is extremely common in patients with renal insufficiency, which includes
dialysis and renal transplant patients. Our efforts are targeting the importance of e.g. endothelial
dysfunction, oxidative stress, and inflammation as contributing factors to the high rate of CVD. An
important part of our efforts is treatment studies,often initiated from our own unit. Such studies include the
ALERT trial in renal transplant patients, the AURORA trial in haemodialysis patients, and the SHARP trial
in preuremic and dialysis patients. In a new study we are investigating if a low-dose aldosterone blockade
by Spirolactone may have a positive effect on cardiovascular morbidity and mortality in haemodialysis
patients. Other trials involve e.g. studies in patients with early IgA nephropathy using a corticosteroid
compound acting primarily in the gut (budesonide
Based on our substantial track record on both clinical and experimental studies in chronic allograft
nephropathy (CAN), we are presently investigating early markers of CAN in biopsies, based upon findings
from Tissue Micro Array investigations in lost grafts. Presently we are participating in three different
treatment protocols which include switching of immunosuppressive regimen from calcineurine-based
treatment to mycophenolate (TRANCEPT) or mTOR inhibitors (CONVERT and ASCERTAIN).
Superb biobanks have been collected with genomic materials from patients participating in e.g. the
MIMICK trial, which we have used to analyze genomic aberrations in inflammation-related genes as well
as telomere length in DNA material, and shown a striking relationship to the degree of inflammation,
oxidative stress, fetuin levels and patient survival in the MIMICK trial.
The role of FGF-23 in phosphate regulation and calcium/phosphate
homeostasis in chronic kidney disease
Torbjörn Linde, PerAnton Westerberg
FGF-23 is a secreted growth factor that is produced in bone and circulates in the bloodstream to ultimately
regulate phosphate handling and vitamin D production in the kidney. An important pathophysiological role
of FGF23 has been implicated in several hereditary and acquired disorders.
Our studies, aiming to understand the molecular mechanisms and the endocrine action of FGF-23, are
important for several reasons. Identification of FGF23 down-stream targets within the kidney proximal
tubule as well as the parathyroid glands will be critical for understanding the molecular mechanisms of
FGF-23 on Pi and vitamin D metabolism. Furthermore, it will provide opportunities to modify FGF-23
signalling and consequently to develop novel drug targets for disorders of calcium and Pi homeostasis.
101

Clinical studies on chronic kidney disease (CKD) and haemodialysis (HD)
Björn Wikström, Magnus Lindberg, Per Lindberg
Despite substantial progress in kidney disease and dialysis care during recent decades, morbidity and
mortality remains very high in this patient group. Notably there is an unacceptable high risk for
cardiovascular complications e.g. myocardial infarction, stroke and peripheral vascular disease. Aiming to
reduce the risk for CKD and HD patients we are studying various factors that may be of importance for the
occurrence of long-term complications.
An unrestricted fluid intake by patients on HD may have serious consequences and prolonged fluid
overload is a potential life-threatening condition. To be prescribed fluid restrictions often generates a
treatment related stressor and compliance may be difficult to achieve. We aim to describe the prevalence of
non-adherence to fluid restrictions among haemodialysis patients, to evaluate the impact of self-efficacy
and other individual characteristics on adherence, and to study possible effects of a social-learning theorybased
intervention designed to improve adherence behaviour. In a recent multi centre study, involving 133
patients, we could define clinically relevant subgroups of haemodialysis patients by their profiles regarding
self-efficacy, attention style and depressive symptoms.
Biomarkers of renal injury
Jan Melin, Per Venge, Per Sangfelt, Fredrik Rorsman, Bengt Fellström
Acute kidney injury is an increasing problem, and there are many conditions and procedures that put the
kidneys at risk. Current markers of renal injury, such as creatine, are unspecific, but new biomarkers that
show the actual degree of renal injury are now emerging; e.g. Human Neutrophil Lipocalin/Neutrophil
gelatinase-associated lipocalin (HNL/NGAL), Kidney injury molecule (KIM-1), and Cystatin. We are
currently evaluating several of these new biomarkers of renal injury in different clinical settings. The
ability to identify parenchymal renal injury at a much earlier time than today would be beneficial for the
patient, and would allow the physicians to customize the treatment.
Members of the group during 2011
Bengt Fellström, Professor, M.D, PhD
Torbjörn Linde, Assoc. professor, M.D, PhD
Björn Wikström, Assoc. professor, M.D, PhD
Hans Furuland, M.D, PhD
Thomas Nilsson, MD, PhD
Jan Melin, M.D, PhD
Charlotte Welsh, MD, PhD
Inga Soveri, M.D., PhD
Natalia Ferraz, PhD, Postdoc
Per-Anton Westerberg, MD; PhD-student
Funding
ALF 700 kSEK
Swedish Research Council 600 kSEK
Industrial grants 700 kSEK
102
Ulf Nisbeth, M.D, PhD-student
Eva Carlsson, MD, tentative PhD student
Nektarios Karefyllakis, MD , tentative PhD
student
Mattias Tejde, MD, tentative PhD student
Hilde Kloster, Masters Pharm, PhD-student
Magnus Lindberg, RN, PhD-student
Åsa Lidman, Research nurse
Yvonne Lundholm, Research nurse

Publication 2009-2011
1. Lindberg M, Prütz K-G, Lindberg P, Wikström B. Interdialytic weight gain and ultrafiltration rate in
haemodialysis: lessons about fluid adherence from a national registry of clinical practice Hemodial
Int. 2009 Apr;13(2):181-8
2. Snaedal S, Heimbürger O, Qureshi AR, Danielsson A, Wikström B, Fellström B, Fehrman-Ekholm I,
Carrero JJ, Alvestrand A, Stenvinkel P, Bárány P. Comorbidity and acute clinical events as
determinants of C-reactive protein variation in hemodialysis patients: implications for patient survival.
Am J Kidney Dis. 2009 Jun;53(6):1024-33.
3. Sadollah Abedini, Ingar Holme, Bengt Fellström 3 , Alan Jardine 4 , Ed Cole 5 , Bart Maes 6 and Hallvard
Holdaas 1 , on behalf of the ALERT study group. Cerebrovascular events in renal transplant recipients
Transplantation 2009; 87:112-117
4. Gudrun E. Norby 1 , Ingar Holme 2 , Bengt Fellström 3 , Alan Jardine 4 , Edward Cole 5 , Sadollah Abedini 6
and Hallvard Holdaas 6 , on behalf of the ALERT study group. Effect of fluvastatin on cardiac
outcomes in SLE renal transplanted patients: a randomized placebo-controlled study. Arthritis &
Rheumatism 2009; ;60(4):1060-4
5. Kloster Smerud H, Kristjánsson G, Osagi S, Hällgren R., Fellström B. Gluten Sensitivity in Patients
with IgA Nephropathy Nephrol Dial Transpl 2009 ; 4(8):2476-81
6. Soveri I, Abedini S, Holdaas H, Jardine A, Eriksson N, Fellström B. Metabolic syndrome and
cardiovascular risk in renal transplant recipients: effects of statin treatment. Clin Transplant. 2009
Nov-Dec;23(6):914-20.
7. Holme I, Fellstrom B, Jardine A, Holdaas H. Comparison of predictive ability of lipoprotein
components to that of traditional risk factors of coronary events in renal transplant recipients.
Atherosclerosis. 2009, 201: 234-9.
8. Fellström, Jardine, Schmieder, Holdaas et al . Rosuvastatin and Cardiovascuular Events in Patients
Undergoing Hemodialysis. New Engl J Med 2009; 360:1395-1407
9. Abedini S, Holme I, Maerz W, Weihrauch , Fellström B, Jardine A.,Cole E, Maes B, Neumayer,
Gronhagen-Riska C , .Ambuhl P and. Holdaas H.. Inflammation in renal transplantation . Clin J Am
Soc Nephrol 2009;4: 1246 – 1254
10. Soveri I, Arnlöv J, Berglund L, Lind L, Fellström B, Sundström J. Kidney function and discrimination
of cardiovascular risk in middle-aged men. J Intern Med. 2009 ; 266(4):406-13
11. Fellström, JArdine, Holdaas, . Rosuvastatin in Patients Undergoing Hemodialysis New Engl J
Med 2009;361:1 ( July 2009 ) Author reply
12. Richard Marsell, Majd Mirza, Hans Mallmin, Magnus Carlsson, Dan Mellström, Eric Orwoll, Claes
Ohlsson, Kenneth Jonsson, Östen Ljunggren and Tobias Larsson. Relation Between Fibroblast Growth
Factor-23, Body Weight and Bone Mineral Density in Elderely Men. Osteoporos Int. 2009
Jul;20:1167-73.
13. Sadollah Abedini, Alan Jardine, Bengt Fellström, Andreas Meinitzer, Winfried März, Georgina
Bermann, and Hallvard Holdaas, . Asymmetric Dimethylarginine (ADMA) predicts progression to
graft failure and major cardiac events in renal transplant recipients (RTR). Kidney Int. 2010
Jan;77(1):44-50
14. Holme I, Fellström B, Jardine A, Holdaas H. Comparison of predictive ability of lipoprotein
components to that of traditional risk factors of coronary events in renal transplant recipients.
Atheroclerosis 2010; 201: 234-9.
15. SHARP Collaborative Group ( Fellström co-autor and in Steering Committee ), Study of Heart and
Renal Protection (SHARP) : Randomized trial to assess the effects of lowering low-density
lipoprotein cholesterol among 9438 patients with chronic kidney disease . Am Heart J 2010; 0:1-
10.e10
103

16. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from
170,000 participants in 26 randomised trials. Cholesterol Treatment Trialists? (CTT)
Collaboration,Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes
EH, Keech A, Simes J, Collins R (contributions by Fellström and others to database and manuscript ).
Lancet. 2010 Nov 13;376(9753):1670-81.
17. Westerberg PA, Ljunggren O, Larsson TE, Wadström J, Linde T. Fibroblast growth factor-23 and
mineral metabolism after unilateral nephrectomy, Nephrol Dial Transplant. 2010 Dec;25(12):4068-71
18. Kloster Smerud H, Fellström B, Hällgren R, Osagie S, Venge P, Kristjánsson G. Gastrointestinal
sensitivity to soy and milk proteins in patients with IgA nephropathy. Clin Nephrol. 2010
Nov;74(5):364-71.
19. Lindberg M, Fernandes MA. Self-efficacy in relation to limited fluid intake amongst portuguese
haemodialysis patients J Ren Care. 2010 Sep;36(3):133-8
20. Lindberg M, Wikström B, Lindberg P. Subgroups of haemodialysis patients in relation to fluid intake
restrictions: a cluster analytical approach.J Clin Nurs. 2010 Nov;19(21-22):2997-3005
21. Wikström B, Bhandari S, Barany P, Kalra P, Ladefoged S, Wilske J, et al. Iron isomaltoside 1000 : a
new intravenous iron for treating iron deficiency in chronic kidney disease. JN. Journal of Nephrology
(Milano. 1992). 2011;24(5):589-596.
22. Dahle D, Mjoen G, Oqvist B, Scharnagl H, Weihrauch G, Grammer T, et al. Inflammation-associated
graft loss in renal transplant recipients. Nephrology, Dialysis and Transplantation. 2011;26(11):3756-
3761.
23. Jardine A, Gaston R, Fellström B, Holdaas H. Organ Transplantation 2 : Prevention of cardiovascular
disease in adult recipients of kidney transplants. The Lancet. 2011;378(9800):1419-1427.
24. Westerberg P, Linde T, Eklöf H, Ljunggren Ö. Repeated venous sampling for determination of a
gradient of fibroblast growth factor 23 for localization of an osteomalacia causing tumor. Acta
Endocrinologica. 2011;7(3):395-403.
25. Dzabic M, Rahbar A, Yaiw K, Naghibi M, Religa P, Fellström B, et al. Intragraft Cytomegalovirus
Protein Expression Is Associated With Reduced Renal Allograft Survival. Clinical Infectious
Diseases. 2011;53(10):969-976.
26. Holdaas H, Rostaing L, Seron D, Cole E, Chapman J, Fellström B, et al. Conversion of Long-Term
Kidney Transplant Recipients From Calcineurin Inhibitor Therapy to Everolimus : A Randomized,
Multicenter, 24-Month Study. Transplantation. 2011;92(4):410-418.
27. Holdaas H, Holme I, Schmieder R, Jardine A, Zannad F, Norby G, et al. Rosuvastatin in Diabetic
Hemodialysis Patients. Journal of the American Society of Nephrology. 2011;22(7):1335-1341.
28. Baigent C, Landray M, Reith C, Emberson J, Wheeler D, Tomson C, et al. The effects of lowering
LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of
Heart and Renal Protection): a randomised placebo-controlled trial. The Lancet.
2011;377(9784):2181-2192.
29. Fellström B. Cardioprotective role of statins in chronic kidney disease: do we have the answer?.
Kidney International. 2011;79(9):931-932.
30. Fernström A, Giaever J, Granroth B, Hylander B, Jensen G, Christensson A, et al. Achievement of
recommended treatment targets for bone and mineral metabolism in haemodialysis patients using
paricalcitol : An observational study. Scandinavian Journal of Urology and Nephrology.
2011;45(3):196-205.
31. Verbeke F, Van Biesen W, Honkanen E, Wikström B, Jensen P, Krzesinski J, et al. Prognostic Value
of Aortic Stiffness and Calcification for Cardiovascular Events and Mortality in Dialysis Patients :
Outcome of the Calcification Outcome in Renal Disease (CORD) Study. Clinical Journal of the
American Society of Nephrology. 2011;6(1):153-159.
104

32. Kloster Smerud H, Bárány P, Lindström K, Fernström A, Sandell A, Påhlsson P, et al. New
Treatment of IgA nephropathy : Enteric Budesonide Targeted to the Ileocaecal Region Ameliorates
Proteinuria. Nephrology, Dialysis and Transplantation. 2011;26(10):3237-3242.
33. Lindberg M, Wikström B, Lindberg P. A behavioural nursing intervention for reduced fluid overload
in haemodialysis patients: Initial results of acceptability, feasibility and efficacy. Wiley-Blackwell;
Journal of nursing and healthcare of chronic illness. 2011;3(2):87-98.
34. Dimopoulou A, Raland H, Wikström B, Magnusson A. MDCT angiography with 3D image
reconstructions in the evaluation of failing arteriovenous fistulas and grafts in hemodialysis patients.
Acta Radiologica. 2011;52(9):935-942.
35. Holme I, Fellström BC, Jardine AG, Schmieder RE, Zannad F, Holdaas H. Prognostic model for total
mortality in hemodialysis patients from the Assessments of Survival and Cardiovascular Events
(AURORA) study. J Int Med, 2011 , Aug 3. doi: 10.1111/j.1365-2796.2011.02435.x. [Epub ]
Reviews
1. Fellström B, Holdaas H, Jardine AG, Svensson MK, Gottlow M, Schmieder RE, Zannad F; AURORA
Study Group. Cardiovascular disease in patients with renal disease: the role of statins Curr Med Res
Opin. 2009 Jan;25(1):271-85.
2. McQuarrie EP, Fellström BC, Holdaas H, Jardine AG. Cardiovascular disease in renal transplant
recipients J Ren Care. 2010 May;36 Suppl 1:136-45.
3. Bengt C Fellström. Cardioprotective Role of Statins in Chronic Kidney Disease: Do We Have the
Answer? Kidney Intl. 2011 May;79(9):931-2.
4. Alan G Jardine, Robert S Gaston, Bengt Fellstrom, Hallvard Holdaas. Prevention of cardiovascular
disease and new-onset diabetes in solid-organ transplantation. Lancet, 2011;378(9800):1419-27.
105

Rheumatology
Lars Rönnblom
Rheumatic diseases are a major cause of morbidity and affect a large proportion of the population. Our
research group is organized in three major project groups, which study several aspects of autoimmune
rheumatic diseases. The research areas encompass the genetic background to systemic lupus erythematosus
(SLE) and primary Sjögren’s syndrome, the regulation of the immune system and mechanisms for loss of
tolerance, the clinical picture of psoriatic arthritis and the connection between chronic inflammation and
development of lymphoma. We have been pioneers in several of these research areas. Our studies will
clarify central autoimmune mechanisms and our ultimate goal is to contribute to the development of
improved diagnostic tools and new therapeutic strategies in rheumatic diseases. Members of our group
coordinate the Swedish SLE network, the Scandinavian Sjögren´s syndrome research network and the
national auto-lymphoma study. We have during the year participated with scientific presentations in all
major international rheumatology meetings and received two research awards.
Identification and functional analysis of risk genes that contribute to loss of
immunological tolerance
We have investigated 78 genes in the type I interferon (IFN) pathway and identified IKBKE and IL8 as
new risk loci for SLE. This work has been done in collaboration with Prof. Ann-Christine Syvänen’s
research group and with the contribution of the Swedish SLE network. In collaboration with Prof. Timothy
Vyse (King´s College, UK) we have identified five genes associated to SLE, namely IFIH1, IKZF1, IRF8,
NCF2 och TYK2. We have together with Assoc. Prof. Betsy Barnes continued our studies of IRF5 in SLE.
IRF5 is a key mediator of Toll-like receptor signaling and IFN-� production. We have shown that IRF5
expression and alternative splicing are significantly up-regulated in SLE patients, and enhanced transcript
and protein levels were associated with a risk haplotype of IRF5.
In a candidate gene study of 84 genes we have detected an association between variants in EBF1, BLK and
TNFSF4 and pSS. In addition, gene variants in the CHRM3 gene and the LTA/LTB/TNF locus have been
found associated with pSS. We have continued to collect and classify patients according to established
criteria and disease phenotypes. Collaborations with investigators in France, UK and the USA have been
established.
Regulation of the type I interferon response by immune cells
We showed recently the mechanisms by which natural killer cells (NK) enhance the IFN-� production by
pDC when stimulated with interferogenic IC. Our study revealed that the cellular cross-talk between NK
cells and pDC is mediated by LFA-1 and the cytokine MIP-1�. Our results indicate that the regulation of
the type I IFN system is deficient in SLE and among our observations is the finding that SLE patients
display an insufficient negative feed-back signal once the type I IFN production is activated.
Bioresource of healthy blood donor samples
We have established a bioresource with 1000 blood samples collected from healthy blood donors. The
samples have been genotyped with ImmunoChip containing 186 000 SNPs in genes earlier found to be
associated with autoimmune diseases. Recruitment of 1000 new blood donors into the Bioresource is
ongoing. The Bioresource will offer an unique opportunity to perform cellular and genetic studies with
selected genotyped samples collected repeatedly.
106

Studies of associations between inflammatory rheumatic diseases and
malignant lymphomas
Eva Baecklund, Ann Knight, Gunnel Nordmark, Carin Backlin, Lilian Vasaitis, Karin Hellgren,
Amelie Kinch, Karin Hjorton
During 2011, we have reported that APRIL, a B-cell proliferating factor is increased in lymphoma tissue in
patients with SLE and in RA patients with high disease activity, and that expression of a new germinal
center marker (LMO2) in lymphoma tissue predicts survival in RA patients. We have shown that the
presence of germinal centre formation in the minor salivary glands in pSS patients predicts future
lymphoma development. Collection of blood and lymphoma tissue has successfully continued during 2011
for future immunological and genetic studies.
Psoriatic arthritis; pathophysiological and clinical studies in early and manifest
disease
Ulla Lindqvist, Peter Matt, Sandra Kleinau, Dan Henrohn
The background for the clinical and experimental scientific work is our 10 years old cohort of early PsA,
the early Swedish Psoriatic Arthritis Register (SwePsA) consisting of 360 patients where the main part has
been followed for 5 years. We recently published a study on inflammation in skin present in different PsA
classification groups and could show that there is a gross pathology of HA in both involved and noninvolved
psoriatic skin. Our future work will be focused on the inflammatory effect of LMW HA in
different sites of inflammation in PsA.
Members of the group during 2011
Lars Rönnblom, MD, PhD, Professor
Gunnar Alm, Professor em
Maija-Leena Eloranta, PhD, Assoc Professor
Gunnel Nordmark, MD, PhD
Karolina Tandre, PhD, Research engineer
Anne Trönnberg, BMA
Charlottta, Jakobsson, BMA
Olle Berggren, PhD student
Niklas Hagberg, PhD student
Dag Leonard, MD, PhD student
Karin Eriksson, MD, PhD student
107
Rezvan Kiani Dehkordi, Research nurse
Eva Baecklund, MD, PhD, associate professor
Ann Knight, MD, PhD
Gunnel Nordmark, MD, PhD
Lilian Vasaitis, MD, PhD student
Karin Hellgren, MD, PhD student
Amelie Kinch, MD, PhD student
Karin Hjorton, MD
Carin Backlin, Project coordinatator
Ulla Lindqvist, MD, associate professor.
Peter Matt, MD, PhD-student

Funding
Lars Rönnblom
Swedish research council 1200 kSEK
The Swedish SLE network (VR) 220 kSEK
Position LR (VR) 616 kSEK
King Gustav V 80 year foundation 450 kSEK
Gunnel Nordmark
King Gustav V 80 year foundation 100 kSEK
Swedish Rheumatism Society 150 kSEK
Maija-Leena Eloranta
King Gustav V 80 year foundation 100 kSEK
Eva Baecklund
Swedish Cancer Society 500 kSEK
King Gustav V 80 year foundation 100 kSEK
Lions Cancerfoundation 100 kSEK
108
Swedish Rheumatism Society 500 kSEK
ALF grant 1510 kSEK
Combine 1000 kSEK
Söderbergs foundation 443 kSEK
The Sjögren’s syndrome network 180 kSEK
ALF grant 50% position 575 kSEK
Eva Baecklund/Ann Knight
ALF grant 310 kSEK
Ulla Lindqvist
Swedish Psoriasis Society 150 kSEK
ALF grant 100 kSEK
Publications 2009-2011
1. Ley C, Ekman S, Ronéus B, Eloranta ML. Interleukin-6 and high mobility group box protein-1 in
synovial membranes and osteochondral fragments in equine osteoarthritis. Res Vet Sci, 2009; 86:490-
7.
2. Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun JG, Wang C, Padyukov L, Truedsson L,
Alm G, Eloranta ML, Jonsson R, Rönnblom L, Syvänen AC. Additive effects of the major risk alleles
of IRF5 and STAT4 in primary Sjögren´s syndrome. Genes Immune, 2009; 10:68-76.
3. Eloranta ML, Lövgren T, Finke D, Mathsson L, Rönnelid J, Kastner B, Alm GV, Rönnblom L.
Regulation of interferon- production induced by RNA-containing immune complexes in plasmacytoid
dendritic cells. Arthritis Rheum, 2009; 60:2418-27.
4. Isaksson M, Ardesjö B, Rönnblom L, Kämpe O, Eloranta ML, Lobell A. Plasmacytoid dendritic cells
promote priming of autoimmune Th17 cells and experimental autoimmune encephalomyelitis. Eur J
Imm, 2009; 39:2925-35.
5. Lood C, Gullstrand B, Truedsson L, Olin AI, Alm GV, Rönnblom L, Sturfelt G , Eloranta ML,
Bengtsson AA. C1q inhibits the immune complex induced IFNα production in plasmacytoid dendritic
cells – a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. Arthritis
Rheum, 2009; 60:3081-90.
6. Schepis D, Gunnarsson I, Eloranta ML, Lampa J, Jacobson SH, Kärre K, Berg L.Increased proportion
of CD56(bright) natural killer cells in active and inactive systemic lupus erythematosus. Immunology,
2009;126:140-6.
7. Espinosa A, Dardalhon V, Brauner S, et al.Loss of the lupus autoantigen Ro52/Trim 21 induces tissue
inflammation and systemic autoimmunity by disregulating the IL-23 Th17 pathway. J Exp Med, 2009;
206:1661-71.
8. Gateva V, Sandling JK, Hom G, et al. RR.A Large-Scale Replication Study Identifies TNIP1,
PRDM1, JAZF1, UHRF1BP1, and IL10 as Novel Risk Loci for Systemic Lupus Erythematosus.
Nature Gen, 2009;41:1228-33.

9. Enocsson H, Sjöwall C, Skogh T, Eloranta ML, Rönnblom L, Wetterö J. Interferon-alpha mediates
suppression of C-reactive protein (CRP) – explanation to muted CRP response in lupus flares?
Arthritis Rheum, 2009, 30;60 :3755-60.
10. Sokka T, Kautiainen H, Pincus T, Toloza S, Castelar Pinheiro G, Lazovskis J, et al. Disparities in
rheumatoid arthritis disease activity according to gross domestic product in 25 countries in the
QUEST-RA database. Annals of the Rheumatic Diseases. 2009;68:1666-1672.
11. Askling J, van Vollenhoven R, Granath F, Raaschou P, Fored C, Baecklund E, et al. Cancer risk in
patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies : does the risk
change with the time since start of treatment?. Arthritis and Rheumatism. 2009;60:3180-3189.
12. Arne M, Janson C, Janson S, Boman G, Lindqvist U, Berne C, et al. Physical activity and quality of
life in subjects with chronic disease : chronic obstructive pulmonary disease compared with
rheumatoid arthritis and diabetes mellitus. Scandinavian Journal of Primary Health Care. 2009;27:141-
147.
13. Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, et al. Anti-tumour necrosis
factor therapy in rheumatoid arthritis and risk of malignant lymphomas : relative risks and time trends
in the Swedish Biologics Register. Annals of the Rheumatic Diseases. 2009;68:648-653.
14. Svenungsson E, Gustafsson J, Leonard D, Sandling Jet al.. A STAT4 risk allele is associated with
ischemic cerebrovascular events and antiphospholipid antibodies in Systemic Lupus Erythematosus.
Ann Rheum Dis, 2010;69:834-40.
15. Feng D, Stone RC, Eloranta ML, Sangster-Guity N, Nordmark G, Sigurdsson S, Wang C, Alm GV,
Syvänen AC, Rönnblom L, Barnes BJ. Genetic variants and disease-associated factors contribute to
enhanced interferon regulatory factor 5 expression in blood cells of systemic lupus erythematosus
patients. Arthritis Rheum, 2010; 62:562-573.
16. Eloranta ML, Franck-Larsson K, Lövgren T, Kalamajski S, Rönnblom A, Rubin K, Alm GV,
Rönnblom L. Type I interferon system activation and association to disease manifestations in systemic
sclerosis. Ann Rheum Dis, 2010; 69:1396-402.
17. Lindqvist C, Christiansson L, Simonsson B, Enblad G, Olsson-Strömberg U, Loskog A. T regulatory
cells control T-cell proliferation partly by the release of soluble CD25 in patients with B-cell
malignancies. Immunology. 2010;131:371-376.
18. Nordmark G, Kristjansdottir G, Theander, E, Appel S, Eriksson P, Vasaitis L, Kvarnström M, Delaleu
N, Lundmark P, Lundmark A, Sjöwall C, Brun JG, Jonsson MV, Harboe E, Goransson LG, Söderkvist
P, Eloranta ML, Alm G, Baecklund E, Wahren-Herlenius M, Omdal R, Rönnblom L, Jonsson R,
Syvänen AC. Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with
primary Sjögren´s syndrome. Genes Immune, 2011, 12:100-9.
19. Sokka T, Kautiainen H, Pincus T, Verstappen S, Aggarwal A, Alten R, et al. Work disability remains
a major problem in rheumatoid arthritis in the 2000s : data from 32 countries in the QUEST-RA
Study. Arthritis Research & Therapy. 2010;12:R42-.
20. Hellgren K, Smedby K, Feltelius N, Baecklund E, Askling J. Do rheumatoid arthritis and lymphoma
share risk factors? : A comparison of lymphoma and cancer risks before and after diagnosis of
rheumatoid arthritis. Arthritis and Rheumatism. 2010;62:1252-1258.
21. Billing E, McKenna S, Staun M, Lindqvist U. Adaptation of the Psoriatic Arthritis Quality of Life
(PsAQoL) instrument for Sweden. Scandinavian Journal of Rheumatology. 2010;39:223-228.
22. Prokopec K, Rhodiner M, Matt P, Lindqvist U, Kleinau S. Down regulation of Fc and complement
receptors on B cells in rheumatoid arthritis. Clinical Immunology. 2010;137:322-329.
23. Hellgren K, Iliadou A, Rosenquist R, Feltelius N, Backlin C, Enblad G, et al. Rheumatoid arthritis,
treatment with corticosteroids, and risk of malignant lymphomas : results from a case-control study.
Annals of the Rheumatic Diseases. 2010;69:654-659.
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24. Knight A, Sandin S, Askling J. Increased risk of autoimmune disease in families with Wegener's
granulomatosis. J Rheumatol. 2010 Dec;37:2553-8.
25. Knight A, Sandin S, Askling J. Occupational risk factors for Wegener's granulomatosis: a case-control
study. Ann Rheum Dis. 2010 Apr;69:737-40.
26. Cunninghame Graham D, Morris D, Bhangale T, Criswell L, Syvänen A, Rönnblom L, et al.
Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus. PLoS
genetics. 2011;7(10):e1002341-.
27. Fernberg P, Edgren G, Adami J, Ingvar Å, Bellocco R, Tufveson G, et al. Time Trends in Risk and
Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients. American
Journal of Transplantation. 2011;11:2472-2482.
28. Löfström B, Backlin C, Pettersson T, Lundberg I, Baecklund E. Expression of APRIL in Diffuse
Large B Cell Lymphomas from Patients with Systemic Lupus Erythematosus and Rheumatoid
Arthritis. Journal of Rheumatology. 2011;38:1891-1897.
29. Baecklund E, Backlin C, Mansouri M, Klareskog L, Askling J, Iliadou A, et al. LMO2 protein
expression predicts survival in patients with rheumatoid arthritis and diffuse large B-cell lymphoma.
Leukemia and Lymphoma. 2011;52:1146-1149.
30. Lindqvist C, Christiansson L, Thörn I, Mangsbo S, Paul-Wetterberg G, Sundström C, et al. Both
CD4(+) oxP3(+) and CD4(+) oxP3(-) T cells from patients with B-cell malignancy express cytolytic
markers and kill autologous leukaemic B cells in vitro. Immunology. 2011;133:296-306.
31. Appel S, Le Hellard S, Bruland O, Brun J, Omdal R, Kristjansdottir G, et al. Potential association of
muscarinic receptor 3 gene variants with primary Sjogren's syndrome. Annals of the Rheumatic
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32. Simard J, Baecklund E, Kinch A, Brattström C, Ingvar Å, Molin D, et al. Pediatric Organ
Transplantation and Risk of Premalignant and Malignant Tumors in Sweden. American Journal of
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33. Smith C, Oscarson M, Rönnblom L, Alimohammadi M, Perheentupa J, Husebye E, et al. TSGA10-A
Target for Autoantibodies in Autoimmune Polyendocrine Syndrome Type 1 and Systemic Lupus
Erythematosus. Scandinavian Journal of Immunology. 2011;73:147-153.
34. Simard J, Arkema E, Sundström A, Geborek P, Saxne T, Baecklund E, et al. Ten years with biologics
: to whom do data on effectiveness and safety apply? Rhematology Int. 2011;50:204-213.
35. Leonard D, Akhter T, Nordmark G, Rönnblom L, Naessen T. Increased carotid intima thickness and
decreased media thickness in premenopausal women with systemic lupus erythematosus: an
investigation by non-invasive high-frequency ultrasound. Scandinavian Journal of Rheumatology.
2011;40:279-282.
36. Stone R, Feng D, Deng J, Singh S, Yang L, Fitzgerald-Bocarsly P, et al. IRF5 activation in monocytes
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37. Björkholm M, Ohm L, Eloranta S, Derolf Å, Hultcrantz M, Sjöberg J, et al. Success Story of Targeted
Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden
From 1973 to 2008. Journal of Clinical Oncology. 2011;29(18):2514-2520.
38. Ley C, Svala E, Nilton A, Lindahl A, Eloranta M, Ekman S, et al. Effects of high mobility group box
protein-1, interleukin-1β, and interleukin-6 on cartilage matrix metabolism in three-dimensional
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39. Sandling J, Garnier S, Sigurdsson S, Wang C, Nordmark G, Gunnarsson I, et al. A candidate gene
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40. Nordmark G, Kristjansdottir G, Theander E, Appel S, Eriksson P, Vasaitis L, et al. Association of
EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes
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derivative, in murine and human SLE. Arthritis and Rheumatism. 2011;
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encoding complement inhibitors CD46 and CFH affect the age at nephritis onset in patients with
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Reviews
1 Rönnelid J, Barbasso Helmers S, Storfors H, Grip C, Rönnblom L, Franck-Larsson K, Nordmark G,
Lundberg IE. Use of a commercial line blot assay as a screening test for autoantibodies in
inflammatory myopathies. Autoimmunity reviews, 2009; 9:58-61.
2. Finke D, Eloranta ML, Rönnblom L. Endogenous type I interferon inducers in autoimmune diseases.
Autoimmunity, 2009; 42: 349-352.
3. Pisetsky D, Rönnblom L. SLE: A matter of Life and death. Arthritis Rheum, 2009; 60:1567-70.
4. Rönnblom L, Alm GV, Eloranta ML. Type I interferon and lupus. Curr Opin Rheumatol, 2009;
21:471-7.
5. Rönnblom L. Potential role of IFN in adult lupus. Arthritis Res Ther, 2010, 12(Suppl 1):S3.
6. Rönnblom L, Elkon KB. Cytokines as therapeutic targets in systemic lupus erythematosus. Nature
Reviews Rheum, 2010; 6: 339-347.
7. Rönnblom L. The type I interferon system in the etiopathogenesis of autoimmune diseases. Uppsala
Journal of Medical Sciences. 2011;116(4):227-237.
8. Rönnblom L, Alm G, Eloranta M. The type I interferon system in the development of lupus. Seminars
in Immunology. 2011;23:113-121.
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Clinical Microbiology and Infection Medicine
The section for Clinical Microbiology and Infection medicine
consists of several individual groups with the common overall aim
to combat emerging and re-emerging infectious diseases. The
challenge of infection is quite unlike any other disciplines in
medicine, as it goes beyond the boundaries of knowledge about
mankind, requiring a broad perspective on human in relation to
nature, an insight in the biology of the microorganism, a deep
understanding of the host parasite interactions as well as a
humanistic approach on the individual patient. The profile of the
research groups has this plethora with the wide spectrum from the
individual patient at one end, to the infectious diseases in a changing
world at the other.
Infectious diseases
Björn Olsen, Jan Sjölin, Otto Cars, Hilpi Rautelin, Jonas Blomberg
Influenza
Josef Järhult, Neus Latorre-Margalef, Goran Orozovic, Conny Tolf, Anna Gillman, Jonas
Waldenström, and Björn Olsen
During the last century, Influenza A virus (IAV) caused three pandemics. In 1918-1920, the Spanish Flu
killed at least 50 million people. All pandemic viruses contain avian genetic material achieved through a
reassortment process. There are two different strategies used in treatment and prophylaxis of IAV: 1)
Vaccines are effective but the production of vaccines is slow, 2) antiviral drugs like the neuramidase
inhibitors oseltamivir (OC) (Tamiflu) and zanamivir (ZA) (Relenza) are the options in the early phase of a
pandemic. OC is stable in water and not removed or degraded in sewage treatment plants. In the
downstream water ducks, the natural reservoir of IAV, are exposed to OC resulting in resistance induction
of viruses in their gastrointestinal tract. With mallards as an animal model and by virological, chemical and
molecular techniques we have detected induction of resistance in IAV and retention of resistance mutations
in repeated replications and transmission without drug pressure. Our results will be of value for
organizations and authorities working with strategic pandemic preparedness planning, like WHO.
Campylobacter and other gastrointestinal pathogens
Johan Dicksved, Patrik Ellström, Petra Griekspoor, David Lennebratt, Anders Lannergård, Jenny
Olofsson, Jonas Waldenström, Hilpi Rautelin, Björn Olsen
Epidemiologically speaking the Campylobacter bacterium is still a conundrum. On one hand the bacterium
is considered as sensitive to environmental stress, while on the other hand it is widely distributed in several
host species. Furthermore, despite efforts we have not found efficient ways of reducing prevalence of the
bacteria in our farm animals and not fully understood re-colonization after stock rotations. Together with
continuing studies of Campylobacter in the natural reservoirs we have taken a new grip on the
epidemiology of Campylobacter. Building on the knowledge gained, we will use our own novel
epidemiological tools, and some of the latest state of the art techniques to explore a very promising
unresolved epidemiological pathway – the role of protozoan as intermediate hosts for survival in the
environment. This pathway will be complemented with a population genetic characterization of
campylobacters from humans, farm animals, wild birds and water using the technique of multilocus
sequence typing on a unique collection of strains.
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Tick borne infections
Erik Salaneck, Christian Ehrenborg, Göran Günther, Mats Lindeborg, Emma Löfström, Björn
Olsen
Birds fly. This fact makes them extremely important as vehicle and transmitters of various parasites and
potential carriers of pathogenic microorganisms. The new concept ”ornithological-medicine” is a research
area that will give new insights into the ecology, epidemiology and infection biology of vector borne
infections in general and tick born infections in particular. A basic knowledge on the mechanisms of the
spread of and occurrence of zoonoses will be very important for agriculture and veterinary medicine.
Borrelia spp and Ehrlichia spp. can cause serious infections in animals and humans and therefore basic
research on the biology, pathogenicity and virulence of tick borne zoonoses is important. We will study the
importance of seabirds and terrestrial birds in the dispersal of the tick borne pathogens. Further, by
developing infection models we can study the interaction, virulence, pathology and infection biology
between host, vector and microorganism.
Interplay between antibacterial and antifungal treatment and innate and
specific immunological responses in severe infections
Mia Furebring, Miklos Lipcsey, Markus Castegren, Anders Lignell, Eva Söderberg, Paul Skorup,
Anna Hedberg, Eva Tano, Jan Sjölin
The overall aim is to study the interplay between treatment and innate and specific immunological
responses in severe sepsis and septic shock as well as in neurosurgical infections. Translational projects
involving clinical studies, in vitro experiments and animal models with a focus mainly on clinical issues
that cannot be solved by randomized clinical trials.
During 2011 the importance of bactericidal antibiotic effect for the treatment of septic shock has been
studied in our intensive care porcine model in order to relate the pharmacodynamic effects to clinical
outcome parameters in hypoperfusion and organ dysfunction. To more closely mimic the clinical situation
we have also developed secondary sepsis models by using the biological effects of endotoxin tolerance.
The effect of endotoxin tolerance on clinical symptoms has not previously been well studied, but in a recent
study we have shown that organ dysfunction, induced by the systemic inflammatory response, was
attenuated in in all organs studied with the exception of the lungs, where a worse outcome was seen.
In order to better understand the negative results of clinical trials on immunomodulating therapy for the
adjunctive treatment in septic shock, the temporal development of endotoxin tolerance and antiinflammatory
mechanisms is currently being studied by the use of our long-term intensive care sepsis
model. With this model that suppresses the innate host response we have also started to develop ventilatorassociated
pneumonia models and Candida infection models for the study of the pharmacodynamic effects
of antifungals.
Two pharmacodynamic studies have been published during 2011. In the first study, an in vitro
pharmacokinetic model for combination studies of drugs with different half lives was used and it was
demonstrated that voriconazole interacted negatively with the fungicidal effect of amphotericin B, also in
Candida strains with defined resistance mechanisms to voriconazole. In the second study the effect of
protein binding was studied and the concept of free drug concentration being principally responsible for the
pharmacodynamic effect was challenged.
A clinical study evaluating the pharmacodynamic effect of aminoglycosides for the treatment of
gramnegative meningitis has been published and we could show that the addition of aminoglycosides to �lactam
antibiotics improves the effect by fewer relapses and shorter treatment durations, probably by an
increased bacterial killing capacity. In neurosurgical patients the effect of the innate immune response on
the specific immunity has been studied by vaccination of patients with T-cell dependent and T-cell
independent vaccines.
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Development of treatment strategies for bacterial infections in order to
increase dosage efficacy and reduce resistance development.
Otto Cars, Elisabeth Löwdin, Thomas Tängdén, Matti Karvanen, Patricia Komp Lindgren, Pernilla
Lagerbäck, Juliana Larsson, Christer Malmberg, Rachel Hickman, Petter Bertilsson-Forsberg, Lisa
Albrecht
Infections with multi drug resistant (MDR) Gram negative bacteria are a rapidly increasing concern worldwide
and new antibiotic groups with Gram negative effect are not expected within the next 10 years. This is
a major threat to modern medicine which is dependent on effective antibiotics after surgery,
immunosuppressive therapies etc. In the absence of new antibiotics, we aim to optimize the use, dosage
regimens and combinations of existing antibiotics with respect to bactericidal effect as well as minimizing
the risk for emergence of resistant strains. Our studies include the carbapenems, colistin and tigecycline
which are often the last effective treatment for infections with MDR Gram negative bacteria.
By looking at the pharmacodynamics and pharmacokinetics of different drugs, alone and in combination at
both static concentrations and in our in vitro kinetic system which mimics human pharmacokinetics, we can
improve the knowledge on how to design dosage regimens for optimal antibacterial efficacy and optimal
resistance prevention. In collaboration with the pharmacometrics group at Uppsala University in silico
models are also created to better predict the efficacy of different dosing regimens.
For example, we have screened several antibiotic combinations by time-kill experiments in vitro against
e.g. Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, where we have some
interesting, previously unreported indications of increased antibacterial effect with the chosen combinations
(two to three drugs) compared to the drugs alone. The effect of ertapenem at different dosage against E.coli
with and without an ESBL plasmid has also been investigated as well as the magnitude of the inconvenient
artefact caused by unspecific binding of colistin to glass and plastic in commonly used laboratory material.
MDR development and resistance prevention in Acinetobacter baumannii is also under investigation,
including molecular mechanisms, mutator phenotypes and fitness costs of mutants, with specific aim at
colistin and tigecyclin. All of this work is important to discover suitable candidates for combination
therapies in clinical use.
Cytomegalovirus infections
Britt-Marie Eriksson, Fredrik Sund, Gabriel Westman
CMV specific and general T-cell immunity was studied in 50 patients with Alzheimers disease and in 50
age-matched controls. Our hypothesis was that persons with Alzheimers disease have an aged immune
system with an immune profile corresponding to that seen in the very old with an inversed CD4:CD8 ratio
and a shift from naive T-cells to memory T-cells. In CMV-seropositive individuals a great proportion of Tcells
directed to CMV antigen has been observed. Flow cytometry with tetramer analysis as well as highly
sensitive CRP and Il-6 analyses have now been performed, and the results are now analyzed. The study is
carried out in collaboration with Dep. of Geriatrics (Lars Lannfelt) and Clinical Immunology (Olle
Korsgren, Anna-Karin Lidehäll).
In collaboration with the specialists of gastro-intestinal diseases and microbiology (Mari Thörn, Per
Sangfelt, Fredrik Rorsman, Kåre Bondeson) enteric biopsies have been collected from patients with newly
diagnosed inflammatory bowel disease (IBD). Patients with irritable bowel syndrome serve as controls. The
purpose is to find out if CMV has a pathogenic role in IBD from start or is reactivated in patients treated
with immunosuppression. Also, viral presence in biopsies is compared to amount of viral DNA in faeces.
Up till now around 80 out of 120 patients have been included.
Antibiotic Resistance
Karin Bergström, Jonas Bonnedahl, Mirva Drobni, Badrul Hasan, Johan Kaarme, Birgitta Lytsy,
Ylva Molin, Johan Stedt, Susanne Sütterlin, Åsa Melhus, Björn Olsen,
The main force behind emergence of antibiotic resistance is the use of antimicrobial agents in human and
veterinary medicine and domestic animal husbandry, providing a strong selection pressure for bacteria to
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acquire resistance. However, there is also evidence that epidemic spread of drug-resistant bacteria and
horizontal transfer of resistance genes are contributing factors to resistance emergence. It is important to
realize that there are no closed systems – the bacteria we select for in environments close to humans will,
back and forth, find their way to bacterial communities in nature and vice versa. In recent studies, we have
shown the presence of antibiotic resistant bacteria in areas lacking antibiotic usage. This strongly indicates
that the resistance emergence in countries like Sweden, are not only governed by national concerns but also
by what happens in a larger context. The knowledge of antibiotic resistance in the environment is still
limited and we need to find methods to explore this field and link it to consumption of antibiotics in our
societies. We have brought together experts in different fields to evaluate how bacterial resistance is
transferred and maintained within all potential reservoirs, including humans, domestic animals, wildlife and
the environment. Our strengths complement each other in terms of methodological and practical skills, and
in our joint team we have physicians, veterinarians, ecologists, micro- and molecular biologists, and
chemists. Further, we harbour valuable sets of bacterial collections from different reservoirs that are a good
foundation for comparative studies.
Exo- och endogenous retroviruses, and development of new diagnostics
Jonas Blomberg, Christina Öhrmalm, Amal Elfaitouri, Vidar Blikstad, Anna Sjösten, Agnes Bölin-
Wiener
We study the occurrence of both exo- and endogenous retroviruses, devolop new diagnostics, and are also
engaged in the safety issues during blood transfusions and transplantation. Endogenous retroviruses (ERVs)
are present in all vertebrates. Their pathogenic potential is largely unknown. Especially active ERVs occur
in mice, cats and pigs. They are potental zoonotic sources of contagion. We have a unique database of
retroviruses, as well as unique bioinformatics tools, so we are well positioned to develop diagnostic test for
these viruses. We investigate if some of them are associated with the chronic fatigues syndrome. With
respect to diagnosis, we have continued to work with our, now patented, multiplex nucleic acid based assay
Variation tolerant Capture Multiplex Assay; VOCMA. Using this technique we have developed several
diagnostic microbiological panels. A new type of multiplex serological test for IgG and IgM antibodies has
also been developed, and used on sera from blood donors and patients suffering from the Chronic fatigue
syndrome.
Antiviral resistance
Johan Lennerstrand, Per Stålhandske, Sultan Golbob, Despina Triantafillidou, Ciara Quigley
We are focusing on antiviral resistance to Hepatitis C virus (HCV) and HIV. Current treatment of HCV
with interferon and ribavirin is only partially effective, but new more effective drugs, e.g. protease
inhibitors, are under way. As there are natural, pre-existing, protease-resistant mutations, we have
developed a molecular diagnostic method that allows us to detect protease-resistant mutations in a broad
spectrum of HCV genotypes. The method will be used to monitor resistance to a novel protease inhibitor in
a clinical study in the Uppsala region. We are also developing novel methods for clinical use in disease
progression and monitoring of recidive during antimetabolite cancer therapy. The patented method platform
enables measuring several DNA building block enzyme activities simultaneously, in real-time and in
solution.
Virus-induced immune suppression – novel therapeutic targets in hepatitis C
and other chronic virus infections
Anders Bergqvist, Kåre Bondeson, Bo Albinsson, Bengt Kallin, Sara Sundström, Juan Wang
Hepatitis C virus (HCV) constitutes a global health problem since it often causes persistent infections with
chronic hepatitis that may result in liver cirrhosis and liver cancer. No robust protection against challenge
has yet been accomplished and antiviral chemotherapy is hampered by considerable side-effects and limited
efficiency. To combat the disease, a better understanding of the intrinsic features of the virus and the
specific immune response that decides disease progression is therefore essential. Previous studies have
shown HCV chronicity is associated with a dysfunctional T cells response. We have shown that expression
115

of the HCV core protein triggers calcium oscillations that activates the nuclear factor of activated T cell
(NFAT) pathway. Prolonged expression of core resulted in anergy-like, hyporesponsive state characterized
by decreased inducibility of IL-2 – a cytokine required for sustained CTL responses. We are further
deciphering the mechanisms whereby HCV counteracts the development of an efficient immune response
and pathology. The results of our study will give a better understanding of the disease and may provide a
novel rational for treatment of HCV infections.
Pathogenesis in severe cases of flu and other respiratory infections,
and multiplex methods for molecular diagnosis
Kåre Bondeson, Bo Albinsson, Midori Kjellin, Karolina Gullsby, Bengt Kallin, Anders Bergqvist
Influenza and other respiratory diseases constitute a major health problem worldwide. Although most cases
resolves spontaneously without major consequences, a significant fraction will display more serious
complications that require intensive care and may have fatal outcome, including viral pneumonia and acute
respiratory distress syndrome. The aim of the study is to identify the critical factors that are associated with
severe disease outcome. Characterization of the disease mechanisms and factors associated with pathology
will facilitate future identification of specific risk groups that require more individualized health care. We
also develop new sensitive and more specific molecular diagnostics that can identify B. pertussis and other
Bordetella spp., as well as several highly multiplexed real-time PCR methods of bacterial and viral targets.
New virus vaccines
Bror Morein, Kefei Hu, Saideh Berenjian
Based on the now established ISCOM-technology, we have developed a new adjuvant concept for vaccine
against several viruses, including influenza, RSV and rabies. We are also developing new anti-cancer
drugs: The concept is based on differentation of effect on replication versus apoptosis. Xenograft
experiments have shown effects in vivo.
Members of the groups during 2011
Björn Olsen, MD PhD, Professor
Jan Sjölin MD, PhD, Professor,
Otto Cars MD, PhD, Professor,
Hilpi Rautelin, MD PhD, Professor
Jonas Blomberg, MD, PhD, Professor emiritus
Bror Morein, VMD, PhD, Professor emiritus
Göran Friman, Professor emeritus
Gunnar Kahlmeter, Adjunct professor
Nils Ilbäck, Adjunct professor
Björn Herrmann PhD, Assoc. Professor.
Eva Hjelm PhD, Assoc. Professor
Åsa Melhus, PhD, MD, Assoc. Professor
Jonas Waldenström, PhD, Assoc Professor
Johan Lennerstrand, PhD, Assoc. Professor
Lovisa Svensson, PhD
Conny Tolf, PhD, Post-Doc
Diana Axelsson-Olsson, PhD
John Wahlgren, PhD
Mirva Drobni, PhD, Post-Doc
Erik Salaneck MD, PhD
116
Jonas Bonnedahl, MD PhD student
Jorge Hernandez, PhD student
Neus Latorre-Margalef, PhD student
Badrul Hasan, Vet. PhD student
Jenny Olofsson, PhD student
Josef Järhult, MD, PhD student
Stefan Svahn, PhD student
Johan Stedt, PhD student
Petra Griekspoor, PhD student.
Patrik Ellström PhD
Johan Dicksved PhD
Anders Lannergård, MD, PhD
David Lennebratt MD PhD student
Anna Nilsson Biomedical Scientist
Eva Haxton coordinator, Ph Lic
Christian Ehrenborg MD, PhD
Mats Lindeborg, MD, PhD student
Emma Löfström, MD, PhD student
Göran Günther, MD, PhD
Christina Nyström-Rosander MD, PhD

Marie Edvinsson MD, PhD
Markus Klint, PhD Post-doc
Guma Abdeldaim, PhD
Linus Christerson, PhD student
Rachel Hickman, Lab Technician
Petter Bertilsson-Forsberg, project worker
Lisa Albrecht, project worker
Maria Blomqvist, project worker
Kenneth Nilsson, PhD, MD.
Karin Elfving, PhD student
Katharina Wallménius, project worker
Susanne Sütterlin, MD, PhD student
Johan Kaarme, MD, PhD student
Birgitta Lytsy MD, PhD
Ylva Molin, Post-doc
Marie Gisselsson-Solén
Karin Bergström, veterinary, PhD-student
Miklos Lipcsey MD, PhD,
Mia Furebring MD, PhD,
Markus Castegren PhD student
Anders Lignell PhD student
Eva Söderberg PhD student
Paul Skorup PhD student
Anna Hedberg PhD student
Elisabeth Löwdin, MD, PhD
Thomas Tängdén, MD, PhD student
Matti Karvanen, PhD student
Pernilla Lagerbäck, Post doc
Patricia Komp Lindgren, Post doc
Juliana Larsson, Lab Technician
Funding 2011
FORMAS 2.5 MSEK
Gov. Strategic Grant 2.5 MSEK
VR 0.9 MSEK
VR/MSB/FORMAS 1.5 MSEK
EU 2.0 MSEK
Olle Engkvist Foundation 1.5 MSEK
ALF 4.7 MSEK
Publications 2009-2011
117
Christer Malmberg, Lab Technician
Martin Sundqvist, MD, PhD
Erika Matuschek PhD
Peter Drobni, PhD
Lena Bieber, Lab. Technician
Jenny Åhman, Lab. Technician
Stina Bengtsson, MA, Ecologist
Robert Smyth, Microbiologist
Charlotte Bjelkenbrant, Microbiologist
Gunilla Cederbrant, Microbiologist
Hanna Odén, Lab. Technician
Alexandra Porcak, Ecologist
Kåre Bondeson, MD PhD
Anders Bergqvist, PhD, researcher
Per Stålhandske, PhD, researcher
Bo Albinsson, MD PhD
Bengt Kallin, PhD, ass prof
Christina Öhrmalm, PhD, postdoc
Amal Elfaitouri, PhD, postdoc
Kefei Hu, PhD
Saideh Berenjian, PhD
Vidar Blikstad, MD, PhD-student
Agnes Bölin-Wiener, MD
Sultan Golbob, BMA
Despina Triantafillidou, BMA stud
Ciara Quigley, student
Sara Sundström, PhD-student (KI)
Juan Wang, student
Vinnova 1.2 MSEK
SSF 0.8 MSEK
Ohlinder Nielsen Fundation 0.2 MSEK
KAW Foundation 0.4 MSEK
MERUK and ESCMID 0.6 MSEK
Per Sundquist foundation 1.0 MSEK
Regional Research Council 0.5 MSEK
1. Nilsson K. Septicaemia with Rickettsia helvetica in a patient with acute febrile illness, rash and
myasthenia. Journal of Infection. 2009;58(1):79-82.

2. Jansson B, Karvanen M, Cars O, Plachouras D, Friberg L. Quantitative analysis of colistin A and
colistin B in plasma and culture medium using a simple precipitation step followed by LC/MS/MS.
Journal of Pharmaceutical and Biomedical Analysis. 2009;49(3):760-767.
3. Söderström H, Järhult J, Olsen B, Lindberg R, Tanaka H, Fick J. Detection of the antiviral drug
oseltamivir in aquatic environments. PloS one. 2009;4(6):e6064-.
4. Olsen B, Ehrenborg C. Svininfluensan har kraft att utvecklas till en pandemi. DN-debatt, 28 april.
2009;
5. Sylvan S, Madalinski K, Hellstrom U. Anti-preS responses influence the anti-HBs response in
newborns after vaccination with the third generation Sci-B-Vac (TM) vaccine. Vaccine.
2009;28(2):446-451.
6. Latorre-Margalef N, Gunnarsson G, Munster V, Fouchier R, Osterhaus A, Elmberg J, et al. Does
influenza A affect body condition of wild mallard ducks, or vice versa? : A reply to Flint and Franson.
Proceedings of the Royal Society of London. Biological Sciences. 2009;276(1666):2347-2349.
7. Jaenson T, Eisen L, Comstedt P, Mejlon H, Lindgren E, Bergström S, et al. Risk indicators for the
tick Ixodes ricinus and Borrelia burgdorferi sensu lato in Sweden. Blackwell; Medical and Veterinary
Entomology. 2009;23(3):226-237.
8. Vikerfors A, Haggar A, Darenberg J, Low A, Melhus Å, Hedlund J, et al. Severe group A
streptococcal infections in Uppsala County, Sweden : clinical and molecular characterization of a case
cluster from 2006 to 2007. Scandinavian Journal of Infectious Diseases. 2009;41(11-12):823-830.
9. Bergman A, Lignell A, Melhus Å. The first documented case of Aspergillus cardiac surgical site
infection in Sweden : an epidemiology study using arbitrarily primed PCR. Acta Pathologica,
Microbiologica et Immunologica Scandinavica (APMIS). 2009;117(8):568-74.
10. Lipcsey M, Carlsson M, Larsson A, Algotsson L, Eriksson M, Lukinius A, et al. Effect of a single
dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour
porcine model. Critical Care Medicine. 2009;37(10):2782-2790.
11. Carlsson M, Lipcsey M, Larsson A, Tano E, Rubertsson S, Eriksson M, et al. Inflammatory and
circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic
shock : a model of endotoxin elimination. Critical Care Medicine. 2009;37(3):1031-e4.
12. Sendi P, Johansson L, Dahesh S, Van-Sorge N, Darenberg J, Norgren M, et al. Bacterial phenotype
variants in group B streptococcal toxic shock syndrome. Emerging Infectious Diseases.
2009;15(2):223-232.
13. Heddini A, Cars O, Qiang S, Tomson G. Antibiotic resistance in China : a major future challenge. The
Lancet. 2009;373(9657):30-30.
14. Örtqvist Å, Holmberg H, Norman C, Cars O. Doxycyklin är ingen -hostmedicin : Antibiotika vid akut
bronkit är både onödigt och riskabelt. Läkartidningen. 2009;106(24-25):1666-7.
15. Earnshaw S, Monnet D, Duncan B, O'Toole J, Ekdahl K, Goossens H, et al. European Antibiotic
Awareness Day, 2008 - the first Europe-wide public information campaign on prudent antibiotic use :
methods and survey of activities in participating countries. Euro surveillance : bulletin européen sur
les maladies transmissibles = European communicable disease bulletin. 2009;14(30):19280-.
16. Skorup P, Rizzo L, Machado-Boman L, Janson C. Asthma management and asthma control in Sao
Paulo, Brazil and Uppsala, Sweden : a questionnaire-based comparison. The Clinical Respiratory
Journal. 2009;3(1):22-28.
17. Studahl M, Günther G, Rosengren L. Serum S-100B protein levels in patients with herpes simplex
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Trimethoprim use. PLoS ONE. 2010;5(2):e9233-.
127. Sundqvist M, Geli P, Andersson D, Sjölund-Karlsson M, Runehagen A, Cars H, et al. Little evidence
for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use. Oxford
University Press; Journal of Antimicrobial Chemotherapy. 2010;65(2):350-360.
128. Molin Y, Frisk P, Hjelm E, Blomberg J, Friman G, Ilbäck N. Arsenic trioxide influences viral
replication in target organs of coxsackievirus B3-infected mice. Microbes and infection. 2010;12(12-
13):1027-1034.
129. Klint M, Thollesson M, Bongcam-Rudloff E, Birkelund S, Nilsson A, Herrmann B. Mosaic structure
of intragenic repetitive elements in histone H1-like protein Hc2 varies within serovars of Chlamydia
trachomatis. BioMed Central; BMC Microbiology. 2010;10:81-.
130. Edvinsson M, Hjelm E, Thelin S, Friman G, Nyström-Rosander C. Presence of Chlamydophila
pneumoniae DNA but not mRNA in stenotic aortic heart valves. International Journal of Cardiology.
2010;143(1):57-62.
131. Blomberg J, Sperber G, Jern P, Benachenhou F. Towards a retrovirus database, RetroBank. In:
Centennial Retrovirus Meeting. Prague, Czech Republic: Medimond International Proceedings,
Bologna, Italy; 2010. p. 19-22.
132. Xia H, Liu L, Nordengrahn A, Kiss I, Merza M, Eriksson R, et al. A microsphere-based immunoassay
for rapid and sensitive detection of bovine viral diarrhoea virus antibodies. Journal of Virological
Methods. 2010;168(1-2):18-21.
133. LeBlanc N, Leijon M, Jobs M, Blomberg J, Belak S. A novel combination of TaqMan RT-PCR and a
suspension microarray assay for the detection and species identification of pestiviruses. Veterinary
Microbiology. 2010;142(1-2):81-86.
125

134. Muradrasoli S, Bálint A, Wahlgren J, Waldenström J, Belák S, Blomberg J, et al. Prevalence and
phylogeny of coronaviruses in wild birds from the Bering Strait area (Beringia). PLoS ONE.
2010;5(10):e13640-.
135. Hu K, Berenjian S, Larsson R, Gullbo J, Nygren P, Lövgren T, et al. Nanoparticulate Quillaja saponin
induces apoptosis in human leukemia cell lines with a high therapeutic index. International Journal of
Nanomedicine. 2010;5(1):51-62.
136. Benachenhou F. Retroviral long Terminal Repeats; Structure, Detection and Phylogeny. [Thesis].
Uppsala: Acta Universitatis Upsaliensis; 2010. Digital Comprehensive Summaries of Uppsala
Dissertations from the Faculty of Medicine, 531.
137. Molin Y, Frisk P, Hjelm E, Blomberg J, Friman G, Ilbäck N. Arsenic trioxide influences viral
replication in target organs of coxsackievirus B3-infected mice. Microbes and infection. 2010;12(12-
13):1027-1034.
138. Abdeldaim G, Strålin K, Korsgaard J, Blomberg J, Herrmann B. Multiplex quantitative PCR for
detection of lower respiratory tract infection and meningitis caused by Streptococcus pneumoniae,
Haemophilus influenzae and Neisseria meningitidis. BMC Microbiology. 2010;10:310-.
139. Muradrasoli S, Mohamed N, Belák S, Czifra G, Herrmann B, Berencsi G, et al. Broadly targeted
triplex real-time PCR detection of influenza A, B and C viruses based on the nucleoprotein gene and a
novel "MegaBeacon" probe strategy. Journal of Virological Methods. 2010;163(2):313-322.
140. Fernberg P, Edgren G, Adami J, Ingvar Å, Bellocco R, Tufveson G, et al. Time Trends in Risk and
Risk Determinants of Non-Hodgkin Lymphoma in Solid Organ Transplant Recipients. American
Journal of Transplantation. 2011;11(11):2472-2482.
141. Edberg M, Furebring M, Sjölin J, Enblad P. Neurointensive care of patients with severe communityacquired
meningitis. Acta Anaesthesiologica Scandinavica. 2011;55(6):732-739.
142. Zeitlinger M, Derendorf H, Mouton J, Cars O, Craig W, Andes D, et al. Protein Binding : Do We
Ever Learn?. Antimicrobial Agents and Chemotherapy. 2011;55(7):3067-3074.
143. Naik S, Lundberg J, Kumar R, Sjölin J, Jansen J. Economic evaluation of caspofungin versus
liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and
neutropenia in Sweden. Scandinavian Journal of Infectious Diseases. 2011;43(6-7):504-514.
144. Cars O, Hedin A, Heddini A. The global need for effective antibiotics : moving towards concerted
action. Drug resistance updates. 2011;14(2):68-69.
145. Alvan G, Edlund C, Heddini A. The global need for effective antibiotics : a summary of plenary
presentations. Drug resistance updates. 2011;14(2):70-76.
146. Grundmann H, Klugman K, Walsh T, Ramon-Pardo P, Sigauque B, Khan W, et al. A framework for
global surveillance of antibiotic resistance. Drug resistance updates. 2011;14(2):79-87.
147. Freire-Moran L, Aronsson B, Manz C, Gyssens I, So A, Monnet D, et al. Critical shortage of new
antibiotics in development against multidrug-resistant bacteria-Time to react is now. Drug resistance
updates. 2011;14(2):118-124.
148. Tängdén T, Enblad P, Ullberg M, Sjölin J. Neurosurgical Gram-Negative Bacillary Ventriculitis and
Meningitis : A Retrospective Study Evaluating the Efficacy of Intraventricular Gentamicin Therapy in
31 Consecutive Cases. Clinical Infectious Diseases. 2011;52(11):1310-1316.
149. Haemig P, Sjöstedt de Luna S, Grafström A, Lithner S, Lundkvist Å, Waldenström J, et al.
Forecasting risk of tick-borne encephalitis (TBE) : Using data from wildlife and climate to predict
next year's number of human victims. Scandinavian Journal of Infectious Diseases. 2011;43(5):366-
372.
150. Pedersen C, Alsiö Å, Lagging M, Langeland N, Färkkilä M, Buhl M, et al. Ribavirin plasma
concentration is a predictor of sustained virological response in patients treated for chronic hepatitis C
virus genotype 2/3 infection. Journal of Viral Hepatitis. 2011;18(4):245-251.
126

151. Andremont A, Bonten M, Kluytmans J, Carmeli Y, Cars O, Harbarth S. Fighting bacterial resistance at
the root : need for adapted EMEA guidelines. Lancet. Infectious diseases (Print). 2011;11(1):6-8.
152. Orozovic G, Orozovic K, Lennerstrand J, Olsen B. Detection of Resistance Mutations to Antivirals
Oseltamivir and Zanamivir in Avian Influenza A Viruses Isolated from Wild Birds. PLoS ONE.
2011;6(1):e16028-.
153. Simard J, Baecklund E, Kinch A, Brattström C, Ingvar Å, Molin D, et al. Pediatric Organ
Transplantation and Risk of Premalignant and Malignant Tumors in Sweden. American Journal of
Transplantation. 2011;11(1):146-151.
154. Nielsen E, Cars O, Friberg L. Pharmacokinetic/Pharmacodynamic (PK/PD) indices of antibiotics
predicted by a semi-mechanistic PKPD model : a step toward model-based dose optimization.
Antimicrobial Agents and Chemotherapy. 2011;55(10):4619-4630.
155. Nielsen E, Cars O, Friberg L. Predicting in vitro antibacterial efficacy across experimental designs
with a semimechanistic pharmacokinetic-pharmacodynamic model. Antimicrobial Agents and
Chemotherapy. 2011;55(4):1571-1579.
156. Lipcsey M, Furebring M, Rubertsson S, Larsson A. Significant differences when using creatinine,
modification of diet in renal disease, or cystatin C for estimating glomerular filtration rate in ICU
patients. Uppsala Journal of Medical Sciences. 2011;116(1):39-46.
157. Jourdain E, Olsen B, Lundkvist Å, Hubálek Z, Sikutová S, Waldenström J, et al. Surveillance for
West Nile Virus in Wild Birds from Northern Europe. Vector Borne and Zoonotic Diseases.
2011;11(1):77-79.
158. Lignell A. In vitro Pharmacodynamics of Antifungal Agents in the Treatment of Candida Infections.
[Thesis]. Uppsala: Acta Universitatis Upsaliensis; 2011. Digital Comprehensive Summaries of
Uppsala Dissertations from the Faculty of Medicine, 633.
159. Lignell A, Löwdin E, Cars O, Sanglard D, Sjölin J. Voriconazole-induced inhibition of the fungicidal
activity of amphotericin B in Candida strains with reduced susceptibility to voriconazole : an Effect
Not Predicted by the MIC Value Alone. Antimicrobial Agents and Chemotherapy. 2011;55(4):1629-
1637.
160. Hasan B, Faruque R, Drobni M, Waldenström J, Sadique A, Uddin Ahmed K, et al. High prevalence
of antibiotic resistance in pathogenic Escherichia coli from large- and small-scale poultry farms in
Bangladesh. Avian diseases. 2011;55(4):689-692.
161. Ardiles-Villegas K, González-Acuña D, Waldenström J, Olsen B, Hernández J. Antibiotic resistance
patterns in fecal bacteria isolated from Christmas shearwater (Puffinus nativitatis) and masked booby
(Sula dactylatra) at remote Easter Island. Avian diseases. 2011;55(3):486-489.
162. Chryssanthou E, Wennberg H, Bonnedahl J, Olsen B. Occurrence of yeasts in faecal samples from
Antarctic and South American seabirds. Mycoses (Berlin). 2011;54(6):e811-e815.
163. Keller J, Shriver W, Waldenström J, Griekspoor P, Olsen B. Prevalence of Campylobacter in wild
birds of the mid-Atlantic region, USA. Journal of Wildlife Diseases. 2011;47(3):750-754.
164. Haemig P, Sjöstedt de Luna S, Grafström A, Lithner S, Lundkvist Å, Waldenström J, et al.
Forecasting risk of tick-borne encephalitis (TBE) : using data from wildlife and climate to predict next
year's number of human victims. Scandinavian Journal of Infectious Diseases. 2011;43(5):366-372.
165. Lindell F, Barker G, Lannergård A. Vanligt med antibiotikaresistens hos barn med urinvägsavledning.
Läkartidningen. 2011;108(46):2376-2379.
166. Gårdlund B, Cronqvist J, Follin P, Furebring M, Gille-Johnson P, Sjölin J. Svår sepsis och septisk
chock kräver omedelbart omhändertagande : [Severe sepsis and septic shock require immediate care].
Läkartidningen. 2011;108(6):271-275.
127

167. Svefors J, Vikerfors T, Furebring M, Lanbeck P, Otto G, Gårdlund B. Nationellt kvalitetsregister kan
ge bättre vård vid livshotande sepsis : [National quality registry can improve care in life-threatening
sepsis]. Läkartidningen. 2011;108(6):279-281.
168. Edberg M, Furebring M, Sjölin J, Enblad P. Neurointensive care of patients with severe communityacquired
meningitis. Acta Anaesthesiologica Scandinavica. 2011;55(6):732-739.
169. Lignell A, Löwdin E, Cars O, Chryssanthou E, Sjölin J. Posaconazole in human serum : A greater
pharmacodynamic effect than predicted by the non-protein-bound serum concentration. Antimicrobial
Agents and Chemotherapy. 2011;55(7):3099-3104.
170. Kashem M, Hashem M, Kabir M, Hasan B. Performances of two commercially available Newcastle
disease vaccines in Bangladesh: A case-control study. 2011;28(2):88-91.
171. Järhult J. Tamiflu® - Use It and Lose It? [Thesis]. Uppsala: Acta Universitatis Upsaliensis; 2011.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 725.
172. Tängdén T, Eriksson B, Melhus Å, Svennblad B, Cars O. Radical reduction of cephalosporin use at a
tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum
beta-lactamase-producing Klebsiella pneumoniae. Journal of Antimicrobial Chemotherapy.
2011;66(5):1161-1167.
173. Günther G, Haglund M, Lindquist L, Forsgren M, Andersson J, Andersson B, et al. Ticke-borne
encephalitis is associated with low levels of interleukin-10 in cerebrospinal fluid.. Infection Eceology
and Epidemiology. 2011;1:6029-.
174. Castegren M. Modulating Organ Dysfunction in Experimental Septic Shock : Effects of
Aminoglycosides, Antiendotoxin Measures and Endotoxin Tolerance. [Thesis]. Uppsala: Acta
Universitatis Upsaliensis; 2011. Digital Comprehensive Summaries of Uppsala Dissertations from the
Faculty of Medicine, 655.
175. Titelman E, Iversen A, Kahlmeter G, Giske C. Antimicrobial susceptibility to parenteral and oral
agents in a largely polyclonal collection of CTX-M-14 and CTX-M-15-producing Escherichia coli and
Klebsiella pneumoniae. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS).
2011;119(12):853-863.
176. Nilsson K, Wallménius K, Påhlson C. Coinfection with Rickettsia helvetica and Herpes simplex virus
2 in a Young Woman with Meningoencephalitis. Hindawi Publishing Corporation; Case Reports in
Infectious Diseases. 2011;:469194-.
177. Revez J, Rossi M, Ellström P, de Haan C, Rautelin H, Hänninen M. Finnish Campylobacter jejuni
Strains of Multilocus Sequence Type ST-22 Complex Have Two Lineages with Different
Characteristics. PLoS ONE. 2011;6(10):e26880-.
178. Gisselsson-Solén M, Melhus Å, Hermansson A. Pneumococcal vaccination in children at risk of
developing recurrent acute otitis media: a randomized study. Acta Paediatrica. 2011;100(10):1354-
1358.
179. Feodoroff B, Lauhio A, Ellström P, Rautelin H. A Nationwide Study of Campylobacter jejuni and
Campylobacter coli Bacteremia in Finland over a 10-Year Period, 1998-2007, with Special Reference
to Clinical Characteristics and Antimicrobial Susceptibility. Clinical Infectious Diseases.
2011;53(8):e99-e106.
180. Unemo M, Shipitsyna E, Domeika M. Gonorrhoea surveillance, laboratory diagnosis and
antimicrobial susceptibility testing of Neisseria gonorrhoeae in 11 countries of the eastern part of the
WHO European region. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS).
2011;119(9):643-649.
181. Bom R, Christerson L, van der Loeff M, Coutinho R, Herrmann B, Bruisten S. Evaluation of High-
Resolution Typing Methods for Chlamydia trachomatis in Samples from Heterosexual Couples.
Journal of Clinical Microbiology. 2011;49(8):2844-2853.
128

182. Christerson L. High Resolution Genotyping of Chlamydia trachomatis. [Thesis]. Uppsala:
Acta Universitatis Upsaliensis; 2011. Digital Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine, 690.
183. Christerson L, Ruettger A, Gravningen K, Ehricht R, Sachse K, Herrmann B. High-Resolution
Genotyping of Chlamydia trachomatis by Use of a Novel Multilocus Typing DNA
Microarray. Journal of Clinical Microbiology. 2011;49(8):2838-2843.
184. Glazkova S, Golparian D, Titov L, Pankratova N, Suhabokava N, Shimanskaya I, et al. Antimicrobial
susceptibility/resistance and molecular epidemiological characteristics of Neisseria gonorrhoeae in
2009 in Belarus. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS).
2011;119(8):537-542.
185. Shimanskaya I, Zhurauskaya L, Pankratov O, Unemo M, Ballard R, Domeika M. Evaluation of Three
Serological Tests Manufactured in Belarus for the Diagnosis of Syphilis. Acta Dermato-
Venereologica. 2011;91(3):299-302.
186. Domeika M, Babayan K, Ismailov R, Shimanskaya I, Chudomirova K, Brilene T, et al. Survey of
Diagnostic Services for Genital Herpes in Fourteen Countries in Eastern Europe. Acta Dermato-
Venereologica. 2011;91(3):333-336.
187. Schön T, Juréen P, Chryssanthou E, Giske C, Sturegård E, Kahlmeter G, et al. Wild-type distributions
of seven oral second-line drugs against Mycobacterium tuberculosis. The International Journal of
Tuberculosis and Lung Disease. 2011;15(4):502-509.
188. Pankratov O, Shimanskaya I, Pankratov V, Navrotsky A, Ballard R, Unemo M, et al. Laboratory
Diagnosis of Sexually Transmitted Infections in Belarus. Acta Dermato-Venereologica.
2011;91(1):64-65.
189. Tano E, Melhus Å. Evaluation of three swab transport systems for the maintenance of clinically
important bacteria in simulated mono- and polymicrobial samples. Acta Pathologica, Microbiologica
et Immunologica Scandinavica (APMIS). 2011;119(3):198-203.
190. Ruettger A, Feige J, Slickers P, Schubert E, Morre S, Pannekoek Y, et al. Genotyping of Chlamydia
trachomatis strains from culture and clinical samples using an ompA-based DNA microarray assay.
Molecular and Cellular Probes. 2011;25(1):19-27.
191. Jourdain E, van Riel D, Munster V, Kuiken T, Waldenstrom J, Olsen B, et al. The Pattern of
Influenza Virus Attachment Varies among Wild Bird Species. PLoS ONE. 2011;6(9):e24155-.
192. Christerson L, de Vries H, Klint M, Herrmann B, Morre S. Multilocus sequence typing of urogenital
Chlamydia trachomatis from patients with different degrees of clinical symptoms. Sexually
Transmitted Diseases. 2011;38(6):490-494.
193. Klint M, Hadad R, Christerson L, Lore B, Anagrius C, Österlund A, et al. Prevalence trends in
Sweden for the new variant of Chlamydia trachomatis. Clinical Microbiology and Infection.
2011;17(5):683-689.
194. Bender N, Herrmann B, Andersen B, Hocking J, van Bergen J, Morgan J, et al. Chlamydia infection,
pelvic inflammatory disease, ectopic pregnancy and infertility: cross-national study. Sexually
Transmitted Infections. 2011;87(7):601-608.
195. Tängdén T, Eriksson B, Melhus Å, Svennblad B, Cars O. Radical reduction of cephalosporin use at a
tertiary hospital after educational antibiotic intervention during an outbreak of extended-spectrum
beta-lactamase-producing Klebsiella pneumoniae. Journal of Antimicrobial Chemotherapy.
2011;66(5):1161-1167.
196. Elfaitouri A, Shao X, Ulfstedt J, Muradrasoli S, Böhlin Wiener A, Golbob S, et al. Murine
Gammaretrovirus Group G3 Was Not Found in Swedish Patients with Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. PLoS ONE. 2011;6(10):e24602-.
197. Reed D, Currier R, Walton S, Conrad M, Sullivan S, Carlton J, et al. The evolution of infectious
agents in relation to sex in animals and humans : brief discussions of some individual organisms. In:
129

Evolution of infectious agents in relation to sex. 2011. 1230p. 74-107. Annals of the New York
Academy of Sciences, 1230.
198. Barrio A, Ekerljung M, Jern P, Benachenhou F, Sperber G, Bongcam-Rudloff E, et al. The First
Sequenced Carnivore Genome Shows Complex Host-Endogenous Retrovirus Relationships. PLOS
ONE. 2011;6(5):e19832-.
199. Nerpin E, Ingelsson E, Risérus U, Sundström J, Larsson A, Jobs E, et al. The combined contribution
of albuminuria and glomerular filtration rate to the prediction of cardiovascular mortality in elderly
men. Nephrology, Dialysis and Transplantation. 2011;26(9):2820-2827.
200. Bröjer C, Järhult J, Muradrasoli S, Söderström H, Olsen B, Gavier-Widén D. Pathobiology and virus
shedding of low pathogenic avian influenza virus (A/H1N1) infection in mallards exposed to
oseltamivir. Journal of Wildlife Diseases. 2011;
201. Järhult J, Muradrasoli S, Wahlgren J, Söderström H, Orozovic G, Gunnarsson G, et al. Environmental
levels of the antiviral oseltamivir induce development of resistance mutation H274Y in influenza
A/H1N1 virus in mallards. PLoS ONE. 2011;6(9):e24742-.
Dissertations 2011
Jonas Bonnedal: Antibiotic resistance in Enterobacteriaceae isolated from wild birds.
Markus Castegren: Modulating organ dysfunction in experimental septic shock: effects of
aminoglycosides, antiendotoxin measures and endotoxin tolerance
Josef Järhult: Tamiflu ® - use it or lose it?
Anders Lignell: In vitro pharmacodynamics of antifungal agents in the treatment of Candida infections.
130

Cardiology and Clinical physiology
The organization consists of three separate groups performing
research in ischemic heart disease and heart failure, arrhythmia
and cardio-pulmonary aspects in acute and chronic lung disease,
respectively. In ischemic heart disease the focus is on Acute
Coronary Syndromes, heart failure and atherothrombotic disease
in general. A major part of the work is the evaluation of
treatments by performing large clinical trials and by quality
registry based evaluation of treatments in clinical routine. In
cardiac arrhythmia there are two main research projects: Atrial
Fibrillation - assessment of Mechanism and novel Interventional
Therapies, and Molecular investigation of Inherited Cardiac
Arrhythmogenic Syndromes. In the area of clinical physiology
focus is on impeded lung function during anaesthesia and in
acute respiratory failure, with an increasing orientation towards
lung inflammation.
Cardiology
Bertil Lindahl
For a long time the research group’s main focus has been on Acute Coronary Syndromes and to a lesser
degree, on heart failure. In recent years the interest has been broadened to atherothrombotic disease in
general and around the coagulation system and platelet function in particular. In order to be able to improve
the treatment and management for the individual patient we work in the following areas:
Understanding the disease(-s) and the unmet needs
We have performed a large number of epidemiological studies based on quality registers or other
epidemiological cohorts. Among these are:
� PCI-related interventions (154).
� Evidence-based treatment and survival for patients with ST-elevation myocardial infarction (165)
� Genetic studies (152, 162,)
� Relation between treatment for prostatic cancer and risk of ischemic heart disease (144).
� Miscellaneous (129, 148, 157, 166)
We also conduct quite a few pathophysiological studies:
� Evalutating effects of opoid receptor agonists on reduction of infarct size in different procine
models (119).
� Platelet function and genetic testing for identification of response to P2Y12 inhibition and the risk
of stent thrombosis and myocardial infarction was investigated in a local case-control study
(TOPAS) of 169 patient recruited from the Swedish Coronary Angiograpy and Angioplasty
Registry (SCAAR). The results verified a difference in the platelet inhibitory effect of clopidogrel
between patients with and without stent thrombosis but with a substantial overlap between cases
and controls (143).
� Effects of antithrombotic treatment on platelet activity and inflammation (140)
� Miscellaneous (161)
131

Diagnosis, risk assessment and tailoring of treatment
During the year the group has continued the elucidation of the pathophysiological basis and the usefulness
of different biomarkers for diagnosis and prognosis of overt or concealed coronary and/or myocardial
disease as well as in development of new assay technologies (93, 124, 132, 134, 138, 164).
Currently the underlying mechanisms are investigated by studies using arrays of biomarkers, coronary
angiograms, CT-angiograms, MRI and also animal and cell studies (133, 139, 142).
Evaluation of treatments
In order to evaluate both old and new treatments we perform both Industry sponsored driven randomized
clinical trials (RCTs), independent, quality registry associated RCTs as well as Quality registry based
evaluation of treatments in clinical routine.
During the year the group has led, analysed and worked on the reporting of studies of adding oral
anticoagulation (the fXa-inhibitor apixaban) to the current routine treatment with aspirin and clopdogrel as
secondary prevention after acute coronary syndrome (141).
We have also e.g. investigated the clinical efficacy and safety of the new reversible P2Y12 inhibitor
ticagrelor in the large PLATO trial (127,130, 146, 147) and the thrombin inhibitor dabigatran in the large
RELY trial (122, 128, 135, 136, 149, 163).
Miscellaneous (101, 150, 153, 155, 156, 158, 159, 160).
Implementation of treatment
During 2011 the results of the randomized quality improvement study: European Quality Improvement
Programme for Acute Coronary Syndrome (EQUIP) have been published; showed that a systematic
improvement program can significantly improve the management of non-ST elevation acute coronary
syndromes (123).
Also other interventions aimed at improving outcome after AMI have been evaluated in randomized or
controlled studies (113, 131).
Members of the group during 2011
Bertil Lindahl, Professor
Lars Wallentin, Professor emeritus
Frank Flachskampf, Professor
Stefan James, Associate professor
Jonas Oldgren, Associate professor
Claes Held, Associate professor
Gerhard Wikström, Associate professor
Bo Lagerqvist, Post Doc
Erik Björklund, Post Doc
Christina Christersson, Post Doc
Emil Hagström, Post Doc
Nina Johnston, Post Doc
Kai Eggers, Post Doc
Christoph Varenhorst, Post Doc
Mohammamd Kavianipour, Post Doc
Axel Åkerblom, Ph.D student
Ziad Hijazi, Ph.D student
132
Cathrin Henriksson, Ph.D student
Birgitta Jönelid, Ph.D student
Julia Aulin, MD
Ola Vedin, MD
Thomasz Baron, Post Doc
Birgitta Fahlström, BMA
Helena Vretman, BMA
Cecilia Jakobsson, Research nurse
Annika Gunnarsson, Research nurse
Helena Wall, Research nurse
Catrin Henriksson, Research nurse
Maria Andreasson, Research nurse
Anita Öström, Adm. assistance

Funding
Swedish Heart-Lung foundation 5.6 MSEK
ALF 3.5 MSEK
Stiftelsen för strategisk forksning – ”Total-AMI" 0.5 MSEK
Industrial grants 10 MSEK
Publications 2009-2011
1. Lindqvist P, Henein MY, Wikström G Right ventricular myocardial velocities and timing estimate
pulmonary artery systolic pressure. Int J Cardiol. 2009 Oct 2;137(2):130-6.
2. Lindqvist P, Wikström G, Waldenström A The use of E/Em and the time interval difference of
isovolumic relaxation (TIVRT-IVRTm) in estimating left ventricular filling pressures. Eur J Heart
Fail. 2008 May;10(5):490-7.
3. James SK, Wallentin L, Lagerqvist B; Swedish Coronary Angiography and Angioplasty Registry
(SCAAR) study group.The SCAAR-scare in perspective. EuroIntervention. 2009 Sep;5(4):501-4.
4. Bonaca MP, Steg PG, Feldman LJ, Canales JF, Ferguson JJ, Wallentin L, Califf RM, Harrington RA,
Giugliano RP. Antithrombotics in acute coronary syndromes. J Am Coll Cardiol. 2009 Sep
8;54(11):969-84.
5. Wallentin L, Becker RC, Budaj A, et al. the PLATO Investigators. Ticagrelor versus Clopidogrel in
Patients with Acute Coronary Syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57.
6. Connolly SJ, Ezekowitz MD, Yusuf S, et al the RE-LY Steering Committee and Investigators.
Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009 Sep
17;361(12):1139-51
7. Szummer K, Lundman P, Jacobson SH, Schön S, Lindbäck J, Stenestrand U, Wallentin L, Jernberg T;
SWEDEHEART. Influence of renal function on the effects of early revascularization in non-STelevation
myocardial infarction: data from the Swedish Web-System for Enhancement and
Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended
Therapies (SWEDEHEART). Circulation. 2009 Sep 8;120(10):851-8.
8. Eggers KM, Lagerqvist B, Venge P, Wallentin L, Lindahl B. Prognostic value of biomarkers during
and after non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2009 Jul
21;54(4):357-64.
9. Lind L, Wallentin L, Kempf T, Tapken H, Quint A, Lindahl B, Olofsson S, Venge P, Larsson A,
Hulthe J, Elmgren A, Wollert KC. Growth-differentiation factor-15 is an independent marker of
cardiovascular dysfunction and disease in the elderly: results from the Prospective Investigation of the
Vasculature in Uppsala Seniors (PIVUS) Study. Eur Heart J. 2009 Oct;30(19):2346-53.
10. Björck L, Rosengren A, Wallentin L, Stenestrand U. Smoking in relation to ST-segment elevation
acute myocardial infarction: findings from the Register of Information and Knowledge about Swedish
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111. Norhammar A, Lagerqvist B, Saleh N. Long-term mortality after PCI in patients with diabetes
mellitus: results from the Swedish Coronary Angiography and Angioplasty Registry.
EuroIntervention. 2010 Apr;5(8):891-7.
112. Plüss CE, Billing E, Held C, Henriksson P, Kiessling A, Karlsson MR, Wallen HN. Long-term effects
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Michaëlsson K, Lind L, Arnlöv J. Plasma parathyroid hormone and risk of congestive heart failure in
the community. Eur J Heart Fail. 2010 Nov;12(11):1186-92.
114. Bennermo M, Nordin M, Lundman P, Boqvist S, Held C, Samnegård A, Ericsson CG, Silveira A,
Hamsten A, Nastase MM, Tornvall P. Genetic and Environmental Influences on the Plasma
Interleukin-6 Concentration in Patients with a Recent Myocardial Infarction: A Case-Control Study. J
Interferon Cytokine Res. 2010 Nov 17.
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Reduction in Acute Coronary Syndrome (TRA*CER) trial: study design and rationale Am Heart J.
2009 Sep;158(3):327-334.e4. Erratum in: Am Heart J. 2010 May;159(5):932
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complications: risk predictors from RIKS-HIA. Heart. 2010 Sep;96(18):1451-7.
117. Bergh CH, Andersson B, Dahlström U, et al Intravenous levosimendan vs. dobutamine in acute
decompensated heart failure patients on beta-blockers. Eur J Heart Fail. 2010 Apr;12(4):404-10.
118. Bergh CH, Andersson B, et al.Intravenous Levosimendan Versus Dobutamine in Acute
Decompensated Heart Failure Patients On Beta-Blockers. Eur J Heart Fail. 2010 Apr;12(4):404-10.
119. Åkerblom A, James S, et al. Eptifibatide is Non-inferior to Abciximab in Primary PCI - Results from
the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). J Am Coll Cardiol. 2010
Aug 3;56 (6):470-475.
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120. Karlsson LO, Grip L, Bissessar E,et al. Opioid receptor agonist Eribis peptide 94 reduces infarct size
in different porcine models for myocardial ischaemia and reperfusion. Eur J Pharmacol. 2011 Jan
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121. Niemelä M, Kervinen K, Erglis A, et al for the Nordic-Baltic PCI Study Group. Randomized
Comparison of Final Kissing Balloon Dilatation Versus No Final Kissing Balloon Dilatation in
Patients With Coronary Bifurcation Lesions Treated With Main Vessel Stenting: The Nordic-Baltic
Bifurcation Study III. Circulation. 2011 Jan 4;123(1):79-86.
122. Oldgren J, Alings M, Darius H, Diener H, Eikelboom J, Ezekowitz M, et al. Risks for Stroke,
Bleeding, and Death in Patients With Atrial Fibrillation Receiving Dabigatran or Warfarin in Relation
to the CHADS(2) Score : A Subgroup Analysis of the RE-LY Trial. Annals of Internal Medicine.
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evaluate the effects of a quality improvement program on management of non-ST-elevation acute
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129. Henriksson C, Larsson M, Arnetz J, Berglin-Jarlöv M, et al. Knowledge and attitudes toward seeking
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131. Grip L, Lindahl B, Levin L, Kärvinge C, Eklund K, Wallentin L. From European to National
guidelines on heart disease. Scandinavian Cardiovascular Journal. 2011;45(1):3-13.
132. Eggers K, Jaffe A, Venge P, Lindahl B. Clinical implications of the change of cardiac troponin I levels
in patients with acute chest pain - An evaluation with respect to the Universal Definition of
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myocardial infarction. European Heart Journal. 2011;32(3):272-283.
134. Bonaca M, Morrow D, Braunwald E, Cannon, et al. Growth Differentiation Factor-15 and Risk of
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IT-TIMI 22. Arteriosclerosis, Thrombosis and Vascular Biology. 2011;31(1):203-210.
135. Eikelboom J, Wallentin L, Connolly S, Ezekowitz M, Healey J, Oldgren J, et al. Risk of Bleeding
With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial
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Fibrillation An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-
LY) Trial. Circulation. 2011;123(21):2363-2372.
136. Liesenfeld K, Lehr T, Dansirikul C, Reilly P, et al. Population pharmacokinetic analysis of the oral
thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY
trial. Journal of Thrombosis and Haemostasis. 2011;9(11):2168-2175.
137. Lopes R, Becker R, Alexander J, Armstrong P, Califf R, Chan M, et al. Highlights from the III
International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, São
Paulo, Brazil. Journal of Thrombosis and Thrombolysis. 2011;32(2):242-266.
138. Jaffe A, Lindahl B, Katus H. Sensitive troponin I assay in patients with suspected acute coronary
syndrome. Journal of the American Medical Association (JAMA). 2011;306(5):488-9; author reply
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139. Armstrong P, Siha H, Fu Y, Westerhout C, Steg P, James S, et al. ST Elevation Acute Coronary
Syndromes in PLATO : Insights from the ECG Substudy. Circulation. 2011;
140. Christersson C, Oldgren J, Wallentin L, Siegbahn A. Treatment with an Oral Direct Thrombin
Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with
Myocardial Infarction.. Journal of Internal Medicine. 2011;270(3):215-223.
141. Oldgren J, Budaj A, Granger C, Khder Y, Roberts J, Siegbahn A, et al. Dabigatran vs. placebo in
patients with acute coronary syndromes on dual antiplatelet therapy : a randomized, double-blind,
phase II trial. European Heart Journal. 2011;32(22):2781-2789.
142. Themudo R, Lindahl B, Johansson L, Venge P, Ahlström H, Barbier C, et al. Unrecognized
myocardial scars detected by delayed-enhanced MRI are associated with increased levels of NTproBNP.
Coronary Artery Disease. 2011;22(3):158-164.
143. Varenhorst C, Koul S, Erlinge D, Lagerqvist B, Siegbahn A, Wallentin L, et al. Relationship between
Clopidogrel-Induced Platelet P2Y12 Inhibition and Stent Thrombosis or Myocardial Infarction after
Percutaneous Coronary Intervention : A Case-Control Study. American Heart Journal.
2011;162(2):363-371.
144. Robinson D, Garmo H, Lindahl B, van Hemelrijck M, Adolfsson J, Bratt O, et al. Ischemic heart
disease and stroke before and during endocrine treatment for prostate cancer in PCBaSe Sweden.
International Journal of Cancer. 2011;
145. Thygesen K, Mair J, Mueller C, Huber K, et al. Recommendations for the use of natriuretic peptides
in acute cardiac care : A position statement from the Study Group on Biomarkers in Cardiology of the
ESC Working Group on Acute Cardiac Care. European Heart Journal. 2011;
146. Storey R, Becker R, Harrington R, Husted S, James S, Cools F, et al. Characterization of dyspnoea in
PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes.
European Heart Journal. 2011;32(23):2945-2953.
147. Storey R, Becker R, Harrington R, Husted S, James S, Cools F, et al. Pulmonary function in patients
with acute coronary syndrome treated with ticagrelor or clopidogrel. American Journal of Cardiology.
2011;108(11):1542-1546.
148. Zimmermann S, Flachskampf F, et al. Out-of-hospital cardiac arrest and percutaneous coronary
intervention for ST-elevation myocardial infarction : Long-term survival and neurological outcome.
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149. Oldgren J, Alings M, Darius H, Diener H, Eikelboom J, Ezekowitz M, et al. Risks for stroke,
bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the
CHADS2 score : a subgroup analysis of the RE-LY trial. Annals of Internal Medicine.
2011;155(10):660-667, W204.
150. Melloni C, James S, White J, Giugliano R, Harrington R, Huber K, et al. Safety and efficacy of
adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function.
American Heart Journal. 2011;162(5):884-892.
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151. Ludvigsson J, James S, Askling J, Ingelsson E. Response to Letter Regarding Article, "Nationwide
Cohort Study of Risk of Ischemic Heart Disease in Patients With Celiac Disease". Circulation.
2011;124(16):E423-E423.
152. Strawbridge R, Dupuis J, et al. Genome-Wide Association Identifies Nine Common Variants
Associated With Fasting Proinsulin Levels and Provides New Insights Into the Pathophysiology of
Type 2 Diabetes. Diabetes. 2011;60(10):2624-2634.
153. Gharacholou S, Lopes R, Alexander K, Mehta R, et al. Age and Outcomes in ST-Segment Elevation
Myocardial Infarction Treated With Primary Percutaneous Coronary Intervention : Findings From the
APEX-AMI Trial. Archives of Internal Medicine. 2011;171(6):559-567.
154. Koutouzis M, Lagerqvist B, James S, Omerovic E, Matejka G, Grip L, et al. Unfractionated heparin
administration in patients treated with bivalirudin during primary percutaneous coronary intervention
is associated lower mortality and target lesion thrombosis : a report from the Swedish Coronary
Angiography and Angioplasty Registry (SCAAR). Heart. 2011;97(18):1484-1488.
155. Wang T, White J, Tricoci P, et al. Upstream Clopidogrel Use and the Efficacy and Safety of Early
Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early
Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary
Syndrome (EARLY ACS) Trial. Circulation. 2011;126(7):722-730.
156. Harnek J, Webb J, Kuck K, Tschope C, et al. Transcatheter Implantation of the MONARC Coronary
Sinus Device for Mitral Regurgitation 1-Year Results From the EVOLUTION Phase I Study (Clinical
Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for The Treatment
of Mitral Regurgitation). JACC. Cardiovascular interventions. 2011;4(1):115-122.
157. Ludvigsson J, James S, Askling J, Stenestrand U, Ingelsson E. Nationwide Cohort Study of Risk of
Ischemic Heart Disease in Patients With Celiac Disease. Circulation. 2011;123(5):483-490.
158. Niemelä M, Kervinen K, Erglis A, Holm N, Maeng M, Christiansen E, et al. Randomized
Comparison of Final Kissing Balloon Dilatation Versus No Final Kissing Balloon Dilatation in
Patients With Coronary Bifurcation Lesions Treated With Main Vessel Stenting : The nordic-baltic
bifurcation study III. Circulation. 2011;123(1):79-86.
159. Morice M, Feldman T, Mack M, Ståhle E, et al. Angiographic outcomes following stenting or
coronary artery bypass surgery of the left main coronary artery : fifteen-month outcomes from the
synergy between PCI with TAXUS express and cardiac surgery left main angiographic substudy
(SYNTAX-LE MANS). EuroIntervention : journal of EuroPCR in collaboration with the Working
Group on Interventional Cardiology of the European Society of Cardiology. 2011;7(6):670-679.
160. Melloni C, James S, White J, Giugliano R, Harrington R, Huber K, et al. Safety and efficacy of
adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function.
American Heart Journal. 2011;162(5):884-892.e1.
161. Kanoni S, Nettleton J, Hivert M, Ye Z, van Rooij F, Shungin D, et al. Total zinc intake may modify
the glucose-raising effect of a zinc transporter (SLC30A8) variant : a 14-cohort meta-analysis.
Diabetes. 2011;60(9):2407-2416.
162. Strawbridge R, Dupuis J, Prokopenko I, Barker A, Ahlqvist E, Rybin D, et al. Genome-wide
association identifies nine common variants associated with fasting proinsulin levels and provides new
insights into the pathophysiology of type 2 diabetes. Diabetes. 2011;60(10):2624-2634.
163. Nagarakanti R, Ezekowitz M, Oldgren J, et al. Dabigatran Versus Warfarin in Patients With Atrial
Fibrillation An Analysis of Patients Undergoing Cardioversion. Circulation. 2011;123(2):131-136.
164. Eggers KM, Nygren M, Venge P, Jernberg T, Wikström BG. High-sensitive troponin T and I are
related to invasive hemodynamic data and mortality in patients with left-ventricular dysfunction and
precapillary pulmonary hypertension. Clin Chim Acta. 2011 Aug 17;412(17-18):1582-8.
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165. Jernberg T, Johanson P, Held C, Svennblad B, Lindbäck J, Wallentin L; SWEDEHEART/RIKS-HIA.
Association between adoption of evidence-based treatment and survival for patients with ST-elevation
myocardial infarction. JAMA. 2011 Apr 27;305(16):1677-84.
166. Larsson S, Lawyer P, Garellick G, Lindahl B, Lundström M. Disease Registries: Use Of 13 Disease
Registries In Five Countries Demonstrates The Potential To Use Outcomes Data To Improve Health
Care’s Value. Health Affairs. 2011 Nov. [Epub ahead of print]
Reviews 2009-2011
1. Charytan DM, Wallentin L, Lagerqvist B, Spacek R, De Winter RJ, Stern NM, Braunwald E, Cannon
CP, Choudhry NK. Early angiography in patients with chronic kidney disease: a collaborative
systematic review. Clin J Am Soc Nephrol. 2009 Jun;4(6):1032-43.
2. S. James, L. Wallentin, B .Lagerqvist. SCAAR scare in perspective. EuroIntervention. 2009
Sep;5(4):501-4
3. Nagueh SF, Appleton CP, Gillebert TC, et al Recommendations for the evaluation of left ventricular
diastolic function by echocardiography. Eur J Echocardiogr. 2009 Mar;10(2):165-93.
4. Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms of action and potential
consequences for clinical use. Eur Heart J. 2009 Aug;30(16):1964-77.
5. Gharacholou SM, Lopes RD, Washam JB, Newby LK, James SK, Alexander JH. Antithrombotic
therapy in acute coronary syndromes: guidelines translated for the clinician. J Thromb Thrombolysis.
2010 May;29(4):516-28.
6. Tubaro M, Danchin N, Goldstein P,et al. Pre-hospital treatment of STEMI patients. A scientific
statement of the Working Group Acute Cardiac Care of the European Society of Cardiology. Acute
Card Care. 2011 May 31. [Epub ahead of print]
7. Lindahl B. Are There Really Biomarkers of Vulnerable Plaque? Clin Chem. 2011 Aug 11. [Epub
ahead of print].
Dissertations 2011
Catrin Henriksson: Coronary Heart Disease and Early Decision Making, from Symptoms to Seeking
Care: Studies with Focus on Pre-hospital Delay in Acute Myocardial Infarction Patients.
144

Cardiology-Arrhythmia
Carina Blomström-Lundqvist
The research group focuses on two different areas, atrial fibrillation (AF) and inherited heart diseases. AF
is associated with decreased quality of life, increased morbidity and mortality. Anti-arrhythmic agents have
poor long term effects for control of AF, and may contribute to the observed higher death rate in AF
populations. Our aim is therefore to assess the mechanism of AF, develop novel surgical and catheter based
interventions for the elimination of AF and to assess predictors of AF recurrence.
Some inherited heart diseases unfold symptom-free or without abnormal findings on examination and may
remain undiagnosed until sudden cardiac death (SCD) occurs. Diagnostic tests and risk stratification tools
are lacking. This translational project aims to identify i) novel genetic mutations in inherited heart diseases
associated with increased risk of SCD and ii) genetic and phenotype risk markers for life-threatening
ventricular arrhythmias, with the goal to develop a quick screening test for these conditions.
Atrial Fibrillation - assessment of arrhythmia mechanism and novel
interventional therapies
There are three ongoing projects evaluating non-pharmacological treatment strategies for AF:
� The CAPTAF (Catheter Ablation compared with Pharmacological Therapy for Atrial Fibrillation)
study, a Nordic multicenter, randomised study comparing the efficacy and safety of pulmonary
vein isolation versus antiarrhythmic drugs as a treatment strategy in AF with regard to quality of
life as primary end-point.
� In substudies of our completed national SWEDMAF trial, we have e.g. evaluated the effects of the
concomitant epicardial catheter based Maze surgery on heart function and further analyzed the
effects on patient’s quality of life.
� The RAMCOR (Randomised AF ablation study using Cryo Or Radiofrequency energy) have
included 60 % of patients with paroxysmal AF, scheduled for pulmonary vein isolation with either
cryo-balloon ablation or radiofrequency ablation, using a novel circular ablation catheter.
Endpoints studied include AF burden, quality of life, atrial function and procedure related
variables.
There are also studies assessing AF mechanism, including analyses of various surgical techniques, which
lesion sets are associated with the highest AF elimination rate and the role of vagal denervation for
elimination of AF. Other projects evaluate the role of inflammation and pre-thrombotic state for the
initiation and perpetuation of atrial fibrillation
Molecular investigation of Inherited Cardiac Arrhythmogenic Syndromes - The
MICAS project.
Some inherited heart diseases unfold symptom-free or without abnormal findings on examination and may
remain undiagnosed until sudden cardiac death (SCD) occurs. Diagnostic tests and risk stratification tools
are lacking. This translational project aims to identify i) novel genetic mutations in inherited heart diseases
associated with increased risk of SCD and ii) genetic and phenotype risk markers for life-threatening
ventricular arrhythmias, with the goal to develop a quick screening test for these conditions. Genetic assays
to screen for mutations in the genes coding for desmoplakin, plakophyllin, plakoglobulin and novel
mutations are being developed and found mutations will be compared with clinical findings (phenotypes) to
create risk markers for life threatening ventricular arrhythmias in Arrhythmogenic Right Ventricular
Cardiomyopathy (ARVC) and other inherited heart diseases, suitable for screening and risk stratification.
The genetic analysis will be performed on samples from SCD victims, patients and their relatives using
Sanger sequencing and/or a screening assay of all exons in these genes. Novel mutations identified in dogs
with ARVC will be searched for in selected patients. The projects are all in collaboration with Marie Allen,
Gen. Path. Department, and Kerstin Lindahl Toh, with co-workers, at Broad Institute and BMC.
145

During 2010 we have started to analyze the most common gene in ARVC: the plakophilin 2 (PKP2) gene,
covering about 45% of ARVC affected individuals. In a pilot study, all 14 exons of PKP2 gene were
screened for mutations by bi-directional Sanger sequencing. So far, we have identified pathogenic
mutations in 14 of 66 (21%) patients from the cardiology clinic with suspected ARVC.
Members of the group during 2011
Carina Blomström Lundqvist, Professor
Per Blomström, Assistant Professor
Birgitta Johansson, M.D., Ph.D.
Stefan Lönnerholm, M.D., Ph.D.
Priit Teder, M.D., Ph.D.
Louise Bagge, PhD student
Helena Malmborg, PhD student
Bozena Ostrowska, PhD student
146
Elena Sciaraffia, PhD student
Johan Probst, PhD student
David Mörtsell, PhD student
Linnea Persson, nurse
Linda Pertell-Hammarlöf, nurse
Carl Sandström, nurse
Åsa Eriksson, assistant
Publications 2009-2011
1. Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA
Investigators (Blomström P). Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J
Med. 2009 Feb 12;360(7):668-78. Erratum in: N Engl J Med. 2009 Jun 4;360(23):2487.
2. Malmborg H, Lönnerholm S, Blomström Lundqvist C. A prospective randomised comparison of
large-tip cryoablation and 8-mm-tip radiofrequency catheter ablation of atrial flutter. Interv Card
Electrophysiol 2009 Mar;24(2):127-31.
3. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, Filippatos G, Fox K, Huber
K, Kastrati A, Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M. ESC guidelines
on management of acute myocardial infarction in patients presenting with persistent ST-segment
elevation. Rev Esp Cardiol. 2009 Mar;62(3):293. English, Spanish.
4. Wikstrom G, Blomström Lundqvist C, Andren B, Lönnerholm S, Blomström P, Freemantle N, Remp T,
Cleland JG; on behalf of the CARE-HF study investigators. The effects of aetiology on outcome in patients
treated with cardiac resynchronization therapy in the CARE-HF trial. Eur Heart J. 2009 Apr;30(7):782-8.
5. ACTIVE Investigators (Blomström P), Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M,
Chrolavicius S, Yusuf S. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N
Engl J Med. 2009 May 14;360(20):2066-78.
6. Bagge L, Blomström P, Nilsson L, Myrdahl G, Jideus L, Blomström Lundqvist C. Epicardial offpump
pulmonary vein isolation and vagal denervation improve long-term outcome and quality of life
in patients with atrial fibrillation. J Thorac Cardiovasc Surg. 2009 May:137(5):1265-71.
7. Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, et al. Management of acute myocardial
infarction in patients presenting with persistent ST-segment elevation. G Ital Cardiol (Rome). 2009
Jul;10(7):450-89. Italian.
8. Lönnerholm S, Blomström P, Nilsson L, Blomström-Lundqvist C. A high quality of life is maintained
late after Maze III surgery for atrial fibrillation. Eur J Cardiothorac Surg. 2009 Sep;36(3):558-62.
9. Sciaraffia E, Malmborg H, Lönnerholm S, Blomström P, Blomström Lundqvist C. The use of
impedance cardiography for optimizing the interventricular stimulation interval in cardiac
resynchronization therapy – a comparison with left ventricular contractility. J Interv Card
Electrophysiol. 2009 Sep;25(3):223-8.
10. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA,
Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC,

Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in
patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51.
11. Sciaraffia E, Malmborg H, Lönnerholm S, Blomström P, Blomström Lundqvist C. Right ventricular
contractility as a measure of optimal interventricular pacing setting in cardiac resynchronization
therapy. Europace. 2009 Nov;11(11):1496-500.
12. Kirchhof P, Bax J, Blomstrom-Lundqvist C, et al. Early and comprehensive management of atrial
fibrillation: Proceedings from the 2 nd AFNET-EHRA consensus conference on atrial fibrillation
entitled “research perspectives in AF”. Europace. 2009 Jul;11(7):860-85.
13. Blomström Lundqvist C. Drug treatment of supraventricular tachycardia. Heart 2009;95:1803-1807.
14. Kirchhof P, Bax J, Blomstrom-Lundquist C, et al. Early and comprehensive management of atrial
fibrillation: executive summary of the proceedings from the 2 nd AFNET-EHRA consensus conference
on atrial fibrillation entitled “research perspectives in AF”. Eur Heart J. 2009 Dec;30(24):2969-77c.
15. Camm AJ, Kirchhof P, Lip GY, et al (European Heart Rhythm Association; European Association for
Cardio-Thoracic Surgery). Guidelines for the management of atrial fibrillation: the Task Force for the
Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 2010
Oct;12(10):1360-420.
16. Camm AJ, Kirchhof P, Lip GY, et al (European Heart Rhythm Association; European Association for
Cardio-Thoracic Surgery). Guidelines for the management of atrial fibrillation: the Task Force for the
Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010
Oct;31(19):2369-429.
17. Stålenheim G, Blomström P, Venemalm L. Chlorhexidine caused anaphylactic reaction. Not only
drugs should be considered in the investigation of allergy, according to a case report. Läkartidningen.
2010 Jan 13-19;107(1-2):37-8.
18. Blomström Lundqvist C, Schwieler J. Kateterablation av förmaksflimmer: för vem och till vilken
nytta. Läkartidningen. 2011;108 (29):1126-1130.
19. Johansson B, Bech-Hanssen O, Berglin E, Blomström P, Holmgren A, Jensen S, et al. Atrial function
after left atrial epicardial cryoablation for atrial fibrillation in patients undergoing mitral valve surgery.
Journal of interventional cardiac electrophysiology (Print). 2011;
20. Regitz-Zagrosek V, Blomstrom Lundqvist C, Borghi C, Cifkova R, Ferreira R, Foidart J, et al. ESC
Guidelines on the management of cardiovascular diseases during pregnancy : The Task Force on the
Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology
(ESC). European Heart Journal. 2011;
21. Raviele A, Giada F, Bergfeldt L, Blanc J, Blomström-Lundqvist C, Mont L, et al. Management of
patients with palpitations : a position paper from the European Heart Rhythm Association. Europace.
2011;13(7):920-934.
22. Ginks M, Sciaraffia E, Karlsson A, Gustafsson J, Hamid S, Bostock J, et al. Relationship between
intracardiac impedance and left ventricular contractility in patients undergoing cardiac
resynchronization therapy. Europace. 2011;13(7):984-991.
23. Lundqvist C, Lip G, Kirchhof P. What are the costs of atrial fibrillation? Europace. 2011;13:II9-II12.
24. Ostrowska Dahlgren B, Allen M, Lindström A, Bjerke M, Blomström-Lundqvist C. A novel variant in
plakophilin-2 gene detected in a family with arrhythmogenic right ventricular cardiomyopathy.
Journal of interventional cardiac electrophysiology. 2011; dec 15 [Epub ahead of print].
25. Connolly S, Camm A, Halperin J, Joyner C, Alings M, Amerena J, et al. Dronedarone in High-Risk
Permanent Atrial Fibrillation. New England Journal of Medicine. 2011;365(24):2268-2276.
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Reviews and books 2009-2011
1. Blomström Lundqvist C, Scheinman M. Supraventricular Arrhythmias. Chapter in book, The AHA
Guidelines and Scientific Statements Handbook, Edited by Valentin Fuster. Chapter 16, page 255-269,
Wiley-Blackwell, 2009. ISBN 978-1-4051-8463-2.
2. Blomström Lundqvist C, Scheinman M. Supraventricular Arrhythmias. Chapter in book, The AHA
Guidelines and Scientific Statements Handbook, Edited by Valentin Fuster. Chapter 16, page 255-269,
Wiley-Blackwell, 2009. ISBN 978-1-4051-8463-2.
3. Blomström Lundqvist C, Bergfeldt L, Läkemedelsboken 2009/2010, Hjärtrytmrubbningar, sid 272-
287. ISBN 91-85574-59-7.
4. Blomström Lundqvist C. Review of chapters in book. The second edition of the ESC Textbook of
Cardiovascular Medicine. Chapter 27: Supraventricular Arrhythmia (lead author: Jeronimo Farré),
chapter 28: Atrial Fibrillation (lead author: John Camm). Edited by John Camm, Thomas Lüscher, and
Patrick Serruys, 2009.
5. Blomström Lundqvist C. Tracings atlas. Springer; 2011.
148

Clinical physiology
Hans Hedenström
Cardio-pulmonary aspects in acute and chronic lung disease
This a new research program based on the results that we have gained during previous years that have
focused on atelectais formation and impeded lung function during anesthesia and in acute respiratory
failure, with an increasing orientation towards lung inflammation.
New techniques for ventilatory support
A number of studies have been conducted comparing fully controlled mechanical ventilation (MV) and
spontaneous breathing combined with a basic mechanical support (APRV or BIPAP). A consistent finding
has been that spontaneous breaths improve lung aeration and function by recruiting lung tissue and
increasing respiratory compliance and gas exchange compared to MV. The advantages and even superiority
of spontaneous breathing are important findings that guide in the development of improved ventilatory
techniques. It has focused our interest in another Swedish invention, neurally adjusted ventilatory assist,
NAVA. This technique is based on the recording of the diaphragm EMG to guide the ventilator in tailoring
the breath according to the demand by the patient (i.e. the respiratory centre of the brain).
Ventilator-induced lung injury
When using conventional mechanical ventilation an optimal ventilator setting is critical, an issue that has
been intensely discussed during the last 10 or 15 years. A desire is to provide “protective ventilation”.
However, it still remains to define what “protective” really is. Our own studies have focused on the
application of suitable positive end expiratory pressure, PEEP. Low PEEP will allow collapse of lung
tissue, and more importantly, cyclic recruitment and collapse of airways and alveoli. Studies how to find
optimum PEEP levels have been performed. They have also stimulated us to do studies using PET and
inflammatory markers together with CT to detect onset of inflammatory responses to ventilatory support
and relate inflammation to morphological changes as assessed by CT.
Steroid resistance
A highly challenging research area is steroid resistance. We encountered this initially when treating SARS
patients in May-June 2003, with surprising success by providing NO inhalation to the patients in a heroic
study in Beijing (Luni Chen et al; Clinical Infectious Diseases 39:1531-1535; 2004). Steroids were given in
high doses in Beijing although their efficacy in the treatment of SARS was under discussion. We suspected
that NO might have augmented the response to steroids. This spurred us to study the combination of
steroids and NO inhalation in a porcine endotoxin sepsis model. Endotoxin down-regulated the
glucocorticoid receptor (GR) and subsequent steroid treatment had no effect. NO up-regulated the GR and
steroids given after the up-regulation resulted in a strong anti-inflammatory response to the treatment. A
positive effect on respiratory mechanics in a mouse asthma model by combining NO and steroid was also
seen in a recent paper from us. These observations create the basis for the third track in our research
program where the effect of sepsis, a common underlying mechanism of acute respiratory failure, on the
GR will be studied.
Detection of small airways disease
Tests of new methods for detection of small airway disesase. Forced oscillation technique (FOT) and
impulse oscillometry (IOS) are relative new methods which have a potential to detect changes in small
peripheral airways. FOT and IOS do not need as much participation in the investigation of the patient in
contrast to conventional measurements of pulmonary function. These methods can also be used in children
and old persons that have difficulties to cooperative optimally at an investigation. Nitrogen wash out test
also have the potential to detect small airway disease and devices with new software makes it easy to apply
149

the method to different patient groups. These methods will be used in patients with asthma, COPD and
cystic fibroses trying to find early changes in peripheral airways and to predict which patients are most
rapidly developing impaired lung function.
Diagnostic in allergies and hypersensitivities
MIDAS is a VINNOVA-sponsored consortium (2008-2012) for research on minimally invasive diagnostics
in allergies and hypersensitivities with main focus on respiratory diseases. Within these
projects, an asthma cohort of ca 400 subjects (schoolchildren and young adults) was formed between
March 2010-February 2012. Approximately 125 matched controls were recruited in parallel. All
subjects answered a broad questionnaire on asthma, rhinitis and eczema symptoms, allergic symptoms,
asthma control, asthma quality of life, use of medication etc. Measurements of exhaled NO at different
flow-rates, nasal NO, exhaled carbon monoxide, lung function and methacholine reactivity are performed.
Blood samples were taken for analysis of IgE sensitisation to important aeroallergens and food allergens,
inflammatory markers (for example eosinophil cationic protein (ECP) and human neutrophil lipocalin
(HNL), reflecting eosinophilic and neutrophilic activation, respectively), and cytokines. Nasopharyngeal
aspirate was collected in order to assess presence of virus via RT-PCR. The overall aim of the baseline
study of asthma cohort was to map asthma disease with emphasis on inflammation and allergic sensitisation
pattern as a basis for future herapeutic interventions.
Evaluation of new information in echocardiography
Comparison of echocardiographic measurements with pressure from the right ventricle and systolic
pulmonary pressure and correlation of these findings with actual pressure measurements from right heart
catheterization (RHC). The possibility for right ventricular pressure estimation in the absence of tricuspid
regurgitation (TR) was of particular interest. This was evaluated by measuring acceleration time (AT) from
the forward flow in the pulmonary valve. In addition correlation of estimated pressure from the right atrium
(RA) by echocardiography and catheterization was evaluated. Last, calculations of pulmonary resistance
(PVR) with a previously suggested formula was compared to PVR from catheterization in a group with
high incidence of pulmonary hypertension and an alternative way of presenting echocardiographic PVR
was evaluated.
Members of the group
Göran Hedenstierna, senior professor
Hans Hedenström, senior lecturer
Frank Flachskampf, professor
Andrei Malinovschi, MD, PhD
Bertil Andrén, MD, PhD
Magnus Roos, MD, PhD
Sven.-Olof Granstam, MD, PhD
Margareta Genberg-Andrén, MD, PhD student
Amir Farkhooy, MD
Görel Nyman, VMD
Lars Bäcklund, professor emeritus
Lars-Eric Bratteby, MD, PhD emeritus
Gösta Samuelsson, MD, PhD emeritus
Bo Sandhagen, PhD emeritus
150
Maria Bergqvist, PhD student
Christof Strang, PhD student
Onnen Mörer, PhD student
Marco Lattuada, PhD student
Sebastien Trachsel, PhD student
Lennart Edmark, PhD student
Angela Hansson, PhD student
Agneta Roneus, lab manager
Karin Fagerbrink, assistant
Maria Swälas, assistant
Birgitta Rinder, assistant
Eva-Maria Hedin, administrator
Staffan Dahl, systems engineer

Publications 2009-2011
1. Jonasson S, Hedenstierna G, Hedenström H, Hjoberg J. Comparisons of effects of intravenous and
inhaled methacholine on airway physiology in a murine asthma model. Respir Physiol Neurobiol.
2009 Feb 28;165(2-3):229-36
2. Jonasson S, Hjoberg J, Hedenstierna G, Basu S. Allergen-induced formation of F(2)-isoprostanes in a
murine asthma model identifies oxidative stress in acute airway inflammation in vivo. Prostaglandins
Leukot Essent Fatty Acids. 2009 Jan;80(1):1-7
3. Kozian A, Schilling T, Schütze H, Heres F, Hachenberg T, Hedenstierna G. Lung computed
tomography density distribution in a porcine model of one-lung ventilation. Br J Anaesth. 2009 Feb
17.
4. Nyman G, Stina Marntell, Anna Edner, Pia Funkquist, Karin Morgan and Göran Hedenstierna Effect
of sedation with detomidine and butorphanol on pulmonary gas exchange in the horse. Acta
Veterinaria Scandinavica 2009, 51:22
5. Jonsson A, Hök B, Andersson L, Hedenstierna G. Methodology investigation of expirograms for
enabling contact free breath alcohol analysis. J Breath Res 3, 2009.
6. Bengt Långström, Anders Grahnen, et al. The risk of exaggerated risk aversion—a life and death
struggle for molecular imaging. Eur J Nucl Med Mol Imaging 2009:1190-1.
7. Reinius H, Jonsson L, Gustafsson S, Sundbom M, Duvernoy O, Pelosi P, Hedenstierna G, Fredén F.
Prevention of Atelectasis in Morbidly Obese Patients during General Anesthesia and Paralysis: A
Computerized Tomography Study. Anesthesiology. 2009 Nov;111(5):979-87.
8. Nilsson MC, Hambraeus JK, Lattuada M, Luni C, Ren L, Alving K, Wiklund P, Hedenstierna G,
Fredén F. Distant effects of nitric oxide inhalation in endotoxemic pigs. Crit Care Med. 2009 Aug 27.
9. Strang CM, Hachenberg T, Fredén F, Hedenstierna G. Development of atelectasis and arterial to endtidal
PCO2-difference in a porcine model of pneumoperitoneum. Br J Anaesth. 2009 Aug;103(2):298-
303. Epub 2009 May 13.
10. Hanson A, Göthberg S, Nilsson K, Larsson LE, Hedenstierna G. VTCO2 and dynamic complianceguided
lung recruitment in surfactant-depleted piglets: a computed tomography study. Pediatr Crit
Care Med. 2009 Nov;10(6):687-92.
11. Baskurt OK, Boynard M, Cocelet GC, Connes P, Cooke BM, Forconi S, Liao F, Hardeman MR, Jung
F, Meiselman HJ, Nash G, Nemeth N, Neu B, Sandhagen B, Shin S, Thurston G, Wautier JL. New
guidelines for hemorheological laboratory techniques. Clinical Hemorheology and Microcirculation
2009;42:75-97.
12. Lind L, Andersson J, Larsson A, Sandhagen B. Shear stress in the common carotid artery is related to
both intima-media thickness and echogenecity. Clinical Hemorheology and Microcirculation
2009;43:299-308.
13. Ahlgren S, Wållberg H, Tran TA, Widström C, Hjertman M, Abrahmsén L, Berndorff D, Dinkelborg
LM, Cyr JE, Feldwisch J, Orlova A, Tolmachev V. Targeting of HER2-expressing tumors using a sitespecifically
99mTc-labeled recombinant Affibody molecule ZHER2:2395 with C-terminal engineered
cysteine. Journal of Nuclear Medicine, 2009; 50:781-789. IF: 6.662
14. Tran TA, Rosik D, Abrahmsén L, Sandström M, Sjöberg A, Wållberg H, Ahlgren S, Orlova A,
Tolmachev V. Design, synthesis and biological evaluation of a HER2-specific affibody molecule for
molecular imaging. Eur J Nucl Med Mol Imaging, 2009;36:1864-73. IF: 4.532
15. Tolmachev V, Friedman M, Sandström M, Eriksson TJ, Hodik M, Rosik D, Ståhl S, Frejd FY,
Orlova A. Affibody molecules for EGFR targeting in vivo: aspects of dimerization and labeling
chemistry. Journal of Nuclear Medicine, 2009;50:274-283. IF: 6.662
151

16. Tolmachev V, Mume E, Sjöberg S, Frejd FY, Orlova A. Influence of valency and labelling chemistry
on in vivo targeting using radioiodinated HER2-binding Affibody molecules. Eur J Nucl Med Mol
Imaging, 2009; 36:692-701. IF: 4.532
17. Ekblad T, Tolmachev V, Orlova A, Lendel C, Abrahmsén L, Eriksson Karlström A. Synthesis and
chemoselective intramolecular cross-linking of a HER2-binding Affibody. Biopolymers. 2009;92:116-
123. IF: 2.823
18. Orlova A, Wållberg H, Stone-Elander S, Tolmachev V. On the selection of a tracer for PET imaging
of HER2-expressing tumors: direct comparison of 124I-labelled Affibody molecule and trastuzumab
in a murine xenograft model. Journal of Nuclear Medicine, 2009;50: 417-425. IF: 6.662
19. Tolmachev V, Orlova A. Update on Affibody molecules for in vivo imaging of targets for cancer
therapy. Minerva Biotecnologica 2009; 21:21-30
20. Ekblad T, Orlova A, Feldwisch J, Wennborg A, Eriksson Karlström A, Tolmachev V. Preparation and
evaluation of synthetic Affibody molecules, labeled with 99mTc using mercaptoacetyl-containing
peptide-based chelators site-specifically conjugated to helix 3. Bioorganic & Medicinal Chemistry
Letters, 2009; 19: 3912-3914 IF: 2.531
21. Tolmachev V, Wållberg H, Andersson K, Wennborg A, Lundqvist H, Orlova A. The influence of Bz-
DOTA and CHX-A’’-DTPA on the biodistribution of ABD-fused anti-HER2 Affibody molecules:
implications for 114mIn-mediated targeting therapy Eur J Nucl Med Mol Imaging, 2009;36:1460-8.
IF: 4.532
22. Nordmark J, Johansson J, Sandberg D, Granstam SO, Huzevka T, Covaciu L, Mörtberg E, Rubertsson
S. Resuscitation. 2009 Nov;80 (11):1234-9.
23. Tolmachev V. Reply: Molecular Imaging of EGFR: It's Time to Go Beyond Receptor Expression. J
Nucl Med 50, 7, 1196, 2009
24. Kozian A, Schilling T, Röcken C, Breitling C, Hachenberg T, Hedenstierna G. Increased Alveolar
Damage After Mechanical Ventilation in a Porcine Model of Thoracic Surgery. J Cardiothorac Vasc
Anesth. 2010 Aug;24(4):617-23
25. Wållberg H, Ahlgren S, Widström C, Orlova A. Evaluation of the radiocobalt-labeled [MMA-DOTA-
Cys61]-Z HER2:2395(-Cys) affibody molecule for targeting of HER2-expressing tumors. Mol
Imaging Biol. 2010 Jan-Feb;12(1):54-62.
26. Pfau G, Schilling T, Kozian A, Lux A, Götte A, Huth C, Hachenberg T. Outcome after implantation of
cardiac resynchronization/defibrillation systems in patients with congestive heart failure and left
bundle-branch block. J Cardiothorac Vasc Anesth. 2010 Feb;24(1):30-6
27. Rees SE, Kjærgaard S, Andreassen S, Hedenstierna G. Reproduction of oxygenation data in oleic acid
induced lung damage a compparison of the MIGET and a simple model of pulmonary gas exchange.
Intensive care Medicine, 2010, Dec;36(12):2117-24.
28. Appelberg J, Janson C, Lindberg E, Pavlenko T, Hedenstierna G. Lung aeration during sleep in
patients with obstructive sleep apnoea. Clin physiol funct imaging Jul;30(4):301-7;2010
29. C. M. Strang; F. Freden; E. Maripuu; T. Hachenberg; G. Hedenstierna. Ventilation-perfusion
distributions and gas exchange during carbon dioxide-pneumoperitoneum in a porcine model. British
Journal of Anaesthesia 2010; Nov;105(5):691-7
30. Hachenberg T, Schilling T, Hedenstierna G. Physiologie des respiratorischen systems. Anästhesie und
Intensivtherapie in der Thoraxkirurgie. 1:2; 13-22:2010. Thieme verlagsgruppe, Stuttgart ISBN 978-3-
13-148771-1
31. Jonasson S, Hedenstierna G, Hjoberg J. Concomitant administration of nitric oxide and
glucocorticoids improves protection against bronchoconstriction in a murine model of asthma J Appl
Physiol 109: 521–531, 2010.
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32. M.R. Pinsky, L. Brochard, J. Mancebo, Göran Hedenstierna "Applied Physiology in Intensive Care
Medicine" 2nd edition. Springer verlag 385-393 ISBN: 978-3-642-01769-8 | 489 2010
33. Tusman G, Bohm SH, Suarez-Sipmann F, Scandurra A, Hedenstierna G. Lung recruitment and
positive end-expiratory pressure have different effects on CO2 elimination in healthy and sick lungs.
Anesth Analg. 2010 Oct;111(4):968-77
34. Kaisdotter Andersson A, Hök B, Ekström M, Hedenstierna G. Influence from breathing pattern on
alcohol and tracer gas expirograms-Implications for alcolock use. Forensic Sci Int. 2010 Jul 8.
35. Engström J, Hedenstierna G, Larsson A. Pharyngeal oxygen administration increases the time to
serious desaturation at intubation in acute lung injury: an experimental study. Crit Care.
2010;14(3):R93
36. Rees SE, Kjærgaard S, Andreassen S, Hedenstierna G. Reproduction of inert gas and oxygenation
data: a comparison of the MIGET and a simple model of pulmonary gas exchange. Intensive Care
Med (2010) 36:2117–2124
37. Urell C, Emtner M, Hedenström H, Tenling A, Breidenskog M, Westerdahl E. Deep breathing
exercises with positive expiratory pressure at a higher rate improve oxygenation in the early period
after cardiac surgery - a randomised controlled trial. Eur J Cardiothorac Surg. 2010 Dec 9
38. Westerdahl E, Möller M. Physiotherapy-supervised mobilization and exercise following cardiac
surgery: a national questionnaire survey in Sweden. J Cardiothorac Surg. 2010 Aug 25;5:67
39. Hanson A, Gothberg S, Nilsson K, Hedenstierna G. Lung aeration during ventilation after recruitment
guided by tidal elimination of carbon dioxide and dynamic compliance was better than after end-tidal
carbon dioxide targeted ventilation : A computed tomography study in surfactant-depleted piglets.
Pediatric Critical Care Medicine. 2011;12(6):E362-E368.
40. Koulouras V, Li R, Chen L, Hedenstierna G. Effects of inhaled carbon monoxide and glucocorticoids
in porcine endotoxin sepsis. International Journal of Clinical and Experimental Medicine.
2011;4(1):53-66.
41. Hedberg J, Hedenström H, Sundbom M. Wireless pH-metry at the gastrojejunostomy after Roux-en-Y
gastric bypass : a novel use of the BRAVO (TM) system. Surgical Endoscopy. 2011;25(7):2302-2307.
42. Hemmes S, Severgnini P, Jaber S, Canet J, Wrigge H, Hiesmayr M, et al. Rationale and study design
of PROVHILO - a worldwide multicenter randomized controlled trial on protective ventilation during
general anesthesia for open abdominal surgery. Trials. 2011;12:111-.
43. Borges J, Hedenstierna G. The Rediscovery of Galligas REPLY. Journal of Nuclear Medicine.
2011;52(6):1004-1004.
44. Dellaca R, Zannin E, Kostic P, Olerud M, Pompilio P, Hedenstierna G, et al. Optimisation of positive
end-expiratory pressure by forced oscillation technique in a lavage model of acute lung injury.
Intensive Care Medicine. 2011;37(6):1021-1030.
45. Kozian A, Schilling T, Schütze H, Senturk M, Hachenberg T, Hedenstierna G. Ventilatory Protective
Strategies during Thoracic Surgery Effects of Alveolar Recruitment Maneuver and Low-tidal Volume
Ventilation on Lung Density Distribution. Anesthesiology. 2011;114 (5):1025-1035.
46. Aliverti A, Kostic P, Lo Mauro A, Andersson-Olerud M, Quaranta M, Pedotti A, et al. Effects of
propofol anaesthesia on thoraco-abdominal volume variations during spontaneous breathing and
mechanical ventilation. Acta Anaesthesiologica Scandinavica. 2011;55(5):588-596.
47. Borges J, Velikyan I, Långström B, Sörensen J, Ulin J, Maripuu E, et al. Ventilation Distribution
Studies Comparing Technegas and "Gallgas" Using (GaCl3)-Ga-68 as the Label. Journal of Nuclear
Medicine. 2011;52(2):206-209.
48. Kostic P, Zannin E, Andersson Olerud M, Pompilio P, Hedenstierna G, Pedotti A, et al. Positive endexpiratory
pressure optimization with forced oscillation technique reduces ventilator induced lung
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injury: a controlled experimental study in pigs with saline lavage lung injury. Critical Care.
2011;15(3):R126-.
49. Höstman S, Engström J, Sellgren F, Hedenstierna G, Larsson A. Non-toxic alveolar oxygen
concentration without hypoxemia during apnoeic oxygenation : an experimental study. Acta
Anaesthesiologica Scandinavica. 2011;55(9):1078-1084.
50. Hedenstierna G. Nitric oxide and steroid : a good mix or not?. Acta Anaesthesiologica Scandinavica.
2011;55(1):1-3.
51. Edmark L, Auner U, Enlund M, Östberg E, Hedenstierna G. Oxygen concentration and characteristics
of progressive atelectasis formation during anaesthesia. Acta Anaesthesiologica Scandinavica.
2011;55(1):75-81.
52. Kaisdotter Andersson A, Hök B, Ekström M, Hedenstierna G. Influence from breathing pattern on
alcohol and tracer gas expirograms : Implications for alcolock use. Forensic Science International.
2011;206(1-3):52-57.
53. Hedberg J, Hedenström H, Sundbom M. Wire-less pH-metry at the gastrojejunostomy after Roux-en-
Y Gastric Bypass : a novel use of the BRAVO-system. Surgical Endoscopy. 2011;25(7):2302-
2307.
54. Hedberg J, Hedenström H, Karlsson F, Edén-Engström B, Sundbom M. Gastric Emptying and
Postprandial PYY Response After Biliopancreatic Diversion with Duodenal Switch. Obesity Surgery.
2011;21(5):609-615.
55. Borges J, Suarez-Sipmann F, Bohm S, Tusman G, Melo A, Maripuu E, et al. Regional Lung Perfusion
estimated by Electrical Impedance Tomography in a piglet model of lung collapse. Journal of applied
physiology. 2011;112(1):225-236.
56. Vimlati L, Kawati R, Hedenstierna G, Larsson A, Lichtwarck-Aschoff M. Spontaneous Breathing
Improves Shunt Fraction and Oxygenation in Comparison with Controlled Ventilation at a Similar
Amount of Lung Collapse. Anesthesia and Analgesia. 2011;113(5):1089-1095.
57. Tusman G, Sipmann F, Borges J, Hedenstierna G, Bohm S. Validation of Bohr dead space measured
by volumetric capnography : reply to Graf. Intensive Care Medicine. 2011;37(8):1397-1398.
58. Schilling T, Kozian A, Senturk M, Huth C, Reinhold A, Hedenstierna G, et al. Effects of volatile and
intravenous anesthesia on the alveolar and systemic inflammatory response in thoracic surgical
patients. Anesthesiology. 2011;115(1):65-74.
59. Vena A, Rylander C, Perchiazzi G, Giuliani R, Hedenstierna G. Lung sound analysis correlates to
injury and recruitment as identified by computed tomography: an experimental study. Intensive Care
Medicine. 2011;37(8):1378-1383.
60. Strang C, Fredén F, Maripuu E, Ebmeyer U, Hachenberg T, Hedenstierna G. Improved ventilationperfusion
matching with increasing abdominal pressure during CO(2)-pneumoperitoneum in pigs.
Acta Anaesthesiologica Scandinavica. 2011;55(7):887-896.
61. Perchiazzi G, Rylander C, Vena A, Derosa S, Polieri D, Fiore T, et al. Lung regional stress and strain
as a function of posture and ventilatory mode. Journal of applied physiology. 2011;110(5):1374-1383.
62. Tusman G, Suarez-Sipmann F, Bohm S, Borges J, Hedenstierna G. Capnography reflects
ventilation/perfusion distribution in a model of acute lung injury. Acta Anaesthesiologica
Scandinavica. 2011;55(5):597-606.
63. Tusman G, Sipmann F, Borges J, Hedenstierna G, Bohm S. Validation of Bohr dead space measured
by volumetric capnography. Intensive Care Medicine. 2011;37(5):870-874.
64. Flachskampf FA, Schmid M, Rost C, Achenbach S, DeMaria AN, Daniel WG. Cardiac imaging after
myocardial infarction. Eur Heart J. 2011 Feb;32(3):272-83
154

Reviews and books
1. Antonelli M, Azoulay E, Bonten M, et al. Year in review in Intensive Care Medicine, 2008: I. Brain
injury and neurology, renal failure and endocrinology, metabolism and nutrition, sepsis, infections and
pneumonia. Intensive Care Med. 2009 Jan;35(1):30-44.
2. Antonelli M, Azoulay E, Bonten M, et al.Year in review in Intensive Care Medicine, 2008: II.
Experimental, acute respiratory failure and ARDS, mechanical ventilation and endotracheal
intubation. Intensive Care Med. 2009 Jan 6.
3. Antonelli M, Azoulay E, Bonten M, et al. Year in review in Intensive Care Medicine, 2008: III.
Paediatrics, Ethics, outcome research and critical care organization, sedation, pharmacology and
miscellanea. Intensive Care Med. 2009 Mar;35(3):405-16.
4. Hedenstierna G: Respiratory Physiology; in Millers Anesthesia 7th edition, 2009, Elsevier ISBN: 978-
1-4160-6624-8
5. M.R. Pinsky, L. Brochard, J. Mancebo, Gцran Hedenstierna "Applied Physiology in Intensive Care
Medicine" 2nd edition, 2009. Springer Verlag ISBN: 3642017681
6. Orman J, Westerdahl E. Chest physiotherapy with positive expiratory pressure breathing after
abdominal and thoracic surgery: a systematic review. Acta Anaesthesiol Scand. 2010 Mar;54(3):261-
7.
7. Hedenstierna G and Edmark L. Mechanisms of atelectasis in the peri-operative period. Best Practice &
Research Clinical Anaesthesiology 24 (2010) 157-169.
8. Antonelli M, Azoulay E, Bonten M, Chastre J, Citerio G, Conti G, et al. Year in review in Intensive
Care Medicine 2010 : I. Acute renal failure, outcome, risk assessment and ICU performance, sepsis,
neuro intensive care and experimentals. Intensive Care Medicine. 2011;37(1):19-34.
9. Antonelli M, Azoulay E, Bonten M, et al. Year in review in Intensive Care Medicine 2010: II.
Pneumonia and infections, cardiovascular and haemodynamics, organization, education, haematology,
nutrition, ethics and miscellanea. Intensive Care Medicine. 2011;37(2):196-213.
10. Antonelli M, Azoulay E, Bonten M, et al. Year in review in Intensive Care Medicine 2010: III. ARDS
and ALI, mechanical ventilation, noninvasive ventilation, weaning, endotracheal intubation, lung
ultrasound and paediatrics. Intensive Care Medicine. 2011;37(3):394-410.
Dissertations 2011
Christof Strang: The effect of CO2-pneumoperitoneum on ventilation perfusion distribution of the lung
155

Diabetes and Metabolic diseases
Research in the field of diabetes and metabolic diseases is focused on
strategies for treatment of diabetes and obesity. The overall aim of the
research on islet transplantation and beta-cell regenerative medicine is to
develop means to intervene with the development of type 1 diabetes
mellitus and find treatment strategies to restore glucose homeostasis in
patients with type 1 diabetes mellitus using cell therapy. Studies are also
undertaken to investigate gastrointestinal physiology of patients subjected
to bariatric surgery with the aim to increase our understanding of
metabolic events induced by the surgery. The research group on diabetes
self care investigates diabetes self management and the balancing act
between rigorous blood glucose control and quality of life.
Diabetes
Per-Ola Carlsson
The overall aim of the research group on islet transplantation and beta-cell regenerative medicine is to
develop means to intervene with the development of type 1 diabetes mellitus and find treatment strategies
to restore glucose homeostasis in patients with type 1 diabetes mellitus using cell therapy. The dual role of
the P.I. as experimental and clinical scientist simplifies translational approaches, and the research group is
active both at the Department of Medical Cell Biology and the Department of Medical Sciences.
Experimental studies are conducted to elucidate the importance of islet endothelial cells and neural cells for
beta-cell regeneration and function, and investigate the concept of islet heterogeneity. Other studies
investigate the adaptation of pancreatic islets to the implantation organ, i.e. the so called engraftment
process, following transplantation, and develop strategies to improve results of pancreatic islet
transplantation by enhancement of engraftment e.g. by improved revascularization. Human islets are tested
in these experimental systems with a focus to produce clinically applicable protocols. We also perform
research to develop safe and effective means to generate new human beta-cells by stimulating adult betacell
proliferation, e.g. by stem cell stimulation, or by stem cell differentiation in vivo. Clinical studies are
performed to prevent development of type 1 diabetes in patients, e.g. by autologous mesenchymal stem cell
transplantation, and we are also involved in studies to improve the results of clinical islet transplantation.
Communication between endothelial or neural cells and beta-cells
Liza Grapensparr, Svitlana Vasylovska, Carl Johan Drott, Johan Olerud, Per-Ola Carlsson
In recent studies we have observed an importance for endothelial-beta-cell communication to maintain
beta-cell proliferation, differentiation and function. An important mediator of these effects seems to be
basement membrane components, predominantly the beta1 chain of laminin secreted by the islet
endothelial cells. New experiments have shown that the glycoprotein thrombospondin-1 (TSP-1) is highly
expressed in the endothelium of islets, and that TSP-1 deficient mice were markedly glucose intolerant,
despite having an increased beta-cell mass. Reconstitution experiments supported that the beta-cell defects
occurring in TSP-1 deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells.
Treatment of TSP-1 deficient mice with the transforming growth factor beta-1 (TGFβ-1) activating
sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented development of decreased
glucose tolerance in these mice. Thus, endothelial derived TSP-1 activates islet TGFβ-1 of importance for
beta-cells.
In other experiments, the possibility for endothelial progenitor cells or neural crest stem cells to stimulate
human beta-cell proliferation and function are investigated. These cell types may be used for cotransplantation
with islets, or used to regenerate the endogenous endocrine pancreas.
156

Heterogeneity of pancreatic islets in health and disease
Sara Ullsten, Joey Lau, Johanna Svensson, Per-Ola Carlsson
We have during the year identified a functional reserve of islet endocrine cells in rodents. Normally 20-
25% of islets are low oxygenated and with low protein biosynthesis, but these cells may be activated upon
need during increased functional demands. On the other hand, more islets become down-regulated when
beta-cell mass is increased. We have also observed that the most blood perfused islets, having a higher
vascular density, have a superior beta-cell function, proliferation and gene expression. Noteworthy, these
islets also seem more prone to develop amyloid deposits in recombinant human islet amyloid
overexpressing (rhIAPP) mice, likely due to their increased IAPP gene expression.
Engraftment of intraportally transplanted islets
Joey Lau, Guangxiang Zang, Per-Ola Carlsson
During the year, we have developed a technique to quantify the blood perfusion of islets experimentally
transplanted intraportally into the liver by combining fluorescent islets for transplantation with a
fluorescent microsphere technique. One month post transplantation the blood perfusion of the
intrahepatically transplanted islets was found to be only 5% of that in native islets. Most interestingly, a six
fold higher blood perfusion was observed in the intrahepatic grafts composed of islets transplanted after
overnight incubation when compared to islets transplanted after four days of culture. By the use of the
biochemical marker pimonidazole the low revascularization and blood perfusion of intraportally
transplanted islets were found to correlate to impaired oxygenation of the tissue. The accumulation of
pimonidazole correlated to an increased apoptosis frequency in the intraportally transplanted islets, and
correlated negatively to islet function and (pro)insulin biosynthesis in the islets.
Transplanting islets into striated muscle and omentum
Daniel Espes, Monica Sandberg, Johanna Svensson, Per-Ola Carlsson
We have previously observed that transplantation of pancreatic islets to their normal micro-environment,
the pancreas, almost restored the islet vascular network and beta-cell function, in contrast to islets
implanted to the liver. We have evaluated the intramuscular site for islet transplantation and found that
mouse and human islets experimentally transplanted into muscle within 14 days the islet vascular network
is fully restored with functional capillaries. Moreover, the oxygenation of intramuscularly transplanted
islets was almost restored. The function of islets transplanted into muscle was proven by curing diabetic
mice, 300 islets implanted to striated muscle fully restored glucose tolerance in recipient diabetic mice. The
experimental data on islet revascularization at the intramuscular site were confirmed by high resolution
magnetic resonance imaging studies of pancreatectomized patients autotransplanted with islets to forearm
muscle. Such grafts showed high plasma volumes indicating normalized vascular density. Ongoing
research projects compare outcome to another promising site, the omentum, and develop means to improve
also early survival of the islet grafts.
Amyloid formation
Sara Bohman, Hanna Liljebäck, Arne Andersson, Per-Ola Carlsson
Isolated and microencapsulated human islets are found to rapidly accumulate much larger amounts of
amyloid than free native and transplanted islets, suggesting an importance of vascular drainage to prevent
amyloid formation. We are presently investigating the possible correlation between vascularisation, blood
perfusion and tendency for amyloid formation in human islets and native and transplanted rhIAPP
overexpressing islets. Of particular relevance for islet transplantation may be our comparison between
different implantation sites with regard to amyloid accumulation and long-term graft function and failure,
when considering the marked differences in revascularization and blood perfusion of islets implanted to the
liver, striated muscle or pancreas
157

Intervention strategies to preserve residual beta-cell mass in newly developed
type 1 diabetes
Danica Gubrianska, Daniel Espes, Per-Ola Carlsson
Possibilites to save residual beta-cell mass in newly diagnosed patients with type 1 diabetes by autologous
transplantation with mesenchymal stem cells are tested. Patients are followed up to five years after
diagnosis, and residual insulin production is investigated in response to metabolic load. New techniques to
visualise beta-cell mass are in parallel developed by positron emission technology using the PET ligand
[ 11 C]-5-hydroxy-tryptophane.
Members of the group 2011
Per-Ola Carlsson, M.D., Ph.D, Professor
Joey Lau, post-doc
Monica Sandberg, post-doc
Sara Bohman, post-doc
Guangxiang Zang, post-doc
Svitlana Vasylovska, post-doc
Daniel Espes, M.D., PhD student
Johanna Svensson, PhD student
Sara Ullsten, PhD student
Liza Grapensparr, PhD student
Funding
Juvenile Diabetes Research Foundation USA 0.5 MSEK
European Foundation for the Study of Diabetes/Novo 0.5 MSEK
Novo Nordisk Foundation DK 2011 0.7 MSEK
Swedish Research Council 1.0 MSEK
Swedish Diabetes Association 0.3 MSEK
Thuring Foundation 0.1 MSEK
Strategic funding, Exodiab 0.6 MSEK
Strategic funding, Stem Therapy 1.0 MSEK
Diabetes Wellness 0.6 MSEK
158
Danica Gubrianska, MD
Carl Johan Drott, MD
Hanna Liljebäck
Astrid Nordin, laboratory engineer
Ing-Britt Hallgren, laboratory engineer
My Quach, laboratory engineer
Lisbeth Sagulin, laboratory engineer
Eva Törnelius, laboratory technician
Violeta Armijo Del Valle, research nurse
Publications 2009-2011
1. Lau J and Carlsson P-O. Low Revascularization of human islets when experimentally transplanted
into the liver Transplantation 87:322, 2009
2. Lau J, Kampf C, Berggren P-O, Nyqvist D, Köhler M and Carlsson P-O. Pancreatic microenvironment
is crucial for the development of a new vascular network in transplanted pancreatic islets. Cell
Transplantation 18:23, 2009
3. Olerud J. Role of thrombospondin-1 in endogenous and transplanted pancreatic islets. Acta
Universitatis Upsaliensis. Digital comprehensive summaries of Uppsala Dissertations from the Faculty
of Medicine 436. 57pp, 2009
4. Olerud J, Johansson M and Carlsson P-O. Prolactin pretreatment improves islet transplantation
outcome. Endocrinology 150:1646-1653, 2009. Selected also as translational highlight for publication
in J Clin Endocrinol Metab
5. Olerud J, Johansson Å and Carlsson P-O. The vascular niche of pancreatic islets. Expert Opinion in
Endocrinology.4:5, 481-491, 2009.

6. Lau J, Henriksnäs J, Svensson J and Carlsson P-O. Oxygenation of transplanted pancreatic islets.
Current opinion in Organ Transplantation. 14:688-693, 2009
7. Johansson Å. Properties of endothelium and its importance in endogenous and transplanted islets of
Langerhans. Acta Universitatis Upsaliensis. Digital comprehensive summaries of Uppsala
Dissertations from the Faculty of Medicine 492. 48pp, 2009
8. Johansson Å, Olerud J, Johansson M and Carlsson P-O. Angiostatic factors normally restrict islet
endothelial cell proliferation and migration: implications for islet transplantation. Transplant Int
22:1182-11188, 2009
9. Johansson Å, Lau J, Sandberg M, Borg H, Magnusson PU and Carlsson P-O. Endothelial cell
signalling supports pancreatic beta-cell function in the rat. Diabetologia 52:2385-2394, 2009
10. Christoffersson G, Henriksnäs J, Johansson L, Rolny C, Ahlström H, Caballero-Corbalan J,
Segersvärd R, Permert J, Korsgren O, Carlsson P-O and Phillipson M. Clinical and experimental
pancreatic islet transplantation to striated muscle: establishment of a vascular system similar to that in
native islets. Diabetes 59:2569-2578, 2010 -Winner of Young Investigator’s Award as best publication
in 2010 by the Scandinavian Society for the Study of Diabetes.
11. Sandberg M, Carlsson F, Nilsson B, Korsgren O, Carlsson P, Jansson L. Syngeneic islet
transplantations into the submandibular gland of mice. Transplantation. 2011;91(2):e17-e19.
12. Carlsson P. Influence of microenvironment on engraftment of transplanted β-cells. Upsala Journal of
Medical Sciences, Supplement. 2011;116(1):1-7.
13. Christoffersson G, Carlsson P, Phillipson M. Intramuscular islet transplantation promotes restored islet
vascularity. Islets. 2011;3(2):69-71.
14. Olerud J, Mokhtari D, Johansson M, Christoffersson G, Lawler J, Welsh N, et al. Thrombospondin-1 :
an islet endothelial cell signal of importance for β-cell function. Diabetes. 2011;60(7):1946-1954.
15. Espes D, Eriksson O, Lau J, Carlsson P. Striated Muscle as Implantation Site for Transplanted
Pancreatic Islets. Journal of Transplantation. 2011;
16. Grapensparr L, Olerud J, Vasylovska S, Carlsson P. The therapeutic role of endothelial progenitor
cells in Type 1 diabetes mellitus. Regenerative Medicine. 2011;6(5):599-605.
17. Olsson R, Olerud J, Pettersson U, Carlsson P. Increased Numbers of Low-Oxygenated Pancreatic
Islets After Intraportal Islet Transplantation. Diabetes. 2011;60(9):2350-2353.
18. Svensson J, Lau J, Sandberg M, Carlsson P. High Vascular Density and Oxygenation of Pancreatic
Islets Transplanted in Clusters Into Striated Muscle. Cell Transplantation. 2011;20(5):783-788.
19. Pettersson U, Henriksnäs J, Carlsson P. Endothelin-1 Markedly Decreases the Blood Perfusion of
Transplanted Pancreatic Islets in Rats. Transplantation Proceedings. 2011;43(5):1815-1820.
20. Jansson L, Carlsson P, Bodin B, Källskog Ö. Flow distribution during infusion of UW and HTK
solution in anaesthetised rats. Langenbeck's archives of surgery (Print). 2011;396(5):677-683.
21. Carlsson P. Influence of microenvironment on engraftment of transplanted beta-cells. Uppsala Journal
of Medical Sciences. 2011;116(1):1-7.
22. Sandberg M, Carlsson F, Nilsson B, Korsgren O, Carlsson P, Jansson L. Syngeneic islet
transplantation into the submandibular gland of mice. Transplantation. 2011;91(2):e17-e19.
23. Olerud J, Johansson M, Christoffersson G, Lawler J, Welsh N, Carlsson P. Thrombospondin-1 : an
islet endothelial cell signal of importance for beta-cell function. Diabetes. 2011;60(7):1946-1954.
24. Olsson R, Carlsson P. A low oxygenated subpopulation of pancreatic islets constitutes a functional
reserve of endocrine cells. Diabetes. 2011;60(8):2068-2075.
159

Endocrinology, Diabetes and Metabolism
Anders Karlsson
Bariatric surgery has proven effective in producing sustainable weight loss in morbid obesity. We have
formed a network at the University Hospital (endocrinology, surgery, obesity unit, MR unit, clinical
nutrition) for studies of obesity. The purpose is to get insight into how to select patients for surgery and
optimize follow-up and to increase the understanding of basal physiological and metabolic regulation in
morbid obesity and weight loss.
Endocrine and metabolic effects of gastric bypass surgery in morbid obesity
We perform exploratory studies of e.g. hormones and appetite peptides, body composition and energy
balance post-surgery, lipid stores examined by magnetic resonance tomography and spectroscopy, vascular
reactivity examined by ultrasound, very low calorie diet prior to surgery evaluated biochemically and by
MRI/MRS.
Long-term outcome of gastric bypass surgery
The morbidity and quality of life is analyzed in a 500 cases cohort, in a collaborative study between
Uppsala and Örebro University Hospitals.
Endocrine dysfunction in traumatic brain injury
Studies in patients following subarachnoid hemorrhage.
Pituitary tumours
We coordinate, and perform analysis of a Swedish National Registry.
Type 2 diabetes, insulin resistance and CHD in ULSAM
The Uppsala Longitudinal Study of Adult Men (ULSAM) is used for phenotypic characterization; genetic
studies and environmental adaptation.
Members of the group during 2011
Anders Karlsson, Professor, group leader
Britt Edén Engström, Post doc
Christian Berne, Professor
Ing-Marie Carlsson, Secretary
Felicity Svensson, research student, physician
Publications 2009-2011
1. Lind L, Eden Engstrom B, Sundbom M, Zethelius B, Karlsson FA. Vasoreactivity is rapidly improved
in obese subjects following bariatric surgery. Int J Obes (Lond). 2009, Dec;33 (12):1390-5.
2. Kullberg J, Ahlstrom A, Johansson L, Bornert P, Haenni A, Sundbom M, Ahlstrom H, Karlsson FA. Gastric bypass
promotes lipolysis more than a similar weight loss induced by low calorie diet. 2010, submitted
3. Johansson HE, Haenni A, Karlsson FA, Edén-Engström B, Ohrvall M, Sundbom M, Zethelius B.
Bileopancreatic diversion with duodenal switch lowers both early and late phases of glucose, insulin
and proinsulin responses after meal Obes Surg. 2010 May;20(5):549-58.
4. Hudecova M, Holte J, Olovsson M, Larsson A, Berne C, Sundstrom-Poromaa I. Prevalence of the
metabolic syndrome in women with a previous diagnosis of polycystic ovary syndrome : long-term
follow-up. Fertility and Sterility. 2011;96(5):1271-1274.
160

5. Basu S, Zethelius B, Helmersson J, Berne C, Larsson A, Ärnlöv J. Cytokine-mediated inflammation is
independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a
community-based cohort of elderly men. International Journal of Clinical and Experimental Medicine.
2011;4(2):164-168.
6. Biglarnia A, Nilsson B, Nilsson T, et al. Prompt reversal of a severe complement activation by
eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney
transplantation.. Transplant International. 2011;24(8):e61-e66.
7. Hudecova M, Holte J, et al. Diabetes and impaired glucose tolerance in patients with polycystic ovary
syndrome-a long term follow-up. Human Reproduction. 2011;26(6):1462-1468.
8. Nathanson D, Zethelius B, Berne C, et al. Plasma levels of glucagon like peptide-1 associate with
diastolic function in elderly men. Diabetic Medicine. 2011;28(3):301-305.
9. Schölin A, Nyström L, Arnqvist H, et al. Proinsulin/C-peptide ratio, glucagon and remission in newonset
Type 1 diabetes mellitus in young adults. Diabetic Medicine. 2011;28(2):156-161.
10. Edholm D, Kullberg J, Hänni A, Karlsson A, Ahlström A, Hedberg J, et al. Preoperative 4-week lowcalorie
diet reduces liver volume and intrahepatic fat, and facilitates laparoscopic gastric bypass in
morbidly obese. Obesity Surgery. 2011;21(3):345-350.
11. Kullberg J, Sundbom M, Haenni A, Freden S, Johansson L, Börnert P, et al. Gastric bypass promotes
more lipid mobilization than a similar weight loss induced by low-calorie diet. Journal of Obesity.
2011;2011:959601-.
12. Hudecova M, Holte J, Moby L, et al. Androgen levels, insulin sensitivity, and early insulin response in
women with polycystic ovary syndrome : a long-term follow-up study. Fertility and Sterility.
2011;95(3):1146-1148.
13. Hedberg J, Hedenström H, Karlsson F, Edén-Engström B, Sundbom M. Gastric Emptying and
Postprandial PYY Response After Biliopancreatic Diversion with Duodenal Switch. Obesity Surgery.
2011;21(5):609-615.
14. Engström S, Berne C, Gahnberg L, Svärdsudd K. Efficacy of screening for high blood pressure in
dental health care. BMC Public Health. 2011;11:194-.
15. Abraham-Nordling M, Byström K, Törring O, et al. Incidence of hyperthyroidism in Sweden.
European Journal of Endocrinology. 2011;165(6):899-905.
16. Berglund L, Berne C, Svärdsudd K, Garmo H, Melhus H, Zethelius B. Seasonal variations of insulin
sensitivity from a euglycemic insulin clamp in elderly men. Uppsala Journal of Medical Sciences.
2011;
17. Zetterling M, Edén Engström B, Hallberg L, Hillered L, Enblad P, Karlsson T, et al. Cortisol and
adrenocorticotropic hormone dynamics in the acute phase of subarachnoid haemorrhage. British
Journal of Neurosurgery. 2011;25(6):684-692.
18. Theorell-Haglöw J, Berne C, Janson C, Lindberg E. The role of obstructive sleep apnea in metabolic
syndrome : A population-based study in women. Sleep Medicine. 2011;12(4):329-334.
19. Engström S, Berne C, Gahnberg L, Svärdsudd K. Efficacy of screeing for high blood pressure in
dental health care. BMC Public Health. 2011;11:194-.
161

Diabetes Nursing Research
Karin Wikblad
Our research programme in a life-cycle perspective includes three parts (1) explore different aspects of selfmanagement
and identify factors of importance for diabetic patients’ self-care, metabolic control and
health; (2) implement and evaluate diabetes care interventions aiming at improving patient prerequisites for
controlling self-management. (3) construct and test psychometric properties of measures for the evaluation
of patient centred care.
Diabetes self-management
Karin Wikblad, Janeth Leksell, Ewa Billing, Anna Lindholm Olinder
There are several ongoing projects in this program; e.g.
Since 1985we have prospectively followed a group of type 1 diabetic patients and have been able to
identify important factors for the management of diabetes. We are now reporting the 25 year follow up.
Another study was designed to examine potential long term effects on glycaemic control and treatment
satisfaction in people with type 1 diabetes who changed from multiple daily insulin injections (MDI) to
insulin pump therapy (CSII, continuous subcutaneous insulin infusion).
The study aims to investigate various aspects of pharmaceutical treatment for sight-threatening eye
complication of diabetes: daily life and health-related quality of life of medical measurement and resource
use in health care. Results hope to improve the care and management of patients undergoing the treatment.
Interventions in diabetes care
Anna Lindholm Olinder, Karin Wikblad, Janeth Leksell
In this area we are currently foremost working in two different projects;
1. Construction and implementation of the person-centered education program “I’m the Boss”
Based on a thorough analysis of successful education programs we have constructed a new program
denoted “I’m the Boss”. The problem-based learning program consists of six three-hour weekly group
sessions dealing with different aspects of living with diabetes. The program was evaluated in a randomized
controlled trial and the results seem promising with significantly improved glycaemic control in patients
with type 1-diabetes.
2. Self-monitoring of blood glucose in people with type 2 diabetes
Self-monitoring of blood glucose is controversial in the management of type 2 diabetes. We have therefore,
in a randomized controlled trial, studied the effects of self-monitoring of blood glucose in 188 patients with
type 2-diabetes. The intervention group received education how to interpret and act upon their blood
glucose values while the control group got usual care. In our preliminary analyses we found no
improvement at all in HbA1c or quality of life, and that patients in the intervention group reported more
negative attitudes than patients in the control group. Their willingness to pay was also significantly lower
than in the control group.
Construction and psychometric testing of measures for the evaluation of
patient centred care
Ewa Billing, Janeth Leksell, Karin Wikblad
We have constructed a short instrument, check your health, intending to measure patients’ wellbeing as
well as the impact of diabetes on daily life. The instrument has been tested on adults with diabetes and
found both reliable and valid. In further studies we have tested the instrument in teenagers with diabetes.
162

'Check your health' showed clinical utility in teenagers with diabetes, and it can probably be used in clinical
settings. We are also actively working with a validation of the Swedish Psoriatic arthritis quality of life
instrument (PSAQoL).There are several ongoing projects in this program; e.g.
Members of the group during 2011
Karin Wikblad, Professor
Ewa Billing, assoc prof
Janeth Leksell, PhD
Funding
The diabetes fund 235 kSEK
163
Anna Lindholm Olinder, PhD
Violeta Armijo del Valle, specialist nurse
Publications 2009-2011
1. Löfvenmark C, Mattiasson AC, Billing E, Edner M. Loneliness and perceived social support in
patients with chronic heart failure. Eur J Cardiovasc Nurs 2009;8:251-58
2. Smide B, Hörnsten Å. People’s reasong about diagnosis in type 2 diabetes. J of Nursing and
Healthcare of Chronic Illness. 2009, (1) p. 253-260.
3. Adolfsson ET, Smide B, Rosenblad A, Wikblad K. Does patient education facilitate diabetic patients'
possibilities to reach national treatment targets? A national survey in Swedish primary healthcare.
Scand J Prim Health Care. 2009;27(2):91-6.
4. Lindholm-Olinder A, Runefors J, Smide B, Kernell A. Post-prandial glucose excursions following
three methods of insulin bolusing in CSII-treated adolescent girls and in comparison with postprandial
glucose levels in girls without diabetes. Practical Diabetes International. 2009; 26: (1):1-6.
5. Olinder AL, Kernell A, Smide B. Missed bolus doses: devastating for metabolic control in CSII
treated adolescents with type 1 diabetes. Pediatr Diabetes. 2009 Apr;10(2):142-8.
6. Smide B. Out-come of foot examinations in Tanzanian and Swedish diabetic patients, a comparative
study. J Clin Nurs. 2009 Feb;18(3):391-8.
7. Viklund G, Wikblad K. Self-perceived health and burden of diabetes in teenagers with type 1 diabetes:
psychometric properties of the Swedish measure 'Check your health' Acta Paediatr. 2009 Nov 27.
8. Viklund G, Wikblad K. Teenagers' perceptions of factors affecting decision-making competence in the
management of type 1 diabetes. J Clin Nurs. 2009; 18(23):3262-70
9. Abdelgadir M, Shebeika W, Eltom M, Berne C, Wikblad K. Health related quality of life and sense of
coherence in Sudanese diabetic subjects with lower limb amputation. Tohoku J Exp Med. 2009
Jan;217(1):45-50.
10. From I, Leksell J, Marusarz M, Roeli K, Sairanen R, Schröder M, Vabo G, Söderhamn O. Good
nursing care for older nursing home clients in a Nordic context . Vård i Norden, Nr. 4, 2009, s. 11.
11. Breimer L, Leksell J. Longitudinal and cross-sectional study of registered nurses in Sweden who
undertake a PhD showing that nurses continue to publish in English after their PhD but male nurses
are more productive than female nurses. Scientometrics, 2010 (in press)
12. Johansson UB, Kaila Päivi, Ahlner-Elmqvist M, Leksell J, Isoaho H, Saarikoski,M Clinical learning
environment, supervision and nurse teacher evaluation scale: psychometric evaluation of the Swedish
version. Journal of Advanced Nursing, 2010 (66): 2085–2093.
13. Lindmark A, Smide B, Leksell J. Perceptions of information about diabetes and health in women after
delivery: – a qualitative study. European Diabetes Nursing, 2010 (7): 12-15.
14. Billing E, Mc Kenna S, Staun M, Lindqvist U. Adaption of the psoriatic arthritis quality of life
(PsAQoL) instrument for Sweden. Scand. J Rheumatology 2010;

15. Löfvenmark C, Rydell Karlsson M, Edner M, Billing E, Mattiasson AC. A group-based educational
programme for family members of patients with chronic heart failure: effects on knowledge and
patients´ health care utilization. Patient Education and Counseling, Patient Educ Couns. 2010 Nov 1.
[Epub ahead of print]
16. Adolfsson ET, Rosenblad A, Wikblad K. The Swedish National Survey of the Quality and
Organization of Diabetes Care in Primary Healthcare--Swed-QOP. Prim Care Diabetes. 2010
Jul;4(2):91-7.
17. Viklund G, Wikblad K. Self-perceived health and burden of diabetes in teenagers with type 1 diabetes:
psychometric properties of the Swedish measure 'check your health'. Acta Paediatr. 2010
Mar;99(3):422-6.
18. Edwall LL, Danielsson E, Smide B, Öhrn I. Interaction between patients with type 2 diabetes and
diabetes nurse specialists during annual check-ups: A study using video recordings. The Internet
Journal of Advanced Nursing Practice, 2010, Vol 11 (1).
19. Edström Plüss C, Billing E, Held C, Henriksson P, Kiessling A, Rydell Karlsson M, et al. Long-term
effects of an expanded cardiac rehabilitation programme after myocardial infarction or coronary artery
bypass surgery: a five-year follow-up of a randomized controlled study. Clinical Rehabilitation.
2011;25(1):79-87.
20. Lindholm Olinder A, Ternulf Nyhlin K, Smide B. Clarifying responsibility for self-management in
adolescents with diabetes using insulin pumps : a qualitative study. Journal of Advanced Nursing.
2011;67(7):1547-1557.
21. Lindholm Olinder A, Ternulf Nyhlin K, Smide B. Reasons for missed meal-time insulin boluses, from
the perspective of adolescents using insulin pumps – “lost focus”. Pediatric Diabetes. 2011;12(4):402-
409.
22. Garmo, Anna, Garmo, Hans, Ärnlöv, Johan, Leksell, Janeth. Long-term treatment effects of insulin
pump therapy . Practical Diabetes, Vol. 28, Nr. 7, 2011, s. 295-99.
164

Teamwork in an emergency department
Åsa Muntlin Athlin
The overall aim was to investigate how implementation of team work in an emergency department can
affect efficiency, quality of care, patient safety and patient satisfaction and work environment. In addition,
the implementation process will be further studied. A longitudinal non-randomized intervention study
design with three follow ups was used.
PuP – Pressure Ulcer Prevention
One of the research projects is a randomized clinical trial, where the aim is to study the effect of a pressure
reducing heel protection and health economic related effects. This study follows the care chain; from prehospital
care to discharge from the hospital. Another research project is about describing and comparing
Swedish nurses’ and nursing students’ knowledge and attitudes to pressure ulcer prevention.
Fundamentals of Care
This is an ongoing research collaboration project with researchers from Australia, UK and Sweden. The
overall aim is to investigate how fundamental aspects of care are delivered to patients within health
systems. Examples of ongoing projects are: exploring stroke patients’ and cancer patients’ experiences of
fundamentals of care. Another project is about improving the fundamentals of care in the sub-acute care,
where the research purpose is to evaluate method of introducing change (Knowledge Translation (KT)
toolkit) and to evaluate the fundamentals of care framework. An additional project is to investigate nursing
clinical handovers with special attention to fundamental aspects of care.
Funding 2011
Uppsala County Council: 175 kSEK
Uppsala-Örebro Regional Research Council - RFR: 225 kSEK
Uppsala University: 203 kSEK
AFA Insurance (co-applicant: Åsa Muntlin Athlin) 2 404 kSEK
Publications 2009-2011
1. von Thiele Schwarz, U., Hasson, H., Muntlin Athlin, Å. (2011) Perceived efficiency in the Emergency
Department – low throughput rates or having a lot to do? Accepted for Publication in Arbete och
Hälsa [Work and Health]
2. Muntlin Å, Carlsson M, Säfwenberg U, Gunningberg L. Outcomes of a nurse-initiated intravenous
analgesic protocol for abdominal pain in an emergency department: a quasi-experimental study.
International Journal of Nursing Studies, 2011 Jan;48(1):13-23
3. Muntlin, Å. Hur kan vi som sjuksköterskor förbättra vården på akutmottagningar för patienter som
söker för buksmärta? (How could nurses improve the pain management in the emergency department
for patients with abdominal pain?) Smärta, 2010, 3: 16-19. In Swedish.
4. Muntlin Å, Carlsson M, Gunningberg L. Barriers to change hindering quality improvement – the
reality of emergency care. Interviews with healthcare professionals. Journal of Emergency Nursing,
2010 Jul;36(4):317-23.
165

Undergraduate Teaching 2011
Medical Education Programme; Approx. students
Clinical Medicine I 28,5 hp 166
Clinical Medicine III 30 hp 167
Clinical Medicine IV 19,5 hp 174
Occupational and Environmental Medicine 142
Physiotherapy Programme:
Internal Medicine 3 hp 70
Physiology 9 hp 104
Nursing Programme:
Pharmacology 6 hp 216
Clinical Microbiology 4,5 hp 210
Nursing and Medical Sciences
within Medical Care 15 hp 200
Biomedicine Laboratory Programme:
Medical Microbiology 10,5 hp 47
Applied Laboratory Methods I 6 hp 36
Applied Laboratory Methods II 38
Projectic 9 hp 35
Diseases - a Clinical Survey 7,5 hp 34
Clinical Chemistry and Hematology, Toxicology and Pharmacology 13,5 p 37
Clinical Physiology 7,0 hp 50
Biomedicine Programme:
Bioinformatics with Statistics 4,5 hp 36
Single Subject Courses
Diabetes Care I 15 hp 16
Diabetes Care I:I 7,5 hp 24
Diabetes Care I:II 7,5 hp 23
Diabetes Care II 7,5 hp 21
Diabetes Adult Learning 7,5 hp 18
Diabetes Care, Scientific Methodology and Essay 15 hp 1
Clinical Drug Development 30 hp 28
Methodology in Clinical Trials 3 hp 6
Basic Medical Statistics 3 hp 5
Treatment and Care of Patients with Arrhythmia 7,5 hp 27
Treatment and Nursing in Congestive Heart Failure 27
Infectious Disease Nursing 15 hp 17
Clinical Clerkship 10
Advanced Course in Medical Sciences 30 hp 2
Work Environment in the New Working Life 7,5 13
TOTAL: 2 000 students
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Core Facilities
The SNP&SEQ Technology Platform in Uppsala
Director: Professor Ann-Christine Syvänen
Providing access to genotyping and sequencing
The objective of SNP&SEQ Technology Platform in Uppsala, headed by professor Ann-Christine Syvänen,
is to make large-scale SNP genotyping and “second generation” DNA sequencing of high quality available
to academic researchers in Sweden and other countries at the lowest possible costs. The SNP&SEQ
Platform has a professional staff, including research engineers/laboratory technicians, bioinformatics and
database specialists, IT-staff and managers for project coordination and technology development. To
assure a high quality of the data produced, the SNP&SEQ Platform works according to the ISO/IEC
17025:2005 quality standard, and the genotyping and sequencing process is accredited by the Swedish
Board for Accreditation and Conformity Assessment (SWEDAC). Genome-wide SNP panels facilitate
association studies in human complex diseases and traits, determination of copy number alterations and
DNA-methylation across the genome. “Second generation” sequencing is applied to sequence large and
small genomes, discovery of SNPs in targeted regions of large genomes, functional analyses of gene
regulation by analysis of chromatin immunoprecipitated DNA and transcriptome sequencing. The
SNP&SEQ Technology Platform constitutes a major part of Genomics Platform of the recently established
Science for Life Laboratory – Uppsala and participates in large collaborative EU projects, including the
FP7 project European Sequencing and Genotyping Infrastructure (ESGI). The SNP&SEQ platform is
supported as a national research infrastructure by the Swedish Research Council for Infrastructures (VR
RFI).
Projects
The users of the services of the SNP&SEQ Technology Platform are affiliated with the Faculties for
Medicine and Pharmacy, Academic Hospital and the Faculty for Science and Technology at Uppsala
University, as well as with all other major Swedish universities, and several other European universities.
During 2011 the demand on the services by the SNP&SEQ platform increased compared to 2010. During
2011, 51 genotyping projects including a total of 52.000 DNA samples and 69 sequencing projects of 1561
DNA or RNA samples were completed. Most of the projects study human diseases or populations, but
genotyping and sequencing in many other organisms, like birds, domestic animals, plants, insects, fungi
and bacteria were also performed. So far the SNP&SEQ Platform has contributed to ~170 publications in
well respected scientific journals, of which 37 appeared in 2011.
For a complete list of publications see www.genotyping.se
For more information see www.genotyping.se , www.sequencing.se
Staff of the SNP&SEQ Technology Platform during 2011
Tomas Axelsson, PhD, SNP genotyping manger
Ulrika Liljedahl, PhD, DNA sequencing manager
Lars Bäckström, computer systems manager
Olof Karlberg, PhD, bioinformatics manager
Camilla Enström, research engineer, SNP genotyping
Edvard Englund, PhD, database systems developer
Helena Fällmar, PhD, research engineer, DNA sequencing
Tommy Hellberg, computer system administrator
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Johanna Lagensjö, research engineer, DNA sequencing
Pia Lindström, research engineer, DNA sequencing
Kristina Larsson, senior research engineer, quality system manger, DNA sequencing
Ulrika Liljegren, research engineer, DNA sequencing
Marie Lindersson, senior research engineer, DNA sequencing and SNP genotyping
Henrik Ljungberg, IT administrator
Per Lundmark, PhD, SNP &SEQ bioinformatics
Dana Magnúsdóttir, research engineer, SNP genotyping
Amanda Raine, PhD, research engineer, DNA sequencing
Karin Sollander, research engineer, DNA sequencing
Ann-Christine Wiman, research engineer, DNA sequencing and SNP genotyping
Ingvar Örn Thorsteinsson, research engineer, SNP genotyping
Kjell Stålberg, PhD, research engineer, sample management and genotyping
Torbjörn Öst, research engineer, SNP genotyping
Lillebil Andersson, administrator
Mathias Bränvall, EU project coordinator
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Uppsala Array Platform – microarray-based analyses and
bioinformatics for research and health care
Director: Associate Professor Anders Isaksson
Uppsala Array Platform provides access to large-scale technologies for research and health care and is
supported by Uppsala University and Uppsala University Hospital. We provide microarray related services
based on the Affymetrix Gene Chip System 3000, which includes analysis of mRNA levels, miRNA levels,
DNA copy measurements and whole genome SNP genotyping etc. In addition we provide bioinformatic
support and develop algorithms for problems that many user face. For more information see the platform
home page:
http://www.medsci.uu.se/plattformar/Uppsala_Array_Platform/
High demand for platform services
By providing a diverse set of array-based analyses and bioinformatics support continues to provide services
to a large number of projects. During 2011 the platform has served 72 projects which includes analysis of
about 1100 samples. The projects mainly come from UU (60%), Akademiska sjukhuset (28%), Companies
(4%), SLU (3%) and other Swedish Universities (7%). The platform has a staff of 6 full-time positions. The
platform has contributed to 21 publications in high ranking international journals during 2009-2011 (see list
below).
Array-based analyses for improved health care
Our vision is to continue to develop the platform and offer a wide variety of array-based analyses. In
particular we want to focus on developing clinical analyses that can become an important part of
individualized treatments in Uppsala. Together with Clinical Genetics we have since 2008 offered arraybased
diagnostics of children with suspected mental retardation of as a routine clinical analysis. We
analyzed about 300 patients during 2011.
Our focus is on developing clinically useful diagnostic and predictive tests based on array analyses. One
example is a pilot project where we work together with researchers at Childrens and Womens Health in
order to offer detailed genomic characterization of formalin fixed tumor samples. We have exciting results
suggesting that the OncoScan technology from Affymetrix is functioning and we are continuing our work
to provide clinically relevant analyses.
Future
Uppsala Array Platform is a part of the Genomics platform in the Science for Life Uppsala project. This
allow us to further improve and integrate the service for our users in the future. http://www.uu.se/node808
Staff of Uppsala Array Platform during 2011
Martin Dahlö, Bioinformatician
Hanna Göransson Kultima Bioinformatician
Anna Haukkala, Research engineer
Publications 2009-2011
169
Anders Isaksson, director
Markus Rasmussen, Bioinformatician
Maria Rydåker, Research engineer
1. Göransson H, Edlund E, Rydåker M, Rasmussen M, Winquist J, Ekman S, Bergqvist M, Thomas AP,
Lambe M, Rosenquist R, Holmberg L, Micke P, Botling J, Isaksson A. Quantification of normal cell
fraction and copy number neutral LOH in clinical tumor samples using SNP array data. PlosONE
2009 Jun 26; 4(6):e6057

2. Björklund P, Cupisti K, Fryknäs M, Isaksson A, Willenberg HS, Åkerström G. Hellman P, Westin G.
Stathmin as a marker for malignancy in pheochromocytomas. Exp Clin Endocr & Diabet.2009, May
15
3. Wensman H, Göransson H, Leuchowius K-L, Strömberg S, Pontén F, Isaksson A, Rutteman GR,
Heldin N-E, Pejler G, Helmmén E. 2009. Extensive expression of cranofacial related homeobox genes
in anine mammary sarcomas. Breast Cancer Res Treat. 2009 Nov;118(2):333-43
4. Laryea D, Isaksson A, Wright CW, Larsson R, Nygren P. 2009. Characterizationof the cytotoxic
activity of indoloquinoline alkaloid cryptolepine in human tumor cell lines and primary cultures of
tumor cells from patients. Invest New Drugs. 2009 Oct;27(5):402-11.
5. Marincevic M, Mansouri M, Kanduri M, Isaksson A, Goransson H, Ekstrom Smedby K, Jurlander J,
Juliusson G, Davi F, Stamatopoulos K, Rosenquist R. Distinct gene expression profiles in subsets of
chronic lymphocytic leukemia expressing stereotyped IGHV4-34 B cell receptors.
Haematologica.2010, Dec;95(12):2072-9.
6. Mondal T, Rasmussen M, Pandey GK, Isaksson A and Kanduri C. Chracterization of the RNA content
of chromatin. Genome Res. 2010, Jul;20(7):899-907.
7. Gustafsson MG, Wallman M, Wickenberg-Bolin U, Göransson H, Fryknäs M, Andersson CR and
Isaksson A. Imroving Bayesian credibility intervals for classifier error rates using maximun entropy
empirically priors. Artif Intell Med 2010, Jun;49(2):93-104.
8. Marincevic M, Cahill M, Gunnarsson R, Isaksson A, Mansouri M, Göransson H, Rasmussen M,
Jansson M, Ryan F, Karlsson K, Adami HO, Davi F, Jurlander J, Juliusson G, Stamatopoulos K and
Rosenquist R.. High-density screening reveals a different spectrum of genomic aberrations in chronic
lymphocytic leukemia patients with 'stereotyped' IGHV3-21 and IGHV4-34 B-cell receptors.
Haematologica. 2010 Sep;95(9):1519-25.
9. Kanduri M, Cahill N, Göransson H, Enström C, Ryan F, Isaksson A and Rosenquist R. Differential
genome-wide methylation profiles in prognostic subsets of chronic lymphocytic leukemia. Blood.
2010, Jan 14;115(2):296-305
10. Gunnarsson R, Isaksson A, Mansouri M, Göransson H, Jansson M, Cahill N, Rasmussen M, Staaf J,
Lundin J, Norin, Buhl AM, Ekström Smedby K, Hjalgrim H, Karlsson K, Jurlander J, Juliusson G and
Rosenquist R. Large but not small copy-number alterations correlate to high-risk genomic aberrations
and survival in chronic lymphocytic leukemia: A high-resolution genomic screening of newly
diagnosed patients. Leukemia. 2010, Jan;24(1):211-5
11. Laryea D, Gullbo J, Isaksson A, Larsson R, Nygren P. Characterization of the cytotoxic properties of
the benzimidazole fungicides, benomyl and carbendazim in human tumor cell lines and primary
cultures of patient tumor cells. Anticancer Drugs. 2010 Jan;21(1):33-42
12. Halldórsdóttir AM, Sander B, Göransson H, Isaksson A, Kimby E, Mansouri M, Rosenquist R,
Ehrencrona H. High-resolution genomic screening in mantle cell lymphoma-specific changes
correlates with genoic complexity, the proliferative signature and survival. Genes Chromosomes
Cancer. 2011 Feb;50(2):113-21.
13. Johansson H, Isaksson M, Fals Sörqvist E, Roos F, Stenberg J, Sjöblom T, Botling J,Micke P,Edlund
K, Fredriksson S, Göransson Kultima H,Ericsson O, Nilsson M. Targeted resequencing of candidate
genes using selector probes. Nucleic Acids Res. 2011 Jan;39(2):e8
14. Rasmussen M, Sundström M, Kultima H, Botling J, Micke P, Birgisson H, et al. Allele-specific copy
number analysis of tumor samples with aneuploidy and tumor heterogeneity. Genome Biology.
2011;12(10):R108-.
15. Micke P, Edlund K, Holmberg L, Kultima H, Mansouri L, Ekman S, et al. Gene copy number
aberrations are associated with survival in histologic subgroups of non-small cell lung cancer. Journal
of Thoracic Oncology. 2011;6(11):1833-1840.
170

16. Johansson H, Isaksson M, Sörqvist E, Roos F, Stenberg J, Sjöblom T, et al. Targeted resequencing of
candidate genes using Selector Probes. Nucleic Acids Research. 2011;39(2):e8-
17. Micke P, Edlund K, Holmberg L, Göransson Kultima H, Mansouri L, Ekman S, et al. Gene Copy
Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung
Cancer. Journal of Thoracic Oncology. 2011;6(11):1833-1840.
18. Gunnarsson R, Mansouri L, Isaksson A, Göransson H, Cahill N, Jansson M, et al. Array-based
genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia.
Haematologica. 2011;96(8):1161-1169.
19. Ronquist G, Larsson A, Ronquist G, Isaksson A, Hreinsson J, Carlsson L, et al. Prostasomal DNA
Characterization and Transfer Into Human Sperm. Molecular Reproduction and Development.
2011;78(7):467-476.
20. Halldórsdóttir A, Kanduri M, Marincevic M, Mansouri L, Isaksson A, Göransson H, et al. Mantle
Cell Lymphoma is Characterized by a Strikingly Homogenous Methylation Profile : a comparative
analysis with chronic lymphocytic leukemia. PLoS ONE. 2011;
21. Brunberg E, Jensen P, Isaksson A, Keeling L. Feather pecking behavior in laying hens : Hypothalamic
gene expression in birds performing and receiving pecks. Poultry Science. 2011;90(6):1145-1152.
171

Awards and Appointments 2011
1. Professor Olle Kämpe - Elected member of the Royal Swedish Academy of Sciences.
2. Professor Lars Wallentin Olof Rudbeckpriset 2011:”för konsekvent klinisk forskning rörande
hjärtinfarkt med införande av nya beslutsgränser till nytta för en individanpassad
patienthandläggning.”
3. Professor Anders Vahlquist - Honorary Member of the European Society for Dermatologic Research.
4. Professor Lars Rönnblom - The Thuréus prize from The Royal Society of Science 2011
5. Professor Kjell Öberg - The Uppsala County Council research prize for his work concerning
diagnosis and treatment of neuroendocrine tumors. Kjell Öberg has also been appointed adjunct
professor at Vanderbilt University, Nashville, USA.
6. Professor Anna Rask Andersen - appointed as adjunct professor at University of Saskatchewan,
Canada.
7. PhD-student Olof Berggren - Swedish Rheumatology Society’s prize for best basal abstract at
Rikstämman.
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