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  • 1.
    Adamsson, Viola
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Reumark, A.
    Fredriksson, I. -B
    Hammarström, E.
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Johansson, G.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Effects of a healthy Nordic diet on cardiovascular risk factors in hypercholesterolaemic subjects: a randomized controlled trial (NORDIET)2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 269, no 2, p. 150-159Article in journal (Refereed)
    Abstract [en]

    Objective. The aim of this study was to investigate the effects of a healthy Nordic diet (ND) on cardiovascular risk factors. Design and subjects. In a randomized controlled trial (NORDIET) conducted in Sweden, 88 mildly hypercholesterolaemic subjects were randomly assigned to an ad libitum ND or control diet (subjects' usual Western diet) for 6 weeks. Participants in the ND group were provided with all meals and foods. Primary outcome measurements were low-density lipoprotein (LDL) cholesterol, and secondary outcomes were blood pressure (BP) and insulin sensitivity (fasting insulin and homeostatic model assessment-insulin resistance). The ND was rich in high-fibre plant foods, fruits, berries, vegetables, whole grains, rapeseed oil, nuts, fish and low-fat milk products, but low in salt, added sugars and saturated fats. Results. The ND contained 27%, 52%, 19% and 2% of energy from fat, carbohydrate, protein and alcohol, respectively. In total, 86 of 88 subjects randomly assigned to diet completed the study. Compared with controls, there was a decrease in plasma cholesterol (-16%, P < 0.001), LDL cholesterol (-21%, P < 0.001), high-density lipoprotein (HDL) cholesterol (-5%, P < 0.01), LDL/HDL (-14%, P < 0.01) and apolipoprotein (apo)B/apoA1 (-1%, P < 0.05) in the ND group. The ND reduced insulin (-9%, P = 0.01) and systolic BP by -6.6 +/- 13.2 mmHg (-5%, P < 0.05) compared with the control diet. Despite the ad libitum nature of the ND, body weight decreased after 6 weeks in the ND compared with the control group (-4%, P < 0.001). After adjustment for weight change, the significant differences between groups remained for blood lipids, but not for insulin sensitivity or BP. There were no significant differences in diastolic BP or triglyceride or glucose concentrations. Conclusions. A healthy ND improves blood lipid profile and insulin sensitivity and lowers blood pressure at clinically relevant levels in hypercholesterolaemic subjects.

  • 2.
    Andersen, Kasper
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Rasmussen, F.
    Lund Univ, Dept Hlth Sci, Lund, Sweden.
    Neovius, M.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    Tynelius, P.
    Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden;Stockholm Cty Council, Ctr Epidemiol & Community Med, Stockholm, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Body size and risk of atrial fibrillation: a cohort study of 1.1 million young men2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 4, p. 346-355Article in journal (Refereed)
    Abstract [en]

    Background: Whilst tall stature has been related to lower risk of vascular disease, it has been proposed as a risk factor for atrial fibrillation. Little is known about other anthropometric measures and their joint effects on risk of atrial fibrillation.

    Objectives: We aim to investigate associations and potential joint effects of height, weight, body surface area (BSA) and body mass index (BMI) with risk of atrial fibrillation.

    Methods: In a cohort covering 1 153 151 18-year-old men participating in the Swedish military conscription (1972-1995), Cox regression was used to investigate associations of height, weight, BSA and BMI with risk of atrial fibrillation.

    Results: During a median of 26.3 years of follow-up, higher height was associated with higher risk of atrial fibrillation (hazard ratio [HR] 2.80; 95% CI 2.63-2.98; for 5th vs. 1st quintile) and so was larger BSA (HR 3.05; 95% CI 2.82-3.28; for 5th vs. 1st quintile). Higher weight and BMI were to a lesser extent associated with risk of atrial fibrillation (BMI: 1.42; 95% CI 1.33-1.52, for 5th vs. 1st quintile). We found a multiplicative joint effect of height and weight. Adjusting for muscle strength, exercise capacity and diseases related to atrial fibrillation attenuated these measures.

    Conclusions: Higher height and weight are strongly associated with higher risk of atrial fibrillation. These associations are multiplicative and independent of each other and are summarized in a strong association of body surface area with risk of atrial fibrillation. The mechanisms remain unknown but may involve increased atrial volume load with larger body size.

  • 3.
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    How selective sweeps in domestic animals provide new insight into biological mechanisms2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 1, p. 1-14Article, review/survey (Refereed)
    Abstract [en]

    Genetic studies of domestic animals are of general interest because there is more phenotypic diversity to explore in these species than in any experimental organism. Some mutations with favourable phenotypic effects have been highly enriched and gone through selective sweeps during the process of domestication and selective breeding. Three such selective sweeps are described in this review. All three mutations are intronic and constitute cis-acting regulatory mutations. Two of the mutations constitute structural changes (one duplication and one copy number expansion). These examples illustrate a general trend that noncoding mutations and structural changes have both contributed significantly to the evolution of phenotypic diversity in domestic animals. How the molecular characterization of trait loci in domestic animals can provide new basic knowledge of relevance for human medicine is discussed.

  • 4. Andersson, P.
    et al.
    Londahl, M.
    Abdon, N. -J
    Terént, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    The prevalence of atrial fibrillation in a geographically well-defined population in Northern Sweden: implications for anticoagulation prophylaxis2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 272, no 2, p. 170-176Article in journal (Refereed)
    Abstract [en]

    Objectives. The aims of this study were to evaluate the community-based prevalence of atrial fibrillation (AF) in a western society using a geographically well-defined population in the northern part of Sweden as a reference and to estimate the proportion of patients eligible for oral anticoagulation (OAC) prophylactic therapy according to the stroke risk indices CHADS2 and CHA2DS2-VASc. Bleeding risk was assessed using the HAS-BLED score.

    Design. The study population was recruited from AURICULA, a Swedish national quality register for patients receiving anticoagulation treatment. All patients with the diagnosis AF in the catchment area are registered in AURICULA.

    Results. Of the 65 532 inhabitants in the catchment area, 1616 were diagnosed with AF (1200 cases were characterized as chronic AF). Thus, the overall prevalence of AF was 2.5%. The prevalence increased with age from 6.3% in patients over 55 years of age to 13.8% in those over 80 years. The prevalence was higher in men than in women in all age groups. Overall, 56.3% and 85.1% of the population were at high risk of stroke (=2 points) according to CHADS2 and CHA2DS2-VASc, respectively. In addition, 26.9% had an increased bleeding risk according to HAS-BLED.

    Conclusion. Within this large Caucasian population, we identified the highest community-based prevalence of AF to date. The prevalence was strongly associated with increasing age and male gender. Using CHA2DS2-VASc instead of CHADS2 widened the indication for OAC prophylactic therapy of AF in this population.

  • 5.
    Ankarcrona, M.
    et al.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Winblad, B.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Monteiro, C.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Fearns, C.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Powers, E. T.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA..
    Johansson, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Westermark, Gunilla T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Presto, J.
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Ctr Alzheimer Res, Huddinge, Sweden..
    Ericzon, B. -G
    Karolinska Univ Hosp, Div Transplantat Surg, Stockholm, Sweden.
    Kelly, J. W.
    Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA.;Scripps Res Inst, Dept Mol & Expt Med, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA..
    Current and future treatment of amyloid diseases2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, no 2, p. 177-202Article, review/survey (Refereed)
    Abstract [en]

    There are more than 30 human proteins whose aggregation appears to cause degenerative maladies referred to as amyloid diseases or amyloidoses. These disorders are named after the characteristic cross--sheet amyloid fibrils that accumulate systemically or are localized to specific organs. In most cases, current treatment is limited to symptomatic approaches and thus disease-modifying therapies are needed. Alzheimer's disease is a neurodegenerative disorder with extracellular amyloid -peptide (A) fibrils and intracellular tau neurofibrillary tangles as pathological hallmarks. Numerous clinical trials have been conducted with passive and active immunotherapy, and small molecules to inhibit A formation and aggregation or to enhance A clearance; so far such clinical trials have been unsuccessful. Novel strategies are therefore required and here we will discuss the possibility of utilizing the chaperone BRICHOS to prevent A aggregation and toxicity. Type 2 diabetes mellitus is symptomatically treated with insulin. However, the underlying pathology is linked to the aggregation and progressive accumulation of islet amyloid polypeptide as fibrils and oligomers, which are cytotoxic. Several compounds have been shown to inhibit islet amyloid aggregation and cytotoxicity in vitro. Future animal studies and clinical trials have to be conducted to determine their efficacy in vivo. The transthyretin (TTR) amyloidoses are a group of systemic degenerative diseases compromising multiple organ systems, caused by TTR aggregation. Liver transplantation decreases the generation of misfolded TTR and improves the quality of life for a subgroup of this patient population. Compounds that stabilize the natively folded, nonamyloidogenic, tetrameric conformation of TTR have been developed and the drug tafamidis is available as a promising treatment. Read more articles from the symposium: Amyloid - a multifaceted player in human health and disease.

  • 6.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rosenquist Brandell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed?2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 4, p. 347-357Article, review/survey (Refereed)
    Abstract [en]

    The remarkable clinical heterogeneity in chronic lymphocytic leukaemia (CLL) has highlighted the need for prognostic and predictive algorithms that can be employed in clinical practice to assist patient management and therapy decisions. Over the last 20 years, this research field has been rewarding and many novel prognostic factors have been identified, especially at the molecular genetic level. Whilst detection of recurrent cytogenetic aberrations and determination of the immunoglobulin heavy variable gene somatic hypermutation status have an established role in outcome prediction, next-generation sequencing has recently revealed novel mutated genes with clinical relevance (e.g. NOTCH1, SF3B1 and BIRC3). Efforts have been made to combine variables into prognostic indices; however, none has been universally adopted. Although a unifying model for all groups of patients and in all situations is appealing, this may prove difficult to attain. Alternatively, focused efforts on patient subgroups in the same clinical context and at certain clinically relevant 'decision points', that is at diagnosis and at initiation of first-line or subsequent treatments, may provide a more accurate approach. In this review, we discuss the advantages and disadvantages as well as the clinical applicability of three recently proposed prognostic models, the MD Anderson nomogram, the integrated cytogenetic and mutational model and the CLL-international prognostic index. We also consider future directions taking into account novel aspects of the disease, such as the tumour microenvironment and the dynamics of (sub)clonal evolution. These aspects are particularly relevant in view of the increasing number of new targeted therapies that have recently emerged.

  • 7. Bellavia, A
    et al.
    Larsson, Susanna C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Fish consumption and all-cause mortality in a cohort of Swedish men and women.2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 1, p. 86-95Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Epidemiological studies of fish consumption and all-cause mortality have provided inconsistent results.

    OBJECTIVE: We examined the dose-response association between fish consumption and mortality from all causes in a large population-based cohort of Swedish men and women.

    METHODS: The study included 72 522 participants (33 973 women and 38 549 men), aged 45-83 years, from the Swedish Mammography Cohort and the Cohort of Swedish Men. Information on fish consumption was obtained through a self-administered questionnaire in 1997. Participants were followed for 17 years (1 January 1998 to 31 December 2014), and data on death and causes of death were ascertained through linkage to the Swedish Cause of Death Register. We used Cox proportional hazard regression to estimate hazard ratios (HRs) of death. Fish consumption was evaluated as a continuous predictor, flexibly modelled with restricted cubic splines to assess potential nonlinear associations.

    RESULTS: During follow-up, 16 730 deaths (7168 women and 9562 men) were recorded. The dose-response association between fish consumption and all-cause mortality was U-shaped. Compared with the median fish consumption (women: 25.0; men: 30.5 g day-1 ), lower levels of consumption were progressively associated with higher mortality risk up to 25% for women [HR 1.25; 95% confidence interval (CI): 1.11, 1.40] and 19% for men (HR 1.19; 95% CI: 1.07, 1.32) with no reported consumption. Increasingly higher levels of fish consumption were associated with higher mortality risk only amongst women, with a 39% higher mortality risk amongst women reporting the highest level of fish consumption (80 g day-1 ; HR 1.39; 95% CI: 1.15, 1.68).

    CONCLUSION: These results indicate a U-shaped association between fish consumption and all-cause mortality, particularly amongst women.

  • 8.
    Bengtsson, A. A.
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Rheumatol, Lund, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Systemic lupus erythematosus: still a challenge for physicians2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 1, p. 52-64Article, review/survey (Refereed)
    Abstract [en]

    Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.

  • 9. Bergström, G
    et al.
    Berglund, G
    Blomberg, A
    Brandberg, J
    Engström, G
    Engvall, J
    Eriksson, M
    de Faire, U
    Flinck, A
    Hansson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Centre for Research Ethics and Bioethics.
    Hedblad, B
    Hjelmgren, O
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jernberg, T
    Johnsson, Å
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Löfdahl, C-G
    Melander, O
    Östgren, C J
    Persson, A
    Persson, M
    Sandström, A
    Schmidt, C
    Söderberg, S
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Toren, K
    Waldenström, A
    Wedel, H
    Vikgren, J
    Fagerberg, B
    Rosengren, A
    The Swedish CArdioPulmonary BioImage Study: objectives and design2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 6, p. 645-659Article in journal (Refereed)
    Abstract [en]

    Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large-scale 'omics' and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

  • 10.
    Björkegren, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Elevated serum levels of methylmalonic acid and homocysteine in elderly people: a population-based intervention study1999In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 246, no 6, p. 603-611Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    There is uncertainty amongst clinicians about the definitions of cobalamin and folate deficiency and therefore about the indications for treatment. In this report we present the results of systematic cobalamin and folic acid treatment based upon serum cobalamin, total homocysteine (tHcy) and methylmalonic acid (MMA) analyses in a population-based sample.

    SUBJECTS:

    A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey (n = 266). Sixty-nine persons who had serum cobalamin < 300 pmol L-1 and serum MMA >/=0.37 micromol L-1 or serum tHcy >/=15 micromol L-1 and who had no cobalamin or folic acid substitution were selected for treatment.

    INTERVENTIONS:

    Initially all 69 patients were given cobalamin orally or intramuscularly. Those who remained high in tHcy were in addition given folic acid treatment.

    MAIN OUTCOME MEASURES:

    Serum cobalamin, serum MMA and serum tHcy.

    RESULTS:

    After 6 months of cobalamin treatment, serum MMA became normal in 13 out of 15 persons. Mean serum tHcy decreased but was normalized in only 15 out of 56 persons. After 3 months of folic acid treatment added to those who still had an abnormal serum tHcy, serum tHcy had normalized in all but one person.

    CONCLUSIONS:

    Cobalamin treatment normalizes increased MMA values and combined cobalamin and folic acid treatment normalizes tHcy, suggesting a pretreatment deficiency of tissue cobalamin and folate in spite of normal serum cobalamin and folate values in the majority of cases.

  • 11.
    Björkegren, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Reported symptoms and clinical findings in relation to serum cobalamin, folate, methylmalonic acid and total homocysteine among elderly Swedes: a population-based study2003In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 254, no 4, p. 343-352Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    The early stages of tissue B12 or folate deficiency often cause diagnostic problems. In this report, the levels of serum cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy), and their relationships with clinical findings and reported symptoms in a representative random population sample are presented.

    DESIGN:

    Cohort study.

    SETTING:

    A general central Swedish population 70 years or older.

    SUBJECTS AND METHODS:

    A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey. A total of 235 (85%) persons responded, of whom 161 had no interfering diseases or medication. Blood specimens for serum cobalamin, folate, MMA and tHcy analyses were drawn.

    MAIN OUTCOME MEASURES:

    Presence of anaemic, gastrointestinal, neurological and psychiatric symptoms, obtained by questionnaire, and vibration sense measurement and findings at a physical and Mini Mental State Examination.

    RESULTS:

    Among a large number of symptoms and clinical findings that traditionally have been linked to vitamin B12 or folate tissue deficiency, only changes in the tongue mucosa and mouth angle stomatitis turned out to be significantly associated with abnormal serum tHcy and serum folate levels. There were no relationships to serum cobalamin and serum MMA.

    CONCLUSIONS:

    Changes in the oral mucosa were the only signs and symptoms found in this study, indicating that these may be the very early markers of metabolic defects. The traditional symptoms of vitamin deficiency may appear later in the course.

  • 12.
    Björkegren, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes: a population-based study2001In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 249, no 5, p. 423-32Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    The possibilities of detecting tissue cobalamin and folate deficiency are under debate. In this report the levels of serum cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) and their interrelations in a representative random population sample are presented.

    DESIGN

    Cohort study.

    SETTING

    A general mid-Swedish population.

    SUBJECTS

    A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey. A total of 235 (85%) persons responded, out of whom 224 had no interfering diseases.

    MAIN OUTCOME MEASURES

    Serum cobalamin, folate, MMA and tHcy.

    RESULTS

    The serum levels of cobalamin, folate, MMA and tHcy were all correlated to cobalamin and folic acid treatment. They were also correlated to the intake of multivitamin preparations. In addition, serum cobalamin was higher in untreated women than in men but not correlated to age. Serum folate was correlated neither to sex nor age. Serum tHcy and MMA were both directly correlated to age but MMA not to sex. MMA was inversely correlated to serum cobalamin but not to serum folate, whereas serum tHcy was inversely correlated to serum cobalamin, folate and creatinine. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin, erythrocyte volume fraction (EVF) or mean red cell volume. Half of the study population had abnormal MMA or tHcy levels, suggesting a latent or overt tissue deficiency of cobalamin or folate.

    CONCLUSIONS

    A substantial proportion of the elderly general population had signs of low tissue levels of cobalamin or folate. Amongst those who took multivitamin preparations this proportion was much lower.

  • 13.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Pacak, K.
    NIH, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Med Neuroendocrinol Program Reprod & Adult E, Bethesda, MD USA..
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Precision medicine in pheochromocytoma and paraganglioma: current and future concepts2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 559-573Article in journal (Refereed)
    Abstract [en]

    Pheochromocytoma and paraganglioma (PPGL) are rare diseases but are also amongst the most characterized tumour types. Hence, patients with PPGL have greatly benefited from precision medicine for more than two decades. According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo)hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2). Categorization into these clusters is highly dependent on mutation subtypes. At least 12 different syndromes with distinct genetic causes, phenotypes and outcomes have been described. Genetic screening tests have a documented benefit, as different PPGL syndromes require specific approaches for optimal diagnosis and localization of various syndrome-related tumours. Genotype-tailored treatment options, follow-up and preventive care are being investigated. Future new developments in precision medicine for PPGL will mainly focus on further identification of driver mechanisms behind both disease initiation and malignant progression. Identification of novel druggable targets and prospective validation of treatment options are eagerly awaited. To achieve these goals, we predict that collaborative large-scale studies will be needed: Pheochromocytoma may provide an example for developing precision medicine in orphan diseases that could ultimately aid in similar efforts for other rare conditions.

  • 14. Björnsdottir, Sigridur
    et al.
    Sääf, Maria
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaelsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ludvigsson, Jonas F
    Risk of Hip Fracture in Addison's Disease: A Population-based Cohort Study2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 2, p. 187-195Article in journal (Refereed)
    Abstract [en]

    Objectives:  The results of studies of bone mineral density (BMD) in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study we compare hip fracture risk in adults with and without AD. Design:  A population-based cohort study. Methods:  Through the Swedish National Patient Register and the Total Population Register, we identified 3,219 patients without prior hip fracture who were diagnosed with AD at the age of ≥30 years during the period 1964-2006, and 31,557 age- and sex-matched controls. Time to hip fracture was measured. Results:  We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture (hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6-2.1; p < 0.001). This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD ≤50 years old had the highest risk of hip fracture (HR = 2.7; 95% CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD (odds ratio (OR) = 2.4; 95% CI, 2.1- 3.0) with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95% CI, 1.8-4.2). Conclusion:  Both clinically undiagnosed and diagnosed AD were associated with hip fractures, with the highest relative risk seen in women diagnosed with AD ≤50 years of age.

  • 15.
    Blokzijl, Andries
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular tools.
    Friedman, Mikaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular tools.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular tools.
    Profiling protein expression and interactions: proximity ligation as a tool for personalized medicine2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, no 3, p. 232-245Article, review/survey (Refereed)
    Abstract [en]

    Blokzijl A, Friedman M, Ponten F, Landegren U (From the Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden). Profiling protein expression and interactions: proximity ligation as a tool for personalized medicine. (Review) J Intern Med 2010; 268: 232-245. The ability to detect very low levels of expressed proteins has enormous potential for early diagnostics and intervention at curable stages of disease. An extended range of targets such as interacting or post-translationally modified proteins can further improve the potential for diagnostics and patient stratification, and for monitoring response to treatment. These are critical building blocks for personalized treatment strategies to manage disease. The past few decades have seen a remarkably improved understanding of the molecular basis of disease in general, and of tumour formation and progression in particular. This accumulated knowledge creates opportunities to develop drugs that specifically target molecules or molecular complexes critical for survival and expansion of tumour cells. However, tumours are highly variable between patients, necessitating the development of diagnostic tools to individualize treatment through parallel analysis of sets of biomarkers. The proximity ligation assay (PLA) can address many of the requirements for advanced molecular analysis. The method builds on the principle that recognition of target proteins by two, three or more antibodies can bring in proximity DNA strands attached to the antibodies. The DNA strands can then participate in ligation reactions, giving rise to molecules that are amplified for highly sensitive detection. PLA is particularly well suited for sensitive, specific and multiplexed analysis of protein expression, post-translational modifications and protein-protein interactions. The analysis of this extended range of biomarkers will prove critical for the development and implementation of personalized medicine.

  • 16.
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    Atrial fibrillation: from atrial extrasystoles to atrial cardiomyopathy - what have we learned from basic science and interventional procedures?2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 5, p. 406-411Article in journal (Other academic)
  • 17.
    Boden, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Molin, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Jernberg, T.
    Kieler, H.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Higher mortality after myocardial infarction in patients with severe mental illness: a nationwide cohort study2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, no 6, p. 727-736Article in journal (Refereed)
    Abstract [en]

    ObjectivesThe aim of this study was to explore the impact of severe mental illness (SMI) on myocardial infarction survival and determine the influence of risk factor burden, myocardial infarction severity and different treatments. Design, setting and participantsThis population-based cohort study, conducted in Sweden during the period 1997-2010, included all patients with a first diagnosis of myocardial infarction in the Swedish nationwide myocardial infarction register SWEDEHEART (n=209592). Exposure was defined as a diagnosis of SMI (i.e. bipolar disorder or schizophrenia) in the national patient register prior to infarction. Bias-minimized logistic regression models were identified using directed acyclic graphs and included covariates age, gender, smoking, diabetes, previous cardiovascular disease, myocardial infarction characteristics and treatment. Main outcome measuresThe outcomes were 30-day and 1-year mortality, obtained through linkage with national population registers. ResultsPatients with bipolar disorder (n=442) and schizophrenia (n=541) were younger (mean age 68 and 63years, respectively) than those without SMI (n=208609; mean age 71years). The overall 30-day and 1-year mortality rates were 10% and 18%, respectively. Compared with patients without SMI, patients with SMI had higher 30-day [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.55-2.56] and 1-year mortality (OR 2.11, 95% CI 1.74-2.56) in the fully adjusted model. The highest mortality was observed amongst patients with schizophrenia (30-day mortality: OR 2.58, 95% CI 1.88-3.54; 1-year mortality: OR 2.55, 95% CI 1.98-3.29). ConclusionSMI is associated with a markedly higher mortality after myocardial infarction, also after accounting for contributing factors. It is imperative to identify the reasons for this higher mortality.

  • 18. Brauner, S.
    et al.
    Zhou, W.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Green, T. M.
    Folkersen, L.
    Ivanchenko, M.
    Lofstrom, B.
    Xu-Monette, Z. Y.
    Young, K. H.
    Pedersen, L. Moller
    Moller, M. Boe
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wahren-Herlenius, M.
    Reduced expression of TRIM21/Ro52 predicts poor prognosis in diffuse large B-cell lymphoma patients with and without rheumatic disease2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 3, p. 323-332Article in journal (Refereed)
    Abstract [en]

    ObjectiveTRIM21 (also known as Ro52) is an autoantigen in rheumatic disease and is predominantly expressed in leucocytes. Overexpression is associated with decreased proliferation, and the TRIM21 gene maps to a tumour suppressor locus. We therefore investigated the expression of TRIM21 in patients with diffuse large B-cell lymphoma (DLBCL) and its potential usefulness as a prognostic biomarker. Materials and methodsTRIM21 expression levels were assessed by immunohistochemistry in lymphoma biopsies from three cohorts of patients with DLBCL: 42 patients with rheumatic disease treated with a cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP)-like regimen, 76 CHOP-treated and 196 rituximab-CHOP-treated nonrheumatic patients. Expression was correlated with clinical and biomedical parameters. TRIM21 expression was assessed in relation to lymphocyte proliferation by quantitative PCR and correlated with H-3-thymidine incorporation and propidium iodine staining. ResultsTRIM21 expression levels differed in the lymphomas compared to normal lymphoid tissue, with reduced expression correlating with shorter overall survival in all three cohorts. In the two larger cohorts, progression-free survival was assessed and was also found to correlate with TRIM21 expression. The association was independent of commonly used clinical prognostic scores, lymphoma subtype and several previously reported prognostic biomarkers. In agreement with this clinical observation, we noted an inverse correlation between TRIM21 expression and proliferation of leucocytes invitro. ConclusionsWe show that loss of TRIM21 expression is associated with more aggressive lymphoma and increased proliferation, whereas maintenance of TRIM21 expression is associated with better prognosis in patients with DLBCL. Based on our findings, we suggest that TRIM21 should be considered as a novel biomarker for lymphoma characterization and for predicting patient survival.

  • 19. Burgaz, A.
    et al.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Rautiainen, S.
    Orsini, N.
    Håkansson, N.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, A.
    Confirmed hypertension and plasma 25(OH)D concentrations amongst elderly men2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 269, no 2, p. 211-218Article in journal (Refereed)
    Abstract [en]

    Objectives.

    The results of experimental studies suggest that vitamin D deficiency activates the renin-angiotensin system and predisposes to hypertension. Results of previous epidemiological studies investigating the association between 25-hydroxyvitamin D [25(OH)D] status and hypertension have not been consistent, perhaps because of their sole reliance on office blood pressure (BP) measurements leading to some misclassification of hypertension status. No previous studies have examined the association between 25(OH)D status and confirmed hypertension assessed with both office and 24-h BP measurements.

    Design.

    In this cross-sectional study, we investigated 833 Caucasian men, aged 71 +/- 0.6 years, to determine the association between plasma 25(OH)D concentrations, measured with high-pressure liquid chromatography mass spectrometry, and the prevalence of hypertension. We used both supine office and 24-h BP measurements for classifying participants as normotensive or confirmed hypertensive; participants with inconsistent classifications were excluded.

    Results.

    In a multivariable adjusted logistic regression model, men with 25(OH)D concentrations < 37.5 nmol L-1 had a 3-fold higher prevalence of confirmed hypertension compared to those with >= 37.5 nmol L-1 25(OH)D (odds ratio = 3.3, 95% CI: 1.0-11.0).

    Conclusions.

    Our results show that low plasma 25(OH)D concentration is associated with a higher prevalence of confirmed hypertension.

  • 20. Burgaz, Ann
    et al.
    Åkesson, A.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, A.
    25-hydroxyvitamin D accumulation during summer in elderly women at latitude 60 degrees N2009In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 266, no 5, p. 476-483Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: During half of the year, cutaneous synthesis of 25-hydroxyvitamin D (25(OH)D) is not detectable at northern latitudes, leaving the population dependent on other sources for optimal vitamin D status. During April to September, 25(OH)D status may be improved by solar exposure. In this study, we measured seasonal differences in serum 25(OH)D concentrations and identified the major predictors of summer 25(OH)D concentrations. DESIGN: We assessed serum 25(OH)D concentrations during both winter and summer amongst 100 women, aged 61-83 years, randomly sampled from the Swedish Mammography Cohort. Participants completed two detailed questionnaires covering diet, use of dietary supplements and sun-related behaviour, the first in January through March and a second time in August through September. RESULTS: The mean seasonal increase in serum 25(OH)D concentrations was 38% from mean 72 +/- 23 nmol L(-1) during winter to 99 +/- 29 nmol L(-1) in summer. High summer 25(OH)D concentrations were associated with higher winter concentrations, preference of staying in sun instead of shade, having a nonsensitive skin type and normal body mass index. Based on multiple linear regression modelling, preferring sun, having nonsensitive skin type and normal weight as compared with preferring shade, having sensitive skin type and being obese, was associated with a 64 nmol L(-1) higher 25(OH)D concentrations during summer. CONCLUSIONS: Women with high winter 25(OH)D serum concentrations, with preference of staying in the sun instead of shade during summer, a skin type allowing for longer sun exposure and a normal weight had the highest summer 25(OH)D concentrations.

  • 21.
    Camm, A. J.
    et al.
    St Georges Univ London, Cranmer Terrace, London SW17 0RE, England..
    Savelieva, I.
    St Georges Univ London, Cranmer Terrace, London SW17 0RE, England..
    Potpara, T.
    Univ Belgrade, Cardiol Clin, Sch Med, Clin Ctr Serbia, Belgrade, Serbia..
    Hindriks, G.
    Herzzentrum Leipzig GmbH, Dept Electrophysiol, Leipzig, Germany..
    Pison, L.
    Maastricht Univ, Dept Cardiol, Med Ctr, NL-6200 MD Maastricht, Netherlands.;Univ Limburg, Cardiovasc Res Inst, NL-6200 MD Maastricht, Netherlands..
    Blomström-Lundqvist, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology-Arrhythmia.
    The changing circumstance of atrial fibrillation: progress towards precision medicine2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 5, p. 412-427Article, review/survey (Refereed)
    Abstract [en]

    The prevalence of atrial fibrillation (AF) in the general population is between 1% and 2% in the developed world and is higher in men than in women. The arrhythmia occurs much more commonly in the elderly, and the estimated lifetime risk of developing AF is one in four for men and women aged 40 years and above. Projected data from multiple population-based studies in the USA and Europe predict a two- to threefold increase in the number of AF patients by 2060. The high lifetime risk of AF and increased longevity underscore the important public health burden posed by this arrhythmia worldwide. AF has multiple aetiologies and a broad variety of presentations. The primary pathologies underlying or promoting the occurrence of AF vary more than for any other cardiac arrhythmia, ranging from autonomic imbalance to organic heart disease and metabolic disorders, such as diabetes mellitus, metabolic syndrome, hyperthyroidism and kidney disease, and lifestyle factors such as smoking, alcohol consumption and participation in endurance sports. Biomarkers are increasingly being investigated and, together with clinical and genetic factors, will eventually lead to a clinically valuable detailed classification of AF which will also incorporate pathophysiological determinants and mechanisms of the arrhythmia. In turn, this will allow the development and application of precision medicine to this troublesome arrhythmia.

  • 22. Carlsson, G
    et al.
    van't Hooft, I
    Melin, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Entesarian, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Laurencikas, E
    Nennesmo, I
    Trebińska, A
    Grzybowska, E
    Palmblad, J
    Dahl, N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordenskjöld, M
    Fadeel, B
    Henter, J-I
    Central nervous system involvement in severe congenital neutropenia: neurological and neuropsychological abnormalities associated with specific HAX1 mutations2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 264, no 4, p. 388-400Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Homozygous mutations in the HAX1 gene were recently identified in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden. Our observations suggested that these patients also develop neurological and neuropsychological symptoms. METHODS: Detailed clinical studies and mutation analyses were performed in the surviving patients belonging to the Kostmann kindred and in two patients not related to this family, along with studies of HAX1 splice variant expression in normal human tissues. RESULTS: Five of six Kostmann family patients and one other patient from northern Sweden harboured homozygous HAX1 mutations (568C-->T, Q190X) and one carried a heterozygous ELA2 gene mutation. One Swedish patient of Kurdish extraction carried alternative homozygous HAX1 mutations (131G-->A, W44X). All the three patients with Q190X mutations who were alive and available for evaluation developed neurological disease with decreased cognitive function, and three of four patients who reached 10 years developed epilepsy. In contrast, the patients with the ELA2 and W44X HAX1 mutations, respectively, showed no obvious neurological abnormalities. Moreover, two alternative HAX1 splice variants were identified in normal human tissues, including the brain. Both transcripts contained exon 5, harbouring the Q190X mutation, whereas the 5' end of exon 2 containing the W44X mutation was spliced out from the second transcript. CONCLUSIONS: We describe neurological and neuropsychological abnormalities for the first time in Kostmann disease patients. These central nervous system symptoms appear to be associated with specific HAX1 mutations.

  • 23. Carrero, J.J.
    et al.
    Stenvinkel, Peter
    Fellström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Qureshi, A.R.
    Lamb, K.
    Heimbürger, O.
    Bárány, Peter
    Radhakrishnan, K.
    Lindholm, B.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordfors, L.
    Shiels, P.G.
    Telomere attrition is associated with inflammation, low fetuin: A levels and high mortality in prevalent haemodialysis patients2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 263, no 3, p. 302-312Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.

  • 24.
    Cederholm, Tommy
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Persson, M.
    Andersson, P.
    Stenvinkel, P.
    Nordfors, L.
    Madden, J.
    Vedin, I.
    Wretlind, B.
    Grimble, R. F.
    Palmblad, J.
    Polymorphisms in cytokine genes influence long-term survival differently in elderly male and female patients2007In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 262, no 2, p. 215-223Article in journal (Refereed)
    Abstract [en]

    Objectives. We asked if single nucleotide polymorphisms (SNP) in inflammatory cytokine genes related to 3-year survival in ill elderly subjects and if genotypes differed between the elderly and a younger control population.

    Design. Prospective observational study.

    Setting. Two geriatric departments at a university hospital.

    Subjects. Eighty three acutely admitted geriatric patients (83 ± 7 year, 70% women) and 207 young healthy subjects (40 ± 1 year, 37% women) were included.

    Outcome measures. Single nucleotide polymorphisms in the genes of tumour necrosis factor (TNF)-α–308 G/A, interleukin (IL)-1β–511 C/T, IL-6–174 G/C and IL-10–1082 A/G were analysed. In the geriatric patients SNP in lymphotoxin (LT)-α +252 G/A and serum levels of TNF-α, IL-6, IL-10, soluble IL-I receptor(R)II were also determined, as well as the 3-year mortality.

    Results. The allele distribution did not differ significantly between the elderly and the young. In the female elderly, 3-year survival was doubled (P < 0.05) in those with the high-producing genotypes of IL-6 –174 GG and TNF-α -308 GA compared with those with low-producing alleles. In contrast, men with high-producing LT-α +252 AA and IL-1β–511 CT&TT genotypes displayed halved 3-year survival (P < 0.05) compared with those with low-producing genotypes, whereas possession of the high-producing IL-10 –1082 GG genotype favoured survival. Serum IL-10 was higher in the high-producing IL-10 genotype in females.

    Conclusion. As high-producing IL-6 –174 genotype favoured 3-year survival in women, whereas the likewise high-producing LT-α +252 and IL-1β -511 genotypes were associated with poor survival in men, we conclude that the specific genotypes, in association with gender, may act as determinants for survival in elderly patients.

  • 25.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Treatment with an Oral Direct Thrombin Inhibitor Decreases Platelet Activity but Increases Markers of Inflammation in Patients with Myocardial Infarction.2011In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 270, no 3, p. 215-223Article in journal (Refereed)
    Abstract [en]

    Background: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. Objectives:  To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). Methods:  A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL)-10 and IL-18 were analysed in serial blood samples.

    Results: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (p<0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (p=0.01 and p=0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (p=0.006 and p<0.001, respectively). Ximelagatran increased IL-10 levels (p=0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (p=0.002).

    Conclusion: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long-term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes.

  • 26. Claesson, Maria
    et al.
    Birgander, L. S.
    Jansson, J-H.
    Lindahl, Bertil
    Burell, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Asplund, K.
    Mattsson, C.
    Cognitive-behavioural stress management does not improve biological cardiovascular risk indicators in women with ischaemic heart disease: a randomized-controlled trial2006In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 260, no 4, p. 320-331Article in journal (Refereed)
    Abstract [en]

    Objectives. Psychosocial factors, such as stress and vital exhaustion, are associated with an increased risk of cardiovascular events, and women report more psychosocial ill-being after an acute myocardial infarction than men. We have earlier shown that a cognitive-behavioural intervention in women with ischaemic heart disease (IHD) improved psychosocial well-being. In the present study, we tested the hypothesis that the improvement in psychosocial well-being is associated with an improvement in biochemical indicators of cardiovascular risk.

    Design. Randomized-controlled trial in northern Sweden.

    Setting. Outpatient care.

    Subjects. Women with IHD were randomized to either a 1-year cognitive-behavioural stress management programme or usual care. Of the 159 women who completed the study, 77 were in the intervention group, and 82 in the control group.

    Interventions. A 1-year cognitive-behavioural stress management programme versus conventional care.

    Results. Group assignment was not found to be a determinant of waist circumference, high sensitive C-reactive protein (hs-CRP), fibrinogen, von Willebrand factor (vWF), plasminogen activator inhibitor type 1 (PAI-1) activity, tissue plasminogen activator (tPA) activity, tPA antigen, tPA-PAI-1 complex, leptin, or HOMA2 insulin resistance index (HOMA2-IR) at follow up. Changes in psychosocial variables were not associated with changes in any of the biological risk indicators.

    Conclusions. Even if our cognitive-behavioural stress management programme had effects on proximal targets, such as stress behaviour and vital exhaustion, we found no improvement in intermediate biochemical targets related to the metabolic syndrome and IHD. Our results challenge the proposition that the relationship between psychological well-being and biological cardiovascular risk indicators is a direct cause-effect phenomenon.

  • 27.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Introduction to symposium on vascular biology, metabolism and cancer2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 112-113Article in journal (Refereed)
  • 28.
    Claesson-Welsh, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    VEGFA and tumour angiogenesis2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 114-127Article, review/survey (Refereed)
    Abstract [en]

    In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

  • 29. Cornelis, M C
    et al.
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ärnlöv, J
    Elmståhl, S
    Söderberg, S
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, Stanford, CA 94305 USA.
    Targeted proteomic analysis of habitual coffee consumption.2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 2, p. 200-211Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Coffee drinking has been implicated in mortality and a variety of diseases but potential mechanisms underlying these associations are unclear. Large-scale systems epidemiological approaches may offer novel insights to mechanisms underlying associations of coffee with health.

    OBJECTIVE: We performed an analysis of known and novel protein markers linked to cardiovascular disease and their association with habitual coffee intake in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS, n = 816) and followed up top proteins in the Uppsala Longitudinal Study of Adult Men (ULSAM, n = 635) and EpiHealth (n = 2418).

    METHODS: In PIVUS and ULSAM, coffee intake was measured by 7-day dietary records whilst a computer-based food frequency questionnaire was used in EpiHealth. Levels of up to 80 proteins were assessed in plasma by a proximity extension assay.

    RESULTS: Four protein-coffee associations adjusted for age, sex, smoking and BMI, met statistical significance in PIVUS (FDR < 5%, P < 2.31 × 10(-3) ): leptin (LEP), chitinase-3-like protein 1 (CHI3L), tumour necrosis factor (TNF) receptor 6 and TNF-related apoptosis-inducing ligand. The inverse association between coffee intake and LEP replicated in ULSAM (β, -0.042 SD per cup of coffee, P = 0.028) and EpiHealth (β, -0.025 SD per time of coffee, P = 0.004). The negative coffee-CHI3L association replicated in EpiHealth (β, -0.07, P = 1.15 × 10(-7) ), but not in ULSAM (β, -0.034, P = 0.16).

    CONCLUSIONS: The current study supports an inverse association between coffee intake and plasma LEP and CHI3L1 levels. The coffee-CHI3L1 association is novel and warrants further investigation given links between CHI3L1 and health conditions that are also potentially influenced by coffee.

  • 30. de Jong, Daphne
    et al.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Inflammatory cells and immune microenvironment in malignant lymphoma2008In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 264, no 6, p. 528-36Article in journal (Refereed)
    Abstract [en]

    It has become clear that the biological and clinical behaviour of malignant lymphoma is not only determined by the properties of the tumour cells themselves but are also largely by the interaction of the tumour cells with their nonmalignant microenvironment. The composition and functional status of the tumour microenvironment is highly variable between different classes of malignant lymphoma and may provide both growth-supportive and growth suppressive signals via components of the adaptive and innate immune response. In this review, the functional interactions and clinical consequences of these insights are discussed in indolent and aggressive B-cell lymphomas and in classical Hodgkin's lymphoma.

  • 31.
    Edgren, G.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden;Soder Sjukhuset, Dept Cardiol, Stockholm, Sweden.
    Hjalgrim, H.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark;Copenhagen Univ Hosp, Dept Hematol, Copenhagen, Denmark.
    Rostgaard, K.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark.
    Dahl, V.
    Publ Hlth Agcy Sweden, Dept Monitoring & Evaluat, Stockholm, Sweden.
    Titlestad, K.
    Odense Univ Hosp, Dept Clin Immunol, Odense, Denmark.
    Erikstrup, C.
    Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark.
    Wikman, A.
    Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden;Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Norda, Rut
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Majeed, A.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden;Alfred Hlth, Dept Gastroenterol, Melbourne, Vic, Australia;Monash Univ, Cent Clin Sch, Melbourne, Vic, Australia.
    Searching for unknown transfusion-transmitted hepatitis viruses: a binational cohort study of 1.5 million transfused patients2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 284, no 1, p. 92-103Article in journal (Refereed)
    Abstract [en]

    Background. Both hepatitis B and C viruses were transmitted through blood transfusion before implementation of donor screening. The existence of additional, yet unknown transfusion transmittable agents causing liver disease could have important public health implications.

    Methods. Analyses were based on the Scandinavian Donations and Transfusions (SCANDAT2) database. Cox regression models were used to estimate the hazard ratio (HR) of developing chronic liver disease in recipients of blood from donors who later developed any chronic liver disease compared to recipients who received blood transfusion from healthy donors. We also studied whether the risk of liver disease was increased in patients who received units from high-risk' donors, defined as donors who had a higher than expected occurrence of liver disease amongst their previous recipients. All analyses were stratified before and after 1992 to account for the effect of screening for hepatitis C virus.

    Results. A total of 1 482 922 transfused patients were included in the analyses. Analyses showed evidence of transfusion transmission of liver diseases before, but not after the implementation of hepatitis C virus screening in 1992, with HRs for any liver disease of 1.38 [95% confidence interval (CI), 1.30-1.46] and 0.99 (95% CI, 0.91-1.07), before and after 1992, respectively. Similarly, blood components from 'high-risk' donors conferred increased risks before, but not after 1992.

    Conclusions. Our data provide no evidence for transfusion transmission of agents causing liver disease after the implementation of screening for hepatitis B and C, and suggest that if such transmission does occur, it is rare.

  • 32. Eeg-Olofsson, K
    et al.
    Cederholm, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Nilsson, P M
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Svensson, A-M
    Gudbjörnsdóttir, S
    Eliasson, B
    New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 268, no 5, p. 471-482Article in journal (Refereed)
    Abstract [en]

    AIMS

    To analyse the association between glycosylated haemoglobin A1c (HbA1c) and cardiovascular disease (CVD) in patients with type 2 diabetes in the Swedish National Diabetes Register (NDR).

    METHODS

    An observational study of 18 334 patients (age 30-79 years, previous CVD in 18%, baseline HbA1c 5.0-10.9%) who were followed for 6 years (mean 5.6 years) from 1997/1998 until 2003.

    RESULTS

    Hazard ratios per 1% unit increase in baseline or updated mean HbA1c for fatal/nonfatal coronary heart disease (CHD), CVD and total mortality were 1.11-1.13, 1.10-1.11 and 1.09-1.10, respectively (all P < 0.001), adjusted for several risk factors and clinical characteristics in Cox regression. Adjusted 6-year event rates increased with higher baseline or updated mean HbA1c with no J-shaped risk curves, in all patients and also when subgrouping by shorter (mean 3 years) or longer (mean 14 years) diabetes duration, by presence or absence of previous CVD, or by treatment with oral hypoglycaemic agents (OHAs) or insulin. Risk reductions of 20% for CHD and 16% for CVD (P < 0.001) were found in patients with a baseline mean HbA1c of 6.5%, compared to those with a mean level of 7.5%. Compared to OHA-treated patients, insulin-treated patients had an increased risk of total mortality, due almost exclusively to an increased risk of non-CVD mortality, and due less to a weakly significant increased risk of fatal CVD. HbA1c was not associated with non-CVD mortality.

    CONCLUSIONS

    This observational study showed progressively increasing risks of CHD, CVD and total mortality with higher HbA1c, and no risk increase at low HbA1c levels even with longer diabetes duration, previous CVD or treatment with either insulin or OHAs. Patients achieving HbA1c <7% showed benefits for risk reduction.

  • 33.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Hjort, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Baron, Tomasz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jernberg, T.
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Cardiol, Stockholm, Sweden.
    Nordenskjold, A. M.
    Orebro Univ, Dept Cardiol, Fac Hlth, Orebro, Sweden.
    Tornvall, P.
    Karolinska Inst, Sodersjukhuset, Dept Clin Sci & Educ, Stockholm, Sweden.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 4, p. 419-428Article in journal (Refereed)
    Abstract [en]

    Background

    Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is receiving increasing interest as a prognostically adverse entity distinct from myocardial infarction with significant coronary artery disease (MI-CAD). However, data are still limited regarding long-term cardiovascular morbidity and cause-specific mortality in MINOCA.

    Methods

    This is a registry-based cohort study using data from patients admitted to Swedish coronary care units. We investigated various nonfatal outcomes (recurrent MI, hospitalization for heart failure or stroke) and fatal outcomes (cardiovascular, respiratory or cancer-related mortality) in 4069 patients without apparent acute cardiovascular disease, used as non-MI controls, 7266 patients with first-time MINOCA and 69267 patients with first-time MI-CAD.

    Results

    Almost all event rates (median follow-up 3.8years) increased in a stepwise fashion across the three cohorts [rates of major adverse events (MAE; composite of all-cause mortality, recurrent MI, hospitalization for heart failure or stroke): n=268 (6.6%), n=1563 (21.5%), n=17777 (25.7%), respectively]. Compared to non-MI controls, MINOCA patients had an adjusted hazard ratio (HR) of 2.12 (95% confidence interval 1.84-2.43) regarding MAE. MINOCA patients had a substantial risk of cardiovascular mortality and the highest numerical risks of respiratory and cancer-related mortality. Male sex, previous heart failure and chronic obstructive pulmonary disease had a stronger prognostic impact in MINOCA than in MI-CAD. Female MINOCA patients with atrial fibrillation were at particular risk.

    Conclusions

    Patients with first-time MINOCA have a considerable risk of adverse events. This stresses the need for a comprehensive search of the cause of MINOCA, thorough treatment of underlying disease triggers and close follow-up.

  • 34.
    Ekman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Almost all institutionalized women are osteoporotic, when measured by heeland finger ultrasound2001In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 249, no 2, p. 173-80Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Since there is a need for simple methods to identify individuals with osteoporosis, we investigated bone status (heel and finger) with ultrasound in an institutionalized elderly population and studied the association between these measures, risk factors for osteoporosis and prevalent osteoporotic fractures. DESIGN: Cross-sectional study. Subjects. Nursing home residents, 237 women and 84 men, mean age 84 years. RESULTS: Altogether 82% of those eligible could undergo heel ultrasound, 65% finger ultrasound and 41% measurements at both sites. Using a transcription of the WHO criterion of osteoporosis, 95% of the women who underwent heel ultrasound were classified as osteoporotic (mean T-score = -4.8) and 92% had Z-scores below zero (mean Z-score=-1.6), whereas 51% of the men were osteoporotic (mean T-score=-2.6) and 77% had Z-scores below zero (mean Z-score=-1.3). Based on finger ultrasound measurements, 99% of the women were classified as osteoporotic (mean T-score=-5.0) and 93% had Z-scores below zero (mean -1.6). The variations in ultrasound values were only moderately explained by age, current weight and walking ability. Amongst women, the association with a prevalent osteoporotic fracture decreased by 43% (95% CI=10-63%) for every SD increase in speed of sound (SOS) of the heel, but no such relationship was found for finger SOS. CONCLUSIONS: Our results from ultrasound measurements at two different anatomical sites indicate that virtually all institutionalized elderly women could be classified as osteoporotic, when measured by these techniques.

  • 35. Emilsson, L.
    et al.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Koster, M.
    Lambe, M.
    Ludvigsson, J. F.
    Review of 103 Swedish Healthcare Quality Registries2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, no 1, p. 94-136Article in journal (Refereed)
    Abstract [en]

    Background and objectives: In the past two decades, an increasing number of nationwide, Swedish Healthcare Quality Registries (QRs) focusing on specific disorders have been initiated, mostly by physicians. Here, we describe the purpose, organization, variables, coverage and completeness of 103 Swedish QRs. Methods: From March to September 2013, we examined the 2012 applications of 103 QRs to the Swedish Association of Local Authorities and Regions (SALAR) and also studied the annual reports from the same QRs. After initial data abstraction, the coordinator of each QR was contacted at least twice between June and October 2013 and asked to confirm the accuracy of the data retrieved from the applications and reports. Results: About 60% of the QRs covered 80% of their target population (completeness). Data recorded in Swedish QRs include aspects of disease management (diagnosis, clinical characteristics, treatment and lead times). In addition, some QRs retrieve data on self-reported quality of life (EQ5D, SF-36 and disease-specific measures), lifestyle (smoking) and general health status (World Health Organization performance status, body mass index and blood pressure). ConclusionDetailed clinical data available in Swedish QRs complement information from government-administered registries and provide an important source not only for assessment and development of quality of care but also for research.

  • 36.
    Eriksson, Barbro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Arnberg, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lörelius, LE
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lundqvist, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Wide, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Neuroendocrine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients1990In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 228, no 2, p. 103-113Article in journal (Refereed)
    Abstract [en]

    A prospective study has been performed on 84 patients with endocrine pancreatic tumours evaluated at the Medical Department in Uppsala. Available information concerning the patients' presenting symptoms, age at diagnosis, clinical syndrome, tumour location, location of metastases, diagnostic radiology, biochemical and histopathological findings has been analysed. Our results indicate that most patients initially show rather vague and non-specific symptoms, with dyspepsia and pain being the most frequent presenting features. The median delay between appearance of the first symptom and diagnosis was 2 years; the delay was 3 5 months in sporadic cases and 14.5 months in familial cases. In spite of improvements in diagnostic methods, the median age at diagnosis (53 years) has not been reduced, and most patients are encountered when the tumour has reached an advanced stage. There is a need for a method of screening patients with still uncharacteristic abdominalsymptoms for a neuroendocrine tumour. The presence of elevated levels of plasma chromogranin in all patients with a proven tumour suggests that such possibilities exist, and the use of this biochemical marker in the future might reduce the age at diagnosis and thus improve the likelihood of cure and survival of patients with endocrine pancreatic tumours.

  • 37.
    Eriksson, D.
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Nordin, Jessika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dalin, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, G. N.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hultin-Rosenberg, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, Johanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zetterqvist, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlsson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallgren, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden..
    Farias, F. H. G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Murén, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ahlgren, Kerstin M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, G.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Tandre, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dahlqvist, S. R.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Soderkvist, P.
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hulting, A. -L
    Wahlberg, J.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Dept Clin & Expt Med, Linkoping, Sweden..
    Ekwall, O.
    Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Inst Clin Sci, Gothenburg, Sweden.;Univ Gothenburg, Dept Rheumatol & Inflammat Res, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden..
    Dahlqvist, P.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Meadows, Jennifer R. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bensing, S.
    Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst MIT & Harvard, Cambridge, MA USA..
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Ctr Mol Med, Stockholm, Sweden.;Metab & Diabet Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Pielberg, Gerli R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 6, p. 595-608Article in journal (Refereed)
    Abstract [en]

    BackgroundAutoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. MethodsTo understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. ResultsWe identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 x 10(-15), MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. ConclusionWhilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

  • 38.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Carlberg, B
    Hillörn, V
    Life-threatening ventricular tachycardia due to liquorice-induced hypokalaemia.1999In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 245, no 3, p. 307-10Article in journal (Refereed)
    Abstract [en]

    We report on a patient with hypokalaemia and severe ventricular tachycardia of torsades de pointes type which turned out to be caused by an apparent mineralocorticoid excess syndrome associated with liquorice consumption. The patient, a 44-year-old woman, attended the hospital because of irregular heart rhythm and she displayed repeated episodes of life-threatening torsades de pointes ventricular tachycardia. The initial serum potassium was low: 2.3 mmol L-1. The patient was treated with potassium and magnesium infusions, and the dysrhythmias eventually ceased. Endocrinological investigations showed no indication of Cushing's syndrome or hyperaldosteronism. After some time it became clear that the patient had ingested moderately large amounts of liquorice every day for 4 months. After the patient stopped this habit the hypokalaemia and dysrhythmias did not recur and after more than 1 year there are no signs of cardiac illness.

  • 39.
    Eriksson, Margaretha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Krakau, Ingvar
    Wedel, Hans
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Birth weight and cardiovascular risk factors in a cohort followed until 80 years of age: The study of men born in 19132004In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 255, p. 236-246Article in journal (Refereed)
  • 40.
    Eriksson, Margaretha
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Wallander, Mari-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Krakau, Ingvar
    Wedel, Hans
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    The impact of birth weight on coronary heart disease morbidity and mortality in a birth cohort followed up for 85 years: a population-based study of men born in 19132004In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 256, no 6, p. 472-81Article in journal (Refereed)
    Abstract [en]

    Objectives. To analyse whether there is a relationship between birth weight on the one hand and coronary heart disease (CHD) and cardiovascular disease (CVD) mortality and morbidity on the other, whether such a relationship is influenced by potential modifying factors from the time of birth, adult height and the presence of diabetes, and what significance these possible associations might have for the CHD and CVD rates in the general population.

    Design. Population-based birth cohort.

    Setting. Sweden.

    Subjects. A total of 1319 singleton men born in 1913, surviving until age 20 and from then on followed until 85 years of age.

    Main outcome measures. CHD and CVD mortality and morbidity events.

    Results. The gestational age adjusted CHD and CVD mortality and morbidity hazard ratios were virtually unaffected by birth weight. Taking possible effect-modifying variables into account did not change the results. The population attributable risk percentage for CHD and CVD mortality and morbidity due to a birth weight ≤3000 g was 1% or less.

    Conclusions. Birth weight did not significantly affect CHD or CVD mortality or morbidity. A birth weight ≤3000 g contributes little to the burden of CHD and CVD on a community level.

  • 41.
    Essand, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Loskog, Angelica S I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Genetically engineered T cells for the treatment of cancer2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 2, p. 166-181Article, review/survey (Refereed)
    Abstract [en]

    T cell immunotherapy is a promising approach to treat disseminated cancer. However, it has been limited by the ability to isolate and expand T cells restricted to tumour-associated antigens. Using ex vivo gene transfer, T cells from patients can be genetically engineered to express a novel T cell receptor or chimeric antigen receptor to specifically recognize a tumour-associated antigen and thereby selectively kill tumour cells. Indeed, genetically engineered T cells have recently been successfully used for cancer treatment in a small number of patients. Here we review the recent progress in the field, and summarize the challenges that lie ahead and the strategies being used to overcome them.

  • 42. Fadeel, B.
    et al.
    Kasemo, B.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Strömme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Nanomedicine: reshaping clinical practice2010In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 267, no 1, p. 2-8Article in journal (Refereed)
  • 43.
    Fears, R.
    et al.
    European Academies Science Advisory Council, c/o German National Academy of Sciences Leopoldina, Halle (Saale), Germany.
    Griffin, G.
    Department of Infectious Diseases and Medicine, St George’s University of London, London, UK.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ter Meulen, V.
    European Academies Science Advisory Council, c/o German National Academy of Sciences Leopoldina, Halle (Saale), Germany.
    van der Meer, J. W. M.
    Radboud University Medical Center, Nijmegen, The Netherlands.
    Assessing and regulating homeopathic products2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 6, p. 563-565Article in journal (Other academic)
  • 44. Ferreira, Daniel
    et al.
    Cavallin, Lena
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Muehlboeck, J-Sebastian
    Mecocci, Patrizia
    Vellas, Bruno
    Tsolaki, Magda
    Kłoszewska, Iwona
    Soininen, Hilkka
    Lovestone, Simon
    Simmons, Andrew
    Wahlund, Lars-Olof
    Westman, Eric
    Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 3, p. 277-290Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria.

    AIMS:

    The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, both for diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs.

    METHODS:

    AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 AD patients, 480 MCI patients and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated.

    RESULTS:

    The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 non-carrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively).

    CONCLUSIONS:

    If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials. This article is protected by copyright. All rights reserved.

  • 45. Freund Levi, Y
    et al.
    Vedin, I
    Cederholm, Tommy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Basun, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Faxén Irving, G
    Eriksdotter, M
    Hjorth, E
    Schultzberg, M
    Vessby, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Wahlund, L-O
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Salem, N
    Palmblad, J
    Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 4, p. 428-436Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF).

    METHODS: A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation.

    RESULTS: At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers.

    CONCLUSIONS: Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.

  • 46.
    Ghia, P.
    et al.
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst Milan, Milan, Italy..
    Nadel, B.
    Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France..
    Sander, B.
    Karolinska Inst, Dept Lab Med, Div Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, SE-14186 Stockholm, Sweden..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Stevenson, F. K.
    Univ Southampton, Canc Res UK Ctr, Canc Sci Unit, Fac Med,Southampton Gen Hosp, Southampton, Hants, England..
    Early stages in the ontogeny of small B-cell lymphomas: genetics and microenvironment2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 282, no 5, p. 395-414Article in journal (Refereed)
    Abstract [en]

    In this review, we focus on the mechanisms underlying lymphomagenesis in chronic lymphocytic leukaemia, follicular lymphoma, mantle cell lymphoma and splenic marginal zone lymphoma. The cells of origin of these small B-cell lymphomas are distinct, as are the characteristic chromosomal lesions and clinical courses. One shared feature is retention of expression of surface immunoglobulin. Analysis of this critical receptor reveals the point of differentiation reached by the cell of origin. Additionally, the sequence patterns of the immunoglobulin-variable domains can indicate a role for stimulants of the B-cell receptor before, during and after malignant transformation. The pathways driven via the B-cell receptor are now being targeted by specific kinase inhibitors with exciting clinical effects. To consider routes to pathogenesis, potentially offering earlier intervention, or to identify causative factors, genetic tools are being used to track pretransformation events and the early phases in lymphomagenesis. These methods are revealing that chromosomal changes are only one of the many steps involved, and that the influence of surrounding cells, probably multiple and variable according to tissue location, is required, both to establish tumours and to maintain growth and survival. Similarly, the influence of the tumour microenvironment may protect malignant cells from eradication by treatment, and the resulting minimal residual disease will eventually give rise to relapse. The common and different features of the four lymphomas will be summarized to show how normal B lymphocytes can be subverted to generate tumours, how these tumours evolve and how their weaknesses can be attacked by targeted therapies.

  • 47.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Karolinska Univ Hosp, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Diepstra, A.
    Univ Groningen, Univ Med Ctr Groningen, Dept Pathol & Med Biol, Groningen, Netherlands..
    Novel treatment concepts in Hodgkin lymphoma2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 3, p. 247-260Article, review/survey (Refereed)
    Abstract [en]

    Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid-1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long-term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18- to 65-year-old patients diagnosed during the period 1992-2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high-dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life-prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first- or second-line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long-term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.

  • 48. Gülen, T
    et al.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlén, B
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mastocytosis: the puzzling clinical spectrum and challenging diagnostic aspects of an enigmatic disease2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 3, p. 211-228Article, review/survey (Refereed)
    Abstract [en]

    Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life-threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions [i.e. urticaria pigmentosa (UP)], the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect-induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.

  • 49.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Response to Letter: 'Sorrow and cardiovascular events'2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 4, p. 415-415Article in journal (Other academic)
  • 50.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Norlund, Fredrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    Stebbins, Amanda
    Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA..
    Armstrong, P W
    University of Alberta, Edmonton, Canada..
    Chiswell, K
    Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA..
    Granger, C B
    Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA..
    López-Sendón, J
    Hospital Universitario La Paz, Instituto de investigacion IdiPaz, Paseo de la Castellana, Madrid, Spain..
    Pella, D
    Department of Medicine, PJ Safarik University, Kosice, Slovakia..
    Soffer, J
    Metabolic Pathways and Cardiovascular Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA..
    Sy, R
    Department of Internal Medicine, College of Medicine, University of the Philippines-Manila, Manila, Philippines..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    White, H D
    Green Lane Cardiovascular Service, Auckland, New Zealand.; University of Auckland, Auckland, New Zealand..
    Stewart, R A H
    Green Lane Cardiovascular Service, Auckland, New Zealand.; University of Auckland, Auckland, New Zealand..
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Psychosocial stress and major cardiovascular events in patients with stable coronary heart disease2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 1, p. 83-92Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Assess the risk of ischaemic events associated with psychosocial stress in patients with stable coronary heart disease (CHD).

    METHODS: Psychosocial stress was assessed by a questionnaire in 14 577 patients (median age 65.0, IQR 59, 71; 81.6% males) with stable CHD on optimal secondary preventive therapy in the prospective randomized STABILITY clinical trial. Adjusted Cox regression models were used to assess associations between individual stressors, baseline cardiovascular risk factors and outcomes.

    RESULTS: After 3.7 years of follow-up, depressive symptoms, loss of interest and financial stress were associated with increased risk (hazard ratio, 95% confidence interval) of CV death (1.21, 1.09-1.34; 1.15, 1.05-1.27; and 1.19, 1.08-1.30, respectively) and the primary composite end-point of CV death, nonfatal MI or nonfatal stroke (1.21, 1.13-1.30; 1.19, 1.11-1.27; and 1.17, 1.10-1.24, respectively). Living alone was related to higher risk of CV death (1.68, 1.38-2.05) and the primary composite end-point (1.28, 1.11-1.48), whereas being married as compared with being widowed, was associated with lower risk of CV death (0.64, 0.49-0.82) and the primary composite end-point (0.81, 0.67-0.97).

    CONCLUSIONS: Psychosocial stress, such as depressive symptoms, loss of interest, living alone and financial stress, were associated with increased CV mortality in patients with stable CHD despite optimal medical secondary prevention treatment. Secondary prevention of CHD should therefore focus also on psychosocial issues both in clinical management and in future clinical trials.

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