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  • 201.
    Barcenilla, Hugo
    et al.
    Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
    Pihl, Mikael
    Core Facility, Flow Cytometry Unit, Linköping University, Linköping, Sweden.
    Wahlberg, Jeanette
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Health, Medicine and Caring Sciences (HMV), Linköping University, Linköping, Sweden; Division of Diagnostics and Specialist Medicine and Faculty of Health Sciences, Örebro University, Örebro, Sweden.
    Ludvigsson, Johnny
    Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden; Division of Pediatrics, Crown Princess Victoria Children's Hospital, Linköping, Sweden.
    Casas, Rosaura
    Division of Pediatrics, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
    Intralymphatic GAD-alum Injection Modulates B Cell Response and Induces Follicular Helper T Cells and PD-1+ CD8+ T Cells in Patients With Recent-Onset Type 1 Diabetes2021Ingår i: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 12, artikel-id 797172Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Antigen-specific immunotherapy is an appealing strategy to preserve beta-cell function in type 1 diabetes, although the approach has yet to meet its therapeutic endpoint. Direct administration of autoantigen into lymph nodes has emerged as an alternative administration route that can improve the efficacy of the treatment. In the first open-label clinical trial in humans, injection of aluminum-formulated glutamic acid decarboxylase (GAD-alum) into an inguinal lymph node led to the promising preservation of C-peptide in patients with recent-onset type 1 diabetes. The treatment induced a distinct immunomodulatory effect, but the response at the cell level has not been fully characterized. Here we used mass cytometry to profile the immune landscape in peripheral blood mononuclear cells from 12 participants of the study before and after 15 months of treatment. The immunomodulatory effect of the therapy included reduction of naïve and unswitched memory B cells, increase in follicular helper T cells and expansion of PD-1+ CD69+ cells in both CD8+ and double negative T cells. In vitro stimulation with GAD65 only affected effector CD8+ T cells in samples collected before the treatment. However, the recall response to antigen after 15 months included induction of CXCR3+ and CD11c+Tbet+ B cells, PD-1+ follicular helper T cells and exhausted-like CD8+ T cells. This study provides a deeper insight into the immunological changes associated with GAD-alum administration directly into the lymph nodes. 

  • 202.
    Barg, Sebastian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gucek, Alenka
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    How Kiss-and-Run Can Make Us Sick: SOX4 Puts a Break on the Pore2016Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, nr 7, s. 1791-1793Artikel i tidskrift (Övrigt vetenskapligt)
  • 203. Barkhordari, Mahnaz
    et al.
    Padyab, Mojgan
    Umeå universitet, Samhällsvetenskapliga fakulteten, Enheten för demografi och åldrandeforskning (CEDAR).
    Sardarinia, Mahsa
    Hadaegh, Farzad
    Azizi, Fereidoun
    Bozorgmanesh, Mohammadreza
    Survival Regression Modeling Strategies in CVD Prediction2016Ingår i: International journal of endocrinology and metabolism, ISSN 1726-9148, Vol. 14, nr 2, artikel-id e32156Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A fundamental part of prevention is prediction. Potential predictors are the sine qua non of prediction models. However, whether incorporating novel predictors to prediction models could be directly translated to added predictive value remains an area of dispute. The difference between the predictive power of a predictive model with (enhanced model) and without (baseline model) a certain predictor is generally regarded as an indicator of the predictive value added by that predictor. Indices such as discrimination and calibration have long been used in this regard. Recently, the use of added predictive value has been suggested while comparing the predictive performances of the predictive models with and without novel biomarkers. Objectives: User-friendly statistical software capable of implementing novel statistical procedures is conspicuously lacking. This shortcoming has restricted implementation of such novel model assessment methods. We aimed to construct Stata commands to help researchers obtain the aforementioned statistical indices. Materials and Methods: We have written Stata commands that are intended to help researchers obtain the following. 1, Nam-D'Agostino X-2 goodness of fit test; 2, Cut point-free and cut point-based net reclassification improvement index (NRI), relative absolute integrated discriminatory improvement index (IDI), and survival-based regression analyses. We applied the commands to real data on women participating in the Tehran lipid and glucose study (TLGS) to examine if information relating to a family history of premature cardiovascular disease (CVD), waist circumference, and fasting plasma glucose can improve predictive performance of Framingham's general CVD risk algorithm. Results: The command is adpredsurv for survival models. Conclusions: Herein we have described the Stata package "adpredsurv" for calculation of the Nam-D'Agostino X2 goodness of fit test as well as cut point-free and cut point-based NRI, relative and absolute IDI, and survival-based regression analyses. We hope this work encourages the use of novel methods in examining predictive capacity of the emerging plethora of novel biomarkers.

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  • 204.
    Baroncelli, Marta
    et al.
    Division of Pediatric Endocrinology and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Raimann, Adalbert
    Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
    Padidela, Raja
    Department of Pediatric Endocrinology, Royal Manchester Children’s Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Division of Pediatric Endocrinology and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; University Hospital, Stockholm, Sweden.
    Bone, Growth Plate and Mineral Metabolism2021Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 94, nr Suppl. 1, s. 22-22Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    The skeletal research field develops rapidly and has produced several exciting findings in the last year and includes advances in the treatment of rare skeletal disorders and an ever deeper under-standing into the fundamental molecular mechanisms that control skeletal development, metabolism, growth, and mineralization.

    The targeting of the C-type natriuretic peptide (CNP) pathway and options to directly antagonize the overactivity of the FGFR3 pathway in achondroplasia continues to be a subject of high inter-est and excitement and in the 2021 yearbook we highlight the dou-ble-blind, randomized placebo-controlled phase 3 study of a CNP analogue (vosoritide) in children with achondroplasia. We also highlight the identification of a novel gene for autosomal domi-nant hypophosphatemic rickets, publication of new growth charts for X-linked hypophosphatemia and two large well-designed pae-diatric vitamin D trials for the prevention of tuberculosis and asthma exacerbation, respectively.

    Translational highlights include review on the recent advances of mineral metabolism and biomineralization, in vivo data sug-gesting that modification of the synovial microenvironment may allow endogenous skeletal stem cells to form hyalin cartilage and thereby heal articular cartilage injuries, as well as a study using gene targeting in zebra fish to reveal the pathogenic mechanism by which mutations in CRTAP and P3H1 causes osteogenesis imper-fecta type VII and VIII, respectively.

    Advances in the understanding of skeletal biology a study by McDonald et al. that challenges the current dogma on the origin and fate of osteoclasts as they show evidence that multinucleated osteoclasts can fission into daughter cells, a.k.a. osteomorphs, that subsequently are recycled into bone resorbing osteoclasts via a RANKL-dependent process. Additional articles in this section directly and indirectly highlight the critical role of loading and mechanical stress on the growing skeleton. Several of these excit-ing findings will be highlighted in the presentation.

  • 205. Barregard, Lars
    et al.
    Haghdoost, Siamak
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för molekylär biovetenskap, Wenner-Grens institut.
    Cooke, Marcus S.
    Human and Methodological Sources of Variability in the Measurement of Urinary 8-Oxo-7,8-dihydro-2 '-deoxyguanosine2013Ingår i: Antioxidants and Redox Signaling, ISSN 1523-0864, E-ISSN 1557-7716, Vol. 18, nr 18, s. 2377-2391Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is a widely used biomarker of oxidative stress. However, variability between chromatographic and ELISA methods hampers interpretation of data, and this variability may increase should urine composition differ between individuals, leading to assay interference. Furthermore, optimal urine sampling conditions are not well defined. We performed inter-laboratory comparisons of 8-oxodG measurement between mass spectrometric-, electrochemical- and ELISA-based methods, using common within-technique calibrants to analyze 8-oxodG-spiked phosphate-buffered saline and urine samples. We also investigated human subject- and sample collection-related variables, as potential sources of variability. Results: Chromatographic assays showed high agreement across urines from different subjects, whereas ELISAs showed far more inter-laboratory variation and generally overestimated levels, compared to the chromatographic assays. Excretion rates in timed 'spot' samples showed strong correlations with 24 h excretion (the 'gold' standard) of urinary 8-oxodG (r(p) 0.67-0.90), although the associations were weaker for 8-oxodG adjusted for creatinine or specific gravity (SG). The within-individual excretion of 8-oxodG varied only moderately between days (CV 17% for 24 h excretion and 20% for first void, creatinine-corrected samples). Innovation: This is the first comprehensive study of both human and methodological factors influencing 8-oxodG measurement, providing key information for future studies with this important biomarker. Conclusion: ELISA variability is greater than chromatographic assay variability, and cannot determine absolute levels of 8-oxodG. Use of standardized calibrants greatly improves intra-technique agreement and, for the chromatographic assays, importantly allows integration of results for pooled analyses. If 24 h samples are not feasible, creatinine- or SG-adjusted first morning samples are recommended.

  • 206.
    Bartoszek, Krzysztof
    et al.
    Linköpings universitet, Institutionen för datavetenskap, Statistik och maskininlärning. Linköpings universitet, Filosofiska fakulteten.
    Okroj, Marcin
    Univ Gdansk, Poland; Med Univ Gdansk, Poland.
    Controversies around the statistical presentation of data on mRNA-COVID 19 vaccine safety in pregnant women2022Ingår i: Journal of Reproductive Immunology, ISSN 0165-0378, E-ISSN 1872-7603, Vol. 151, artikel-id 103503Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The work entitled "Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons" published on April 21, 2021, in The New England Journal of Medicine, presented data collected from American surveillance systems and registries. However, problems with an unanimous interpretation of those results appeared in the public debate and citing articles. Some stated that the risk of miscarriage in vaccinated women was similar to historical values reported before the vaccines approval. The others stated that risk was highly above-normative in women vaccinated during the first and second trimesters. We found several problems with the statistical treatment/interpretation of the originally presented values: a substantial percentage (up to 95.6%) of missing data, an incorrect denominator used for risk estimation, and too short follow-up that disabled the evaluation of the studys endpoint in numerous participants. Eventually, the Authors published a corrigendum on September 8, 2021, and pointed to updated data. Herein, we explain the statistical controversies raised by the original presentation and stress that analyzing the trade-off between knowledge and confusion brought by the release of incomplete results of such a high social interest, should aid in solving the dilemma of whether to publish preliminary data or none.

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  • 207.
    Bass, Joseph J.
    et al.
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Nakhuda, Asif
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Deane, Colleen S.
    Department of Sport and Health Sciences, University of Exeter, Exeter, UK.
    Brook, Matthew S.
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Wilkinson, Daniel J.
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Phillips, Bethan E.
    Mitochondrial Metabolism and Ageing Laboratory, Diabetes and Metabolism Division, Garvan Institute of Medical Research, Australia; School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK.
    Philp, Andrew
    Garvan Inst Med Res, Diabet & Metab Div, Mitochondrial Metab & Ageing Lab, Sydney, NSW 2010, Australia.;Univ Birmingham, Sch Sport Exercise & Rehabil Sci, Birmingham B15 2TT, W Midlands, England..
    Tarum, Janelle
    School of Health Sciences, Örebro University, Örebro, Sweden.
    Kadi, Fawzi
    Örebro universitet, Institutionen för hälsovetenskaper.
    Andersen, Ditte
    Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, UK.
    Garcia, Amadeo Munoz
    Institute of Metabolism and Systems Research, The University of Birmingham, Birmingham, UK; Department of Bio-informatics - BiGCaT, NUTRIM School of Nutrition and Metabolism in Translational Research, Maastricht University, Maastricht, the Netherlands.
    Smith, Ken
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Gallagher, Iain J.
    Physiology, Exercise and Nutrition Research Group, Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK.
    Szewczyk, Nathaniel J.
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Cleasby, Mark E.
    Molecular Physiology of Diabetes Laboratory, Dept. of Comparative Biomedical Sciences, Royal Veterinary College, UK.
    Atherton, Philip J.
    MRC/ARUK Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR), Nottingham Biomedical Research Centre (BRC), School of Medicine, University of Nottingham, Nottingham, UK.
    Overexpression of the vitamin D receptor (VIM) induces skeletal muscle hypertrophy2020Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 42, artikel-id 101059Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: The Vitamin D receptor (VDR) has been positively associated with skeletal muscle mass, function and regeneration. Mechanistic studies have focused on the loss of the receptor, with in vivo whole-body knockout models demonstrating reduced myofibre size and function and impaired muscle development. To understand the mechanistic role upregulation of the VDR elicits in muscle mass/health, we studied the impact of VDR over-expression (OE) in vivo before exploring the importance of VDR expression upon muscle hypertrophy in humans.

    Methods: Wistar rats underwent in vivo electrotransfer (IVE) to overexpress the VDR in the Tibialis anterior (TA) muscle for 10 days, before comprehensive physiological and metabolic profiling to characterise the influence of VDR-OE on muscle protein synthesis (MPS), anabolic signalling and satellite cell activity. Stable isotope tracer (D2O) techniques were used to assess sub-fraction protein synthesis, alongside RNA-Seq analysis. Finally, human participants underwent 20 wks of resistance exercise training, with body composition and transcriptomic analysis.

    Results: Muscle VDR-OE yielded total protein and RNA accretion, manifesting in increased myofibre area, i.e., hypertrophy. The observed increases in MPS were associated with enhanced anabolic signalling, reflecting translational efficiency (e.g., mammalian target of rapamycin (mTOR-signalling), with no effects upon protein breakdown markers being observed. Additionally, RNA-Seq illustrated marked extracellular matrix (ECM) remodelling, while satellite cell content, markers of proliferation and associated cell-cycled related gene-sets were upregulated. Finally, induction of VDR mRNA correlated with muscle hypertrophy in humans following long-term resistance exercise type training.

    Conclusion: VDR-OE stimulates muscle hypertrophy ostensibly via heightened protein synthesis, translational efficiency, ribosomal expansion and upregulation of ECM remodelling-related gene-sets. Furthermore, VDR expression is a robust marker of the hypertrophic response to resistance exercise in humans. The VDR is a viable target of muscle maintenance through testable Vitamin D molecules, as active molecules and analogues. (C) 2020 The Author(s). Published by Elsevier GmbH.

  • 208. Basu, S
    et al.
    Zethelius, B
    Helmersson, J
    Berne, C
    Larsson, A
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap.
    Cytokine-mediated inflammation is independently associated with insulin sensitivity measured by the euglycemic insulin clamp in a community-based cohort of elderly men2011Ingår i: International Journal of Clinical and Experimental Medicine, E-ISSN 1940-5901, Vol. 4, nr 2, s. 164-168Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Both clinical and experimental studies suggest a close relation between an inflammatory state and insulin resistance. We investigated the association between cytokine-mediated inflammation (high sensitivity C reactive protein [hsCRP] and interleukin [IL] 6) and insulin sensitivity (insulin-mediated glucose disposal rate, assessed by the euglycemic insulin clamp) in a community-based cohort, with subgroup analyses of normal weight individuals without diabetes mellitus and metabolic syndrome (NCEP). hsCRP and IL- 6 were inversely associated with insulin sensitivity (multivariable-adjusted regression coefficient for 1-SD increase of hsCRP -0.12 (-0.21-(-0.03), p=0.01) and of IL-6 - 0.11 (-0.21-(-0.02), p=0.01) in models adjusting for age and components of the metabolic syndrome (systolic and diastolic blood pressure, antihypertensive drugs, HDL-cholesterol, triglycerides, fasting plasma glucose, waist circumference). The multivariable-adjusted association between hsCRP, IL-6 and insulin sensitivity were of a similar magnitude in normal weight individuals without diabetes and without the metabolic syndrome. Our data show that cytokine -mediated subclinical inflammation is independently associated with decreased insulin sensitivity also in apparently metabolically healthy normal weight individuals, indicating that the interplay between inflammatory processes and insulin resistance is present already in the early stages of the development of glucometabolic disease. (IJCEM1012002).

  • 209.
    Baudin, Eric
    et al.
    Inst Gustave Roussy, Oncol Endocrinienne & Med Nucl, Villejuif, France.
    Hayes, Aimee R.
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Scoazec, Jean-Yves
    Univ Lyon, Dept Pathol, Lyon, France.
    Filosso, Pier Luigi
    Univ Torino, Dept Thorac Surg, Turin, Italy.
    Lim, Eric
    Royal Brompton Hosp, Dept Thorac Surg, London, England.
    Kaltsas, Gregory
    Natl Univ Athens, Div Endocrinol, Dept Pathophysiol, Athens, Greece.
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England.
    Chen, Jie
    Sun Yat Sen Univ, Affiliated Hosp 1, Dept Gastroenterol, Guangzhou, Guangdong, Peoples R China.
    Kos-Kudła, Beata
    Slaska Akad Med, Klin Endokrynol, Zabrze, Poland.
    Gorbunova, Vera
    Russian Acad Med Sci, FSBI NN Blokhin Russian Canc Res Ctr, Moscow, Russia.
    Wiedenmann, Bertram
    Charite Univ Med Berlin, Campus Charite Mitte, Dept Gastroenterol & Hepatol, Berlin, Germany; Charite Univ Med Berlin, Campus Virchow Klinikum, Berlin, Germany.
    Nieveen van Dijkum, Els
    Acad Med Ctr, Dept Surg, Amsterdam, Netherlands.
    Ćwikła, Jaroslaw B
    Univ Warmia & Mazury, Fac Med Sci, Dept Radiol, Olsztyn, Poland.
    Falkerby, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Valle, Juan W.
    Univ Manchester, Inst Canc Sci, Christie NHS Fdn Trust, Dept Med Oncol, Manchester, Lancs, England.
    Kulke, Matthew H
    Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
    Caplin, Martyn E
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Sundin, Anders (Medarbetare/bidragsgivare)
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Tiensuu Janson, Eva (Medarbetare/bidragsgivare)
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Welin, Staffan (Medarbetare/bidragsgivare)
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Unmet Medical Needs in Pulmonary Neuroendocrine (Carcinoid) Neoplasms2019Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, nr 1, s. 7-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future.

  • 210.
    Bauza-Thorbrügge, Marco
    et al.
    Univ Gothenburg, Sweden.
    Banke, Elin
    Univ Gothenburg, Sweden.
    Chanclon, Belen
    Univ Gothenburg, Sweden.
    Peris, Eduard
    Univ Gothenburg, Sweden.
    Wu, Yanling
    Univ Gothenburg, Sweden.
    Musovic, Saliha
    Univ Gothenburg, Sweden.
    Jönsson, Cecilia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten.
    Strålfors, Peter
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Rorsman, Patrik
    Univ Gothenburg, Sweden; Univ Oxford, England.
    Olofsson, Charlotta S.
    Univ Gothenburg, Sweden.
    Asterholm, Ingrid Wernstedt
    Univ Gothenburg, Sweden.
    Adipocyte-specific ablation of the Ca2+pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue2022Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 63, artikel-id 101535Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. Methods: SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca2+ levels were recorded with dualwavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. Results: We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. Conclusions: Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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  • 211.
    Bauzá-Thorbrügge, Marco
    et al.
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Peris, Eduard
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Zamani, Shabnam
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Micallef, Peter
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Paul, Alexandra
    Department of Biology and Biological Engineering, Division of Chemical Biology, Chalmers University of Technology, Gothenburg, Sweden ; The Department of Biomedical Engineering, University of Texas at Austin, TX, United States.
    Bartesaghi, Stefano
    Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
    Benrick, Anna
    Högskolan i Skövde, Institutionen för hälsovetenskaper. Högskolan i Skövde, Forskningsmiljön hälsa, hållbarhet och digitalisering. Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    Wernstedt Asterholm, Ingrid
    Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
    NRF2 is essential for adaptative browning of white adipocytes2023Ingår i: Redox Biology, E-ISSN 2213-2317, Vol. 68, artikel-id 102951Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes. 

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  • 212.
    Beam, Craig A.
    et al.
    Western Michigan University, MI 49008 USA.
    MacCallum, Colleen
    Western Michigan University, MI 49008 USA.
    Herold, Kevan C.
    Yale University, CT USA; Yale University, CT USA.
    Wherrett, Diane K.
    Hospital Sick Children, Canada; University of Toronto, Canada.
    Palmer, Jerry
    University of Washington, WA 98195 USA; VA Puget Sound Health Care Syst, WA USA.
    Ludvigsson, Johnny
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Barn- och ungdomskliniken i Linköping.
    GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis2017Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, nr 1, s. 43-49Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). We estimate that there is a 98% probability that 20 mu g GAD with alum administered twice yields a positive biological effect. The effect is probably a 15-20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between -0.250 and -0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of -0.294 pmol/ml at 1 year for untreated newly diagnosed patients. The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

  • 213.
    Becerro-Rey, Laura
    et al.
    Univ Extremadura, Spain.
    Martin-Cano, Francisco Eduardo
    Univ Extremadura, Spain.
    Ferrusola, Cristina Ortega
    Univ Extremadura, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Gaitskell-Phillips, Gemma
    Univ Extremadura, Spain.
    da Silva-Alvarez, Eva
    Univ Extremadura, Spain.
    Silva-Rodriguez, Antonio
    Univ Extremadura, Spain.
    Gil, Maria Cruz
    Univ Extremadura, Spain.
    Pena, Fernando J.
    Univ Extremadura, Spain.
    Aging of stallion spermatozoa stored in vitro is delayed at 22C using a 67 mm glucose-10 mm pyruvate-based media2023Ingår i: Andrology, ISSN 2047-2919, E-ISSN 2047-2927Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Most commerce of equine seminal doses is carried out using commercial extenders under refrigeration at 5 degrees C.Objectives: To determine if 10 mM pyruvate in a 67 mM glucose extender and storage at 22 degrees C could be the basis of an alternative storage method to cooling to 5 degrees C.Material and methods: Stallion ejaculates were extendedin: INRA96 (67 mM glucose, non-pyruvate control), modified Tyrodes (67 mM glucose-10 mM pyruvate), supplemented with 0, 10, 50, and 100 mu M itaconate. As itaconate was vehiculated in DMSO, a control vehicle was also included. Sperm motility, viability, mitochondrial membrane potential, and production of reactive oxygen species were measured after collection and again after 48 and 96 h of storage at 22 degrees C. To disclose molecular metabolic changes, spermatozoa were incubated up to 3 h in modified Tyrodes 67 mM glucose-10 mM pyruvate and modified Tyrodes 67 mM glucose, and metabolic analysis conducted.Results: After 96 h of storage aliquots stored in the control, INRA96 had a very poor total motility of 5.6% +/- 2.3%, while in the 67 mM glucose-10 mM pyruvate/10 mu M itaconate extender, total motility was 34.7% +/- 3.8% (p = 0.0066). After 96 h, viability was better in most pyruvate-based media, and the mitochondrial membrane potential in spermatozoa extended in INRA96 was relatively lower (p < 0.0001). Metabolomics revealed that in the spermatozoa incubated in the high pyruvate media, there was an increase in the relative amounts of NAD(+), pyruvate, lactate, and ATP.Discussion and conclusions: Aliquots stored in a 67 mM glucose-10 mM pyruvatebased medium supplemented with 10 mu M itaconate, maintained a 35% total motility after 96 h of storage at 22 degrees C, which is considered the minimum acceptable motility for commercialization. Improvements may be related to the conversion of pyruvate to lactate and regeneration of NAD(+).

  • 214.
    Beger, Richard D.
    et al.
    Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, USA.
    Dunn, Warwick
    School of Biosciences, Phenome Centre Birmingham and Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Birmingham, UK.
    Schmidt, Michael A.
    Advanced Pattern Analysis and Countermeasures Group, Research Innovation Center, Colorado State University, Fort Collins, USA.
    Gross, Steven S.
    Department of Pharmacology, Weill Cornell Medical College, New York, USA.
    Kirwan, Jennifer A.
    School of Biosciences, University of Birmingham, Birmingham, UK.
    Cascante, Marta
    Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Universitat de Barcelona, Barcelona, Spain; Institute of Biomedicine of Universitat de Barcelona (IBUB) and CSIC-Associated Unit, Barcelona, Spain.
    Brennan, Lorraine
    UCD Institute of Food and Health, UCD, Belfield, Ireland.
    Wishart, David S.
    Departments of Computing Science and Biological Sciences, University of Alberta, Edmonton, Canada.
    Oresic, Matej
    Turku Centre for Biotechnology, University of Turku, Turku, Finland.
    Hankemeier, Thomas
    Division of Analytical Biosciences and Cluster Systems Pharmacology, Leiden Academic Centre for Drug Research, Leiden University & Netherlands Metabolomics Centre, Leiden, The Netherlands.
    Broadhurst, David I.
    School of Science, Edith Cowan University, Perth, Australia.
    Lane, Andrew N.
    Center for Environmental Systems Biochemistry, Department Toxicology and Cancer Biology, Markey Cancer Center, Lexington, USA.
    Suhre, Karsten
    Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Doha, Qatar.
    Kastenmüller, Gabi
    Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, Oberschleißheim, Germany.
    Sumner, Susan J.
    Discovery Sciences, RTI International, Research Triangle Park, Durham, USA.
    Thiele, Ines
    University of Luxembourg, Luxembourg Centre for Systems Biomedicine, Campus Belval, Esch-Sur-Alzette, Luxembourg.
    Fiehn, Oliver
    West Coast Metabolomics Center, UC Davis, Davis, USA; Biochemistry Department, King Abdulaziz University, Jeddah, Saudi Arabia.
    Kaddurah-Daouk, Rima
    Psychiatry and Behavioral Sciences, Duke Internal Medicine and Duke Institute for Brain Sciences and Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, USA.
    Metabolomics enables precision medicine: "A White Paper, Community Perspective"2016Ingår i: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 12, nr 10, artikel-id 149Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    INTRODUCTION BACKGROUND TO METABOLOMICS: Metabolomics is the comprehensive study of the metabolome, the repertoire of biochemicals (or small molecules) present in cells, tissues, and body fluids. The study of metabolism at the global or "-omics" level is a rapidly growing field that has the potential to have a profound impact upon medical practice. At the center of metabolomics, is the concept that a person's metabolic state provides a close representation of that individual's overall health status. This metabolic state reflects what has been encoded by the genome, and modified by diet, environmental factors, and the gut microbiome. The metabolic profile provides a quantifiable readout of biochemical state from normal physiology to diverse pathophysiologies in a manner that is often not obvious from gene expression analyses. Today, clinicians capture only a very small part of the information contained in the metabolome, as they routinely measure only a narrow set of blood chemistry analytes to assess health and disease states. Examples include measuring glucose to monitor diabetes, measuring cholesterol and high density lipoprotein/low density lipoprotein ratio to assess cardiovascular health, BUN and creatinine for renal disorders, and measuring a panel of metabolites to diagnose potential inborn errors of metabolism in neonates.

    OBJECTIVES OF WHITE PAPER—EXPECTED TREATMENT OUTCOMES AND METABOLOMICS ENABLING TOOL FOR PRECISION MEDICINE: We anticipate that the narrow range of chemical analyses in current use by the medical community today will be replaced in the future by analyses that reveal a far more comprehensive metabolic signature. This signature is expected to describe global biochemical aberrations that reflect patterns of variance in states of wellness, more accurately describe specific diseases and their progression, and greatly aid in differential diagnosis. Such future metabolic signatures will: (1) provide predictive, prognostic, diagnostic, and surrogate markers of diverse disease states; (2) inform on underlying molecular mechanisms of diseases; (3) allow for sub-classification of diseases, and stratification of patients based on metabolic pathways impacted; (4) reveal biomarkers for drug response phenotypes, providing an effective means to predict variation in a subject's response to treatment (pharmacometabolomics); (5) define a metabotype for each specific genotype, offering a functional read-out for genetic variants: (6) provide a means to monitor response and recurrence of diseases, such as cancers: (7) describe the molecular landscape in human performance applications and extreme environments. Importantly, sophisticated metabolomic analytical platforms and informatics tools have recently been developed that make it possible to measure thousands of metabolites in blood, other body fluids, and tissues. Such tools also enable more robust analysis of response to treatment. New insights have been gained about mechanisms of diseases, including neuropsychiatric disorders, cardiovascular disease, cancers, diabetes and a range of pathologies. A series of ground breaking studies supported by National Institute of Health (NIH) through the Pharmacometabolomics Research Network and its partnership with the Pharmacogenomics Research Network illustrate how a patient's metabotype at baseline, prior to treatment, during treatment, and post-treatment, can inform about treatment outcomes and variations in responsiveness to drugs (e.g., statins, antidepressants, antihypertensives and antiplatelet therapies). These studies along with several others also exemplify how metabolomics data can complement and inform genetic data in defining ethnic, sex, and gender basis for variation in responses to treatment, which illustrates how pharmacometabolomics and pharmacogenomics are complementary and powerful tools for precision medicine.

    CONCLUSIONS KEY SCIENTIFIC CONCEPTS AND RECOMMENDATIONS FOR PRECISION MEDICINE: Our metabolomics community believes that inclusion of metabolomics data in precision medicine initiatives is timely and will provide an extremely valuable layer of data that compliments and informs other data obtained by these important initiatives. Our Metabolomics Society, through its "Precision Medicine and Pharmacometabolomics Task Group", with input from our metabolomics community at large, has developed this White Paper where we discuss the value and approaches for including metabolomics data in large precision medicine initiatives. This White Paper offers recommendations for the selection of state of-the-art metabolomics platforms and approaches that offer the widest biochemical coverage, considers critical sample collection and preservation, as well as standardization of measurements, among other important topics. We anticipate that our metabolomics community will have representation in large precision medicine initiatives to provide input with regard to sample acquisition/preservation, selection of optimal omics technologies, and key issues regarding data collection, interpretation, and dissemination. We strongly recommend the collection and biobanking of samples for precision medicine initiatives that will take into consideration needs for large-scale metabolic phenotyping studies.

  • 215. Beijer, K.
    et al.
    Nowak, C.
    Sundström, J.
    Ärnlöv, Johan
    Högskolan Dalarna, Akademin Utbildning, hälsa och samhälle, Medicinsk vetenskap. Karolinska Institutet.
    Fall, T.
    Lind, L.
    In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study2019Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, nr 11, s. 1998-2006Artikel i tidskrift (Refereegranskat)
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  • 216.
    Beijer, Kristina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Nowak, Christoph
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ärnlöv, Johan
    Karolinska Inst, Div Family Med & Primary Care, Dept Neurobiol Care Sci & Soc, Stockholm, Sweden;Dalarna Univ, Sch Hlth & Social Sci, Falun, Sweden.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    In search of causal pathways in diabetes: a study using proteomics and genotyping data from a cross-sectional study2019Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, nr 11, s. 1998-2006Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis: The pathogenesis of type 2 diabetes is not fully understood. We investigated whether circulating levels of preselected proteins were associated with the outcome 'diabetes' and whether these associations were causal.

    Methods: In 2467 individuals of the population-based, cross-sectional EpiHealth study (45-75 years, 50% women), 249 plasma proteins were analysed by the proximity extension assay technique. DNA was genotyped using the Illumina HumanCoreExome-12 v1.0 BeadChip. Diabetes was defined as taking glucose-lowering treatment or having a fasting plasma glucose of >= 7.0 mmol/l. The associations between proteins and diabetes were assessed using logistic regression. To investigate causal relationships between proteins and diabetes, a bidirectional two-sample Mendelian randomisation was performed based on large, genome-wide association studies belonging to the DIAGRAM and MAGIC consortia, and a genome-wide association study in the EpiHealth study.

    Results: Twenty-six proteins were positively associated with diabetes, including cathepsin D, retinal dehydrogenase 1, alpha-l-iduronidase, hydroxyacid oxidase 1 and galectin-4 (top five findings). Three proteins, lipoprotein lipase, IGF-binding protein 2 and paraoxonase 3 (PON-3), were inversely associated with diabetes. Fourteen of the proteins are novel discoveries. The Mendelian randomisation study did not disclose any significant causal effects between the proteins and diabetes in either direction that were consistent with the relationships found between the protein levels and diabetes.

    Conclusions/interpretation: The 29 proteins associated with diabetes are involved in several physiological pathways, but given the power of the study no causal link was identified for those proteins tested in Mendelian randomisation. Therefore, the identified proteins are likely to be biomarkers for type 2 diabetes, rather than representing causal pathways.

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  • 217.
    Beijer, Kristina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala Univ, Med Sci, Uppsala, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Arnlöv, J.
    Karolinska Inst, Stockholm, Sweden.
    Fall, Tove
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Ingelsson, E.
    Stanford Univ, Palo Alto, CA 94304 USA.
    Lind, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    A targeted proteomic profile of prevalent diabetes in a population-based sample2018Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 61, s. S252-S252Artikel i tidskrift (Övrigt vetenskapligt)
  • 218.
    Bell, Katy J. L.
    et al.
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Azizi, Lamiae
    Univ Sydney, Sch Math & Stat, Sydney, NSW, Australia.
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci, Univ Hosp, Malmö, Sweden.
    Hayen, Andrew
    UTS, Australian Ctr Publ & Populat Hlth Res, Sydney, NSW, Australia.
    Irwig, Les
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Östgren, Carl J.
    Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden.
    Sundström, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Prognostic impact of systolic blood pressure variability in people with diabetes2018Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 13, nr 4, artikel-id e0194084Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Blood pressure variability (BPV) has been associated with risk of cardiovascular events in observational studies, independently of mean BP levels. In states with higher autonomic imbalance, such as in diabetes, the importance of BP variability may theoretically be even greater. We aimed to investigate the incremental value of BPV for prediction of cardiovascular and all-cause mortality in patients with type 2 diabetes.

    Methods: We identified 9,855 patients without pre-existing cardiovascular disease who did not change BP-lowering treatment during the observation period from a Swedish primary health care cohort of patients with type 2 diabetes. BPV was summarized as the standard deviation (SD), coefficient of variation (CV), or variation independent of mean (VIM). Patients were followed for a median of 4 years and associations with cardiovascular and all-cause mortality were investigated using Cox proportional hazards models.

    Results: BPV was not associated with cardiovascular specific or all-cause mortality in the total sample. In patients who were not on BP-lowering drugs during the observation period (n = 2,949), variability measures were associated with all-cause mortality: hazard ratios were 1.05, 1.04 and 1.05 for 50% increases in SD, CV and VIM, respectively, adjusted for Framingham risk score risk factors, including mean BP. However, the addition of the variability measures in this subgroup only led to very minimal improvement in discrimination, indicating they may have limited clinical usefulness (change in C-statistic ranged from 0.000–0.003 in all models).

    Conclusions: Although BPV was independently associated with all-cause mortality in diabetes patients in primary care who did not have pre-existing cardiovascular disease or BP-lowering drugs, it may be of minimal clinical usefulness above and beyond that of other routinely measured predictors, including mean BP.

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  • 219. Bellanger, Martine
    et al.
    Demeneix, Barbara
    Grandjean, Philippe
    Zoeller, R. Thomas
    Trasande, Leonardo
    Response to the Letter by Middlebeek and Veuger2015Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 6, s. L54-L55Artikel i tidskrift (Refereegranskat)
  • 220.
    Belsti, Yitayeh
    et al.
    Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia; University of Gondar, College of Medicine and Health Science, Ethiopia.
    Moran, Lisa
    Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
    Du, Lan
    Monash University, Faculty of Information Technology.
    Mousa, Aya
    Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
    De Silva, Kushan
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Enticott, Joanne
    Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
    Teede, Helena
    Monash Centre for Health Research and Implementation (MCHRI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia; Monash Health, Melbourne, Australia.
    Comparison of machine learning and conventional logistic regression-based prediction models for gestational diabetes in an ethnically diverse population: the Monash GDM Machine learning model2023Ingår i: International Journal of Medical Informatics, ISSN 1386-5056, E-ISSN 1872-8243, Vol. 179, artikel-id 105228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Early identification of pregnant women at high risk of developing gestational diabetes (GDM) is desirable as effective lifestyle interventions are available to prevent GDM and to reduce associated adverse outcomes. Personalised probability of developing GDM during pregnancy can be determined using a risk prediction model. These models extend from traditional statistics to machine learning methods; however, accuracy remains sub-optimal.

    Objective: We aimed to compare multiple machine learning algorithms to develop GDM risk prediction models, then to determine the optimal model for predicting GDM.

    Methods: A supervised machine learning predictive analysis was performed on data from routine antenatal care at a large health service network from January 2016 to June 2021. Predictor set 1 were sourced from the existing, internationally validated Monash GDM model: GDM history, body mass index, ethnicity, age, family history of diabetes, and past poor obstetric history. New models with different predictors were developed, considering statistical principles with inclusion of more robust continuous and derivative variables. A randomly selected 80% dataset was used for model development, with 20% for validation. Performance measures, including calibration and discrimination metrics, were assessed. Decision curve analysis was performed.

    Results: Upon internal validation, the machine learning and logistic regression model's area under the curve (AUC) ranged from 71% to 93% across the different algorithms, with the best being the CatBoost Classifier (CBC). Based on the default cut-off point of 0.32, the performance of CBC on predictor set 4 was: Accuracy (85%), Precision (90%), Recall (78%), F1-score (84%), Sensitivity (81%), Specificity (90%), positive predictive value (92%), negative predictive value (78%), and Brier Score (0.39).

    Conclusions: In this study, machine learning approaches achieved the best predictive performance over traditional statistical methods, increasing from 75 to 93%. The CatBoost classifier method achieved the best with the model including continuous variables.

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  • 221.
    Benchoula, Khaled
    et al.
    Int Islamic Univ Malaysia, Dept Basic Med Sci, Kulliyyah Pharm, Sultan Ahmad Shah St, Kuantan 25200, Pahang, Malaysia.
    Khatib, Alfi
    Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kulliyyah Pharm, Pharmacognosy Res Grp, Sultan Ahmad Shah St, Kuantan 25200, Pahang, Malaysia;Int Islamic Univ Malaysia, Kulliyyah Sci, Cent Res & Anim Facil CREAM, Sultan Ahamad Shah St, Kuantan 25200, Pahang, Malaysia.
    Jaffar, Ashika
    VIT Univ, Sch Biosci & Technol, Vellore 632014, Tamil Nadu, India.
    Ahmed, Qamar Udin
    Int Islamic Univ Malaysia, Dept Pharmaceut Chem, Kulliyyah Pharm, Pharmacognosy Res Grp, Sultan Ahmad Shah St, Kuantan 25200, Pahang, Malaysia.
    Sulaiman, Wan Mohd Azizi Wan
    Int Islamic Univ Malaysia, Dept Basic Med Sci, Kulliyyah Pharm, Sultan Ahmad Shah St, Kuantan 25200, Pahang, Malaysia.
    Abd Wahab, Ridhwan
    Int Islamic Univ Malaysia, Kulliyah Allied Hlth Sci, Sultan Ahmad Shah St, Kuantan 25200, Pahang, Malaysia.
    El-Seedi, Hesham
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Farmakognosi. Alrayan Med Coll, Medina 42541, Saudi Arabia.
    The promise of zebrafish as a model of metabolic syndrome2019Ingår i: Experimental animals, ISSN 1341-1357, E-ISSN 1881-7122, Vol. 68, nr 4, s. 407-416Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Metabolic syndrome is a cluster including hyperglycaemia, obesity, hypertension, and hypertriglyceridaemia as a result of biochemical and physiological alterations and can increase the risk of cardiovascular disease and diabetes. Fundamental research on this disease requires validated animal models. One potential animal model that is rapidly gaining in popularity is zebrafish (Danio rerio). The use of zebrafish as an animal model conveys several advantages, including high human genetic homology, transparent embryos and larvae that allow easier visualization. This review discusses how zebrafish models contribute to the development of metabolic syndrome studies. Different diseases in the cluster of metabolic syndrome, such as hyperglycaemia, obesity, diabetes, and hypertriglyceridaemia, have been successfully studied using zebrafish; and the model is promising for hypertension and cardiovascular metabolic-related diseases due to its genetic similarity to mammals. Genetic mutation, chemical induction, and dietary alteration are among the tools used to improve zebrafish models. This field is expanding, and thus, more effective and efficient techniques are currently developed to fulfil the increasing demand for thorough investigations.

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  • 222.
    Benckert, Martin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Lilja, Mikael
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Söderberg, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Eliasson, Mats
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Improved metabolic health among the obesein six population surveys 1986 to 2009: the Northern Sweden MONICA study2015Ingår i: BMC Obesity, ISSN 2052-9538, Vol. 2, nr 7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    The incidence of CVD is decreasing in spite of increasing BMI in the population. We examined trends in metabolic health among overweight and obese individuals and the influence of lifestyle and socioeconomic status. Six cross sectional population surveys in the Northern Sweden MONICA Study between 1986 and 2009. 8 874 subjects 25 to 64 years participated (74% participation rate). Metabolic health was defined as a total cholesterol level below 5.0 mmol/l, blood pressure below 140/90 mmHg and not having diabetes. In 2009 the age span 25 to 74 years was studied.

    Results

    The prevalence of metabolic health among obese subjects increased by 7.9 % per year (95% confidence interval 5.4; 10.5), reaching 21.0% in 2009. The corresponding figures for overweight subjects were 5.9% per year (4.6; 7.3), reaching 18% in 2009, whereas for the normal-weight subjects, the increase was 6.2% per year (5.3; 7.2), reaching 39% in 2009. The prevalence of metabolic health among subjects with abdominal obesity increased by 5.8% (4.6; 7.0) per year, reaching 17.3% in 2009. Among those with no abdominal obesity the increase was 6.2% (5.2; 7.1), reaching 38% in 2009 (p = <0.001 for all groups). Only among non-obese men and obese women did the increase continue between 2004 and 2009. In the other groups a slight decline or levelling off was noted.

    In 2009 women had a 27% higher prevalence of metabolic health than men. The prevalence of metabolic health among the obese was 19.8% which declined to 15.8% if subjects treated for hypertension or hypercholesterolemia were classified as not healthy. Overweight and obese subjects were less often metabolically healthy (odds ratio 0.54 and 0.59 respectively) compared with normal-weight subjects, independent of sex and age as were subjects with abdominal obesity (odds ratio 0.52). Adjustments for smoking, physical activity and education level did not influence any estimates.

    Conclusions

    This report shows a large increase in prevalence of metabolic health from 1986 to 2009 for all anthropometric categories. Metabolic health remains considerably less prevalent among overweight and obese subjects than among those with normal weight.

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  • 223.
    Bendel, Olof
    et al.
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden.
    Bueters, Tjerk
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden; Division of Neurology, Neurotec Department, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    von Euler, Mia
    Division of Neurology, Neurotec Department, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Ove Ögren, Sven
    Section of Behavioral Neuroscience, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    Sandin, Johan
    Section of Behavioral Neuroscience, Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    von Euler, Gabriel
    Section of Clinical CNS Research, Department of Clinical Neuroscience, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm, Sweden; Division of Neurology, Neurotec Department, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
    Reappearance of hippocampal CA1 neurons after ischemia is associated with recovery of learning and memory2005Ingår i: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 25, nr 12, s. 1586-1595Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The pyramidal neurons of the hippocampal CA1 region are essential for cognitive functions such as spatial learning and memory, and are selectively destroyed after cerebral ischemia. To analyze whether degenerated CA1 neurons are replaced by new neurons and whether such regeneration is associated with amelioration in learning and memory deficits, we have used a rat global ischemia model that provides an almost complete disappearance (to approximately 3% of control) of CA1 neurons associated with a robust impairment in spatial learning and memory at two weeks after ischemia. We found that transient cerebral ischemia can evoke a massive formation of new neurons in the CA1 region, reaching approximately 40% of the original number of neurons at 90 days after ischemia (DAI). Co-localization of the mature neuronal marker neuronal nuclei with 5-bromo-2'-deoxyuridine in CA1 confirmed that neurogenesis indeed had occurred after the ischemic insult. Furthermore, we found increased numbers of cells expressing the immature neuron marker polysialic acid neuronal cell adhesion molecule in the adjacent lateral periventricular region, suggesting that the newly formed neurons derive from this region. The reappearance of CA1 neurons was associated with a recovery of ischemia-induced impairments in spatial learning and memory at 90 DAI, suggesting that the newly formed CA1 neurons restore hippocampal CA1 function. In conclusion, these results show that the brain has an endogenous capacity to form new nerve cells after injury, which correlates with a restoration of cognitive functions of the brain.

  • 224. Bendinelli, B.
    et al.
    Palli, D.
    Masala, G.
    Sharp, S. J.
    Schulze, M. B.
    Guevara, M.
    van der A, D. L.
    Sera, F.
    Amiano, P.
    Balkau, B.
    Barricarte, A.
    Boeing, H.
    Crowe, F. L.
    Dahm, C. C.
    Dalmeijer, G.
    de Lauzon-Guillain, B.
    Egeberg, R.
    Fagherazzi, G.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin. Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
    Krogh, V.
    Huerta, J. M.
    Jakszyn, P.
    Khaw, K. T.
    Li, K.
    Mattiello, A.
    Nilsson, P. M.
    Overvad, K.
    Ricceri, F.
    Rodríguez-Suárez, L.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin.
    Sánchez, M. J.
    Slimani, N.
    Sluijs, I.
    Spijkerman, A. M. W.
    Teucher, B.
    Tjonneland, A.
    Tumino, R.
    van den Berg, S. W.
    Forouhi, N. G.
    Langenberg, C.
    Feskens, E. J. M.
    Riboli, E.
    Wareham, N. J.
    Association between dietary meat consumption and incident type 2 diabetes: the EPIC-InterAct study2013Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, nr 1, s. 47-59Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis: A diet rich in meat has been reported to contribute to the risk of type 2 diabetes. The present study aims to investigate the association between meat consumption and incident type 2 diabetes in the EPIC-InterAct study, a large prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

    Methods: During 11.7 years of follow-up, 12,403 incident cases of type 2 diabetes were identified among 340,234 adults from eight European countries. A centre-stratified random subsample of 16,835 individuals was selected in order to perform a case-cohort design. Prentice-weighted Cox regression analyses were used to estimate HR and 95% CI for incident diabetes according to meat consumption.

    Results: Overall, multivariate analyses showed significant positive associations with incident type 2 diabetes for increasing consumption of total meat (50 g increments: HR 1.08; 95% CI 1.05, 1.12), red meat (HR 1.08; 95% CI 1.03, 1.13) and processed meat (HR 1.12; 95% CI 1.05, 1.19), and a borderline positive association with meat iron intake. Effect modifications by sex and class of BMI were observed. In men, the results of the overall analyses were confirmed. In women, the association with total and red meat persisted, although attenuated, while an association with poultry consumption also emerged (HR 1.20; 95% CI 1.07, 1.34). These associations were not evident among obese participants.

    Conclusions/interpretation: This prospective study confirms a positive association between high consumption of total and red meat and incident type 2 diabetes in a large cohort of European adults.

  • 225.
    Bendix, Marie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Uvnäs-Moberg, Kerstin
    Petersson, Maria
    Kaldo, Viktor
    Åsberg, Marie
    Jokinen, Jussi
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri. Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Insulin and glucagon in plasma and cerebrospinal fluid in suicide attempters and healthy controls2017Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 81, s. 1-7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mental disorders and related behaviors such as suicidality and violence have been associated to dysregulation of e g carbohydrate metabolism. We hypothesized that patients after suicide attempt, compared to healthy controls, would have higher insulin and lower glucagon levels in plasma and cerebrospinal fluid and that these changes would be associated to violent behavior. Twenty-eight medication-free patients (10 women, 18 men), hospitalized after suicide attempt, and 19 healthy controls (7 women, 12 men) were recruited with the aim to study risk factors for suicidal behavior. Psychological/psychiatric assessment was performed with SCID I and II or the SCID interview for healthy volunteers respectively, the Karolinska Interpersonal Violence Scale (KIVS) for assessment of lifetime violence expression behavior, the Montgomery-Asberg-Depression-Scale (MADRS) and the Comprehensive Psychological Rating Scale (CPRS) for symptomatic assessment of depression and appetite. Fasting levels of insulin and glucagon were measured in plasma (P) and cerebrospinal fluid (CSF). Suicide attempters had higher insulin- and lower glucagon-levels in plasma- and CSF compared to controls. Except for P-glucagon these associations remained significant after adjusting for age and/or BMI. Patients reported significantly more expressed interpersonal violence compared to healthy volunteers. Expressed violence was significantly positively correlated with P- and CSF-insulin and showed a significant negative correlation with P-glucagon in study participants. These findings confirm and extend prior reports that higher insulin and lower glucagon levels in plasma and cerebrospinal fluid are associated with suicidal behavior pointing towards a potential autonomic dysregulation in the control of insulin and glucagon secretion in suicidal patients. 

  • 226.
    Bendre, Ameya
    et al.
    Division of Pediatric Endocrinology and Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ottosson, Lars
    Division of Pediatric Endocrinology and Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Baroncelli, Marta
    Division of Pediatric Endocrinology and Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dou, Zelong
    Division of Pediatric Endocrinology and Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Division of Pediatric Endocrinology and Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Growth failure in aggrecan haploinsufficiency is due to a decrease in growth plate matrix volume and hypertrophic cell size2023Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 96, nr Suppl. 4, s. 40-41, artikel-id FC4.4Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: Heterozygous loss-of-function mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (SSOAOD; OMIM#165800). ACAN mutations is a relatively common finding in idiopathic short stature (ISS) and has been reported to be the cause of growth failure in approximately 2% of children with ISS. However, the underlying cellular and molecular mechanisms by which ACAN mutations cause growth failure in SSOAOD have not been elucidated.

    Objective: To investigate the underlying cellular and molecular mechanisms of growth failure using a mouse model of SSOAOD.

    Methods: Cartilage matrix deficiency mouse (Acan cmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth at 1,3,6,12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and distal femoral growth plates. Cell proliferation was assessed by EdU incorporation. Quantification of percentage matrix area was performed using Image J. Single-cell RNA sequencing was carried out on chondro-cytes isolated from 18 day old WT and Acan cmd female mice according to 3’ gene expression protocol (10X Genomics).

    Results: Heterozygous Acancmd mice were born at a normal size and similar to humans with SSOAOD but showed decreased postnatal growth resulting in a gradually worsening dwarfism with reduced total body length and tibial and femoral lengths (p<0.0001). In the growth plates, chondrocytes were found to be more tightly packed with reduced matrix area (p<0.0001) and increased column density in Acan cmd mice compared to WT mice. Growth plate height (p<0.0001), heights of the individual zones (p<0.001), the number of resting zone chondrocytes (p<0.01), proliferative cells per column (p<0.0001), and the size of terminal hypertrophic chondrocytes (p<0.001) were slightly reduced in both male and female Acan cmd mice, especially at 1 week of age. Interestingly, chondrocyte proliferation was similar in Acan cmd and WT mice at all time-points assessed (p=0.90). Female Acan cmd mice exhibited a more pronounced phenotype than male mice.

    Conclusions: Similar to children with heterozygous ACAN mutations, heterozygous Acancmd mice exhibit a growth pattern with postnatal growth failure resulting in adult short stature. The growth failure is primarily caused by decreased matrix production and hypertrophic cell size, whereas chondrocyte proliferation is normal. Single-cell RNA sequencing of growth plate chondrocytes is ongoing and will identify the underlying pathogenic mechanisms and might also identify compensatory mechanisms limiting the effects of aggrecan haploinsufficiency.

  • 227.
    Bendre, Ameya
    et al.
    Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Ottosson, Lars
    Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Baroncelli, Marta
    Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Dou, Zelong
    Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, Ola
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
    Postnatal growth failure of aggrecan deficient mice is due to impaired growth plate chondrogenesis2022Ingår i: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 95, nr Suppl. 2, s. 294-294, artikel-id P1-308Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background: Heterozygous Aggrecan (Acan) mutations cause autosomal short stature (ISS) with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (OMIM#165800) in humans. Cartilage matrix deficiency mouse (Acancmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd mice develop postnatal dwarfism with progressing age. However, the underlying cellular and molecular mechanisms causing the growth failure have not been characterized in detail.

    Objective: To investigate the molecular mechanism of proportionate dwarfism in heterozygous Acan cmd mouse.

    Methods: Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth, at 1, 3, 6, 12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and femoral growth plates. Cell proliferation was assessed by EdU incorpora-tion and assessed by confocal microscopy. Quantification of percentage matrix area was performed using Image J image analysis software.

    Results: Heterozygous Acancmd mice were born with a normal body size. However, postnatal growth was reduced resulting in a gradually worsening dwarfism with reduced total body length (p <0.0001) as well as shorter tibial length (p<0.0001) and femoral length (p<0.0001) than their wild-type littermates. Histomorphometric analyses revealed that growth plate chondrocytes were more tightly packed with reduced matrix area (p<0.001) and increased proliferative column density in Acancmd mice compared to wild-type mice. Interestingly, the number of resting zone chondrocytes, proliferative cells per column and hypertropic cells per column were reduced at 1 week of age. In contrast, the size of terminal hypertrophic chondrocytes were normal during early postnatal growth, but reduced at 12 and 24 weeks of age. Despite the differences in growth plate morphology, chondrocyte proliferation was similar in Acan cmd and WT mice. Interestingly, female mice exhibited a more pronounced growth phenotype than the males.

    Conclusions: Heterozygous Acan cmd mice have a growth disorder that is similar to that in children with heterozygous ACAN mutations in terms of progression with age as well as in magnitude (10-15% smaller). Histomorphometric analyses suggest that the growth failure of aggrecan deficient mice is due to a combination of reduced matrix production and decreased size of the terminal hypertrophic chondrocytes. Further studies will elucidate the pathogenic mechanisms as well as the effect of estrogen on growth in aggrecan haploinsufficiency.

  • 228.
    Benedet, Patricia O.
    et al.
    Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada..
    Safikhan, Nooshin S.
    Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada..
    Pereira, Maria J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lum, Bryan M.
    Univ Alberta, Alberta Diabet Inst, Dept Physiol, Edmonton, AB, Canada.;Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB, Canada..
    Botezelli, José Diego
    Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada..
    Kuo, Cheng-Hsiang
    Natl Cheng Kung Univ, Int Ctr Wound Repair & Regenerat, Tainan, Taiwan..
    Wu, Hua-Lin
    Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan, Taiwan..
    Craddock, Barbara P.
    SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY USA..
    Miller, W. Todd
    SUNY Stony Brook, Dept Physiol & Biophys, Stony Brook, NY USA.;Vet Affairs Med Ctr, Northport, NY USA..
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Yue, Jessica T. Y.
    Univ Alberta, Alberta Diabet Inst, Dept Physiol, Edmonton, AB, Canada.;Univ Alberta, Grp Mol & Cell Biol Lipids, Edmonton, AB, Canada..
    Conway, Edward M.
    Univ British Columbia, Life Sci Inst, Ctr Blood Res, Fac Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Fac Med, Dept Pathol & Lab Med, Vancouver, BC, Canada.;Univ British Columbia, Life Sci Inst, Ctr Blood Res, 4306-2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3, Canada..
    CD248 promotes insulin resistance by binding to the insulin receptor and dampening its insulin-induced autophosphorylation2024Ingår i: EBioMedicine, E-ISSN 2352-3964, Vol. 99, artikel-id 104906Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background

    In spite of new treatments, the incidence of type 2 diabetes (T2D) and its morbidities continue to rise. The key feature of T2D is resistance of adipose tissue and other organs to insulin. Approaches to overcome insulin resistance are limited due to a poor understanding of the mechanisms and inaccessibility of drugs to relevant intracellular targets. We previously showed in mice and humans that CD248, a pre/adipocyte cell surface glycoprotein, acts as an adipose tissue sensor that mediates the transition from healthy to unhealthy adipose, thus promoting insulin resistance.

    Methods

    Molecular mechanisms by which CD248 regulates insulin signaling were explored using in vivo insulin clamp studies and biochemical analyses of cells/tissues from CD248 knockout (KO) and wild-type (WT) mice with diet-induced insulin resistance. Findings were validated with human adipose tissue specimens.

    Findings

    Genetic deletion of CD248 in mice, overcame diet-induced insulin resistance with improvements in glucose uptake and lipolysis in white adipose tissue depots, effects paralleled by increased adipose/adipocyte GLUT4, phosphorylated AKT and GSK3β, and reduced ATGL. The insulin resistance of the WT mice could be attributed to direct interaction of the extracellular domains of CD248 and the insulin receptor (IR), with CD248 acting to block insulin binding to the IR. This resulted in dampened insulin-mediated autophosphorylation of the IR, with reduced downstream signaling/activation of intracellular events necessary for glucose and lipid homeostasis.

    Interpretation

    Our discovery of a cell-surface CD248-IR complex that is accessible to pharmacologic intervention, opens research avenues toward development of new agents to prevent/reverse insulin resistance.

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  • 229.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Brooks, Samantha J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    O'Daly, Owen G
    Almèn, Markus S
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Morell, Arvid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Åberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Gingnell, Malin
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Institutionen för psykologi.
    Schultes, Bernd
    Hallschmid, Manfred
    Broman, Jan-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Schiöth, Helgi B
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study2012Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, nr 3, s. E443-447Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context:

    There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown.

    Objective:

    Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food.

    Intervention:

    Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan.

    Main Outcome Measures:

    Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found.

    Conclusions:

    These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society.

  • 230.
    Benedict, Christian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Jonas, Wenke
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Woting, Anni
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Blaut, Michael
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Schuermann, Annette
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Cedernaes, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals2016Ingår i: Molecular Metabolism, ISSN 2212-8778, Vol. 5, nr 12, s. 1175-1186Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Changes to the microbial community in the human gut have been proposed to promote metabolic disturbances that also occur after short periods of sleep loss (including insulin resistance). However, whether sleep loss affects the gut microbiota remains unknown. Methods: In a randomized within-subject crossover study utilizing a standardized in-lab protocol (with fixed meal times and exercise schedules), we studied nine normal-weight men at two occasions: after two nights of partial sleep deprivation (PSD; sleep opportunity 02: 45-07: 00 h), and after two nights of normal sleep (NS; sleep opportunity 22: 30-07: 00 h). Fecal samples were collected within 24 h before, and after two in-lab nights, of either NS or PSD. In addition, participants underwent an oral glucose tolerance test following each sleep intervention. Results: Microbiota composition analysis (V4 16S rRNA gene sequencing) revealed that after two days of PSD vs. after two days of NS, individuals exhibited an increased Firmicutes: Bacteroidetes ratio, higher abundances of the families Coriobacteriaceae and Erysipelotrichaceae, and lower abundance of Tenericutes (all P < 0.05) - previously all associated with metabolic perturbations in animal or human models. However, no PSD vs. NS effect on beta diversity or on fecal short-chain fatty acid concentrations was found. Fasting and postprandial insulin sensitivity decreased after PSD vs. NS (all P < 0.05). Discussion: Our findings demonstrate that short-term sleep loss induces subtle effects on human microbiota. To what extent the observed changes to the microbial community contribute to metabolic consequences of sleep loss warrants further investigations in larger and more prolonged sleep studies, to also assess how sleep loss impacts the microbiota in individuals who already are metabolically compromised. (C) 2016 The Author(s). Published by Elsevier GmbH.

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  • 231. Benetou, V
    et al.
    Orfanos, P
    Feskanich, D
    Michaëlsson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Pettersson-Kymmer, U
    Ahmed, L A
    Peasey, A
    Wolk, A
    Brenner, H
    Bobak, M
    Wilsgaard, T
    Schöttker, B
    Saum, K-U
    Bellavia, A
    Grodstein, F
    Klinaki, E
    Valanou, E
    Papatesta, E-M
    Boffetta, P
    Trichopoulou, A
    Education, marital status, and risk of hip fractures in older men and women: the CHANCES project2015Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, nr 6, s. 1733-1746Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk.

    INTRODUCTION: The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA.

    METHODS: A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models.

    RESULTS: Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05).

    CONCLUSIONS: The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.

  • 232. Benetou, V
    et al.
    Orfanos, P
    Pettersson-Kymmer, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Farmakologi.
    Bergström, Ulrica
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Svensson, Olle
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Johansson, Ingegerd
    Umeå universitet, Medicinska fakulteten, Institutionen för odontologi, Kariologi.
    Berrino, F
    Tumino, R
    Borch, K B
    Lund, E
    Peeters, P H M
    Grote, V
    Li, K
    Altzibar, J M
    Key, T
    Boeing, H
    von Ruesten, A
    Norat, T
    Wark, P A
    Riboli, E
    Trichopoulou, A
    Mediterranean diet and incidence of hip fractures in a European cohort2013Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 24, nr 5, s. 1587-1598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Prevention of hip fractures is of critical public health importance. In a cohort of adults from eight European countries, evidence was found that increased adherence to Mediterranean diet, measured by a 10-unit dietary score, is associated with reduced hip fracture incidence, particularly among men. INTRODUCTION: Evidence on the role of dietary patterns on hip fracture incidence is scarce. We explored the association of adherence to Mediterranean diet (MD) with hip fracture incidence in a cohort from eight European countries. METHODS: A total of 188,795 eligible participants (48,814 men and 139,981 women) in the European Prospective Investigation into Cancer and nutrition study with mean age 48.6 years (±10.8) were followed for a median of 9 years, and 802 incident hip fractures were recorded. Diet was assessed at baseline through validated dietary instruments. Adherence to MD was evaluated by a MD score (MDs), on a 10-point scale, in which monounsaturated were substituted with unsaturated lipids. Association with hip fracture incidence was assessed through Cox regression with adjustment for potential confounders. RESULTS: Increased adherence to MD was associated with a 7 % decrease in hip fracture incidence [hazard ratio (HR) per 1-unit increase in the MDs 0.93; 95 % confidence interval (95 % CI) = 0.89-0.98]. This association was more evident among men and somewhat stronger among older individuals. Using increments close to one standard deviation of daily intake, in the overall sample, high vegetable (HR = 0.86; 95 % CI = 0.79-0.94) and high fruit (HR = 0.89; 95 % CI = 0.82-0.97) intake was associated with decreased hip fracture incidence, whereas high meat intake (HR = 1.18; 95 % CI = 1.06-1.31) with increased incidence. Excessive ethanol consumption (HR high versus moderate = 1.74; 95 % CI = 1.32-2.31) was also a risk factor. CONCLUSIONS: In a prospective study of adults, increased adherence to MD appears to protect against hip fracture occurrence, particularly among men.

  • 233.
    Bengtsson, Daniel
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Cushing’s disease and aggressive pituitary tumours: Aspects on epidemiology, treatment, and long-term follow-up2021Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).

    One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.

    The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.

    Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD.

     

    Main conclusions of the thesis:

    • Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.
    • Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.
    • Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.
    • Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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  • 234.
    Bengtsson, Daniel
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Daa Schrøder, Henrik
    Department of Pathology (H.D.S.) Odense, Denmark.
    Andersen, Marianne
    Department of Endocrinology (M.A.), Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Maiter, Dominique
    Department of Endocrinology and Nutrition (D.M.), Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium.
    Berinder, Katarina
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    Feldt Rasmussen, Ulla
    Department of Medical Endocrinology and Metabolism (U.F.R, Å.K.R), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Krogh Rasmussen, Åse
    Department of Medical Endocrinology and Metabolism (U.F.R, Å.K.R), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Johannsson, Gudmundur
    Department of Endocrinology (G.J., O.R.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
    Hoybye, Charlotte
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    van der Lely, Aart Jan
    Department of Medicine, Division of Endocrinology (A.J.v.d.L.), Erasmus University MC, Rotterdam, The Netherlands.
    Petersson, Maria
    Department of Endocrinology, Metabolism and Diabetology (K.B., C.H., M.P.), Karolinska University Hospital, Stockholm, Sweden.
    Ragnarsson, Oskar
    Department of Endocrinology (G.J., O.R.), Institute of Medicine, Sahlgrenska Academy, University of Gothenburg; Sahlgrenska University Hospital, Gothenburg, Sweden.
    Burman, Pia
    Department of Endocrinology (D.B., P.B.), Skane University Hospital, Malmö, Sweden.
    Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide2015Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 4, s. 1689-1698Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT/OBJECTIVE: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. DESIGN AND SETTING: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. MAIN OUTCOME: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. RESULTS: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. CONCLUSIONS: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.

  • 235.
    Bengtsson, Daniel
    et al.
    Dept Internal Med, Halsogrand 2, S-39185 Kalmar, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, Linköping, Sweden..
    Ragnarsson, Oskar
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden..
    Berinder, Katarina
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Edén Engström, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism. Uppsala Univ Hosp, Dept Endocrinol & Diabet, Uppsala, Sweden..
    Ekman, Bertil
    Linköping Univ, Dept Endocrinol Linköping, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Hoybye, Charlotte
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Burman, Pia
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Wahlberg, Jeanette
    Linköping Univ, Dept Endocrinol Linköping, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden.;Örebro Univ, Fac Med Sci, Örebro, Sweden..
    Psychotropic Drugs in Patients with Cushing's Disease Before Diagnosis and at Long-Term Follow-Up: A Nationwide Study2021Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, nr 6, s. 1750-1760Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment. Objective: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design: Nationwide longitudinal register-based study. Setting: University Hospitals in Sweden. Subjects: CD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures: Data from the Swedish Prescribed Drug Register and the Patient Register. Results: In the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.53.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension. Conclusions: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

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  • 236.
    Bengtsson, Daniel
    et al.
    Dept Internal Med, Halsogrand 2, S-39185 Kalmar, Region Of Kalma, Sweden.;Linköping Univ, Dept Biomed & Clin Sci, Linköping, Sweden..
    Ragnarsson, Oskar
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden..
    Berinder, Katarina
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Edén Engström, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism. Uppsala Univ Hosp, Dept Endocrinol & Diabet, Uppsala, Sweden..
    Ekman, Bertil
    Linköping Univ, Dept Endocrinol, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Hoybye, Charlotte
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Jaras, Jacob
    Reg Canc Ctr, Stockholm, Sweden..
    Valdemarsson, Stig
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Lund, Sweden..
    Burman, Pia
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Wahlberg, Jeanette
    Linköping Univ, Dept Endocrinol, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden.;Örebro Univ, Fac Med Sci, Örebro, Sweden..
    Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study2022Ingår i: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 6, nr 6Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.

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  • 237.
    Bengtsson, Daniel
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Department of Internal Medicine, Kalmar, Region of Kalmar County , Kalmar, Sweden.
    Ragnarsson, Oskar
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg , Gothenburg, Sweden; Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Berinder, Katarina
    Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Dahlqvist, Per
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Edén Engström, Britt
    Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden; Department of Endocrinology and Diabetes, Uppsala University Hospital, Uppsala, Sweden.
    Ekman, Bertil
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Endokrinmedicinska kliniken.
    Höybye, Charlotte
    Department of Endocrinology, Karolinska University Hospital , Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Burman, Pia
    Department of Endocrinology, Skåne University Hospital, University of Lund, Malmö, Sweden.
    Wahlberg, Jeanette
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Medicincentrum, Endokrinmedicinska kliniken.
    Psychotropic drugs in patients with Cushing's disease before diagnosis and at long-term follow-up - a nationwide study.2021Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, artikel-id dgab079Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    CONTEXT: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment.

    OBJECTIVE: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.

    DESIGN: Nationwide longitudinal register-based study.

    SETTING: University Hospitals in Sweden.

    SUBJECTS: CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.

    MAIN OUTCOME MEASURES: Data from the Swedish Prescribed Drug Register and the Patient Register.

    RESULTS: In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.

    CONCLUSIONS: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.

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  • 238.
    Bengtsson, Daniel
    et al.
    Department Of Biomedical And Clinical Sciences, Linköping University, Linköping, Sweden.
    Ragnarsson, Oskar
    Department Of Internal Medicine And Clinical Nutrition, Institute Of Medicine, Sahlgrenska Academy, University Of Gothenburg, Gothenburg, Sweden; Department Of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Berinder, Katarina
    Department Of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department Of Molecular Medicine And Surgery, Karolinska Institutet, Stockholm, Sweden.
    Dahlqvist, Per
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Edén Engström, Britt
    Department Of Medical Sciences Endocrinology And Mineral Metabolism, Uppsala University, Uppsala, Sweden; Department Of Endocrinology And Diabetes, Uppsala University Hospital, Uppsala, Sweden.
    Ekman, Bertil
    Department Of Endocrinology, Linköping University, Linköping, Sweden; Department Of Health Medicine And Caring Sciences, Linköping University, Linköping, Sweden.
    Höybye, Charlotte
    Department Of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department Of Molecular Medicine And Surgery, Karolinska Institutet, Stockholm, Sweden.
    Järås, Jacob
    Regional Cancer Centre, Stockholm/Gotland, Stockholm, Sweden.
    Valdemarsson, Stig
    Department Of Clinical Sciences, Skåne University Hospital, University Of Lund, Lund, Sweden.
    Burman, Pia
    Department Of Endocrinology, Skåne University Hospital, University Of Lund, Malmö, Sweden.
    Wahlberg, Jeanette
    Department Of Endocrinology, Linköping University, Linköping, Sweden; Department Of Health Medicine And Caring Sciences, Linköping University, Linköping, Sweden; Faculty Of Medical Sciences, Örebro University, Örebro, Sweden.
    Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study2022Ingår i: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 6, nr 6, artikel-id bvac045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)]. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up (n = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery (n = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.

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  • 239.
    Bengtsson, Daniel
    et al.
    Department of Internal Medicine, Kalmar, Region of Kalmar County, Kalmar, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Ragnarsson, Oskar
    Department of Internal Medicine and Clinical Nutrition, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Berinder, Katarina
    Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Dahlqvist, Per
    Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
    Edén Engström, Britt
    Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden; Department of Endocrinology and Diabetes, Uppsala University Hospital, Uppsala, Sweden.
    Ekman, Bertil
    Department of Endocrinology, Linköping University, Linköping, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Höybye, Charlotte
    Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Järås, Jacob
    Regional Cancer Centre, Stockholm/Gotland, Stockholm, Sweden.
    Valdemarsson, Stig
    Department of Clinical Sciences, Skåne University Hospital, University of Lund, Lund, Sweden.
    Burman, Pia
    Department of Endocrinology, Skåne University Hospital, University of Lund, Malmö, Sweden.
    Wahlberg, Jeanette
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Endocrinology, Linköping University, Linköping, Sweden; Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
    Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study2022Ingår i: Journal of the Endocrine Society, E-ISSN 2472-1972, Vol. 6, nr 6, artikel-id bvac045Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls.

    Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort.

    Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included.

    Main outcome measures: Mortality and causes of death.

    Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)]. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up (n = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery (n = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death.

    Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.

  • 240.
    Bengtsson, Daniel
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Medicinska fakulteten. Kalmar Cty Council, Kalmar, Sweden.
    Schroder, H. D.
    Department of Pathology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Berinder, K.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Maiter, D.
    Department of Endocrinology and Nutrition, Cliniques Universitaires St-Luc, Université Catholique de Louvain, Brussels, Belgium.
    Hoybye, C.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Ragnarsson, O.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Feldt-Rasmussen, U.
    Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    Rasmussen, A. Krogh
    Department of Medical Endocrinology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    van der Lely, A.
    Department of Medicine, Division of Endocrinology, Erasmus University, Rotterdam, The Netherlands.
    Petersson, M.
    Department of Molecular Medicine and Surgery, Patient Area Endocrinology and Nephrology, Inflammation and Infection Theme, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden.
    Johannsson, G.
    Univ Gothenburg, Sweden; Sahlgrens Univ Hosp, Sweden.
    Andersen, M.
    Department of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark.
    Burman, P.
    Department of Endocrinology, Skåne University Hospital, University of Lund, Malmö, Sweden.
    Tumoral MGMT content predicts survival in patients with aggressive pituitary tumors and pituitary carcinomas given treatment with temozolomide2018Ingår i: Endocrine, ISSN 1355-008X, E-ISSN 1559-0100, Vol. 62, nr 3, s. 737-739Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    n/a

  • 241.
    Bengtsson, Lisa
    et al.
    Jönköping University, Hälsohögskolan.
    Mohamed, Zhiar
    Jönköping University, Hälsohögskolan.
    Egenvård vid diabetes mellitus typ 2 - En litteraturöversikt2021Självständigt arbete på grundnivå (kandidatexamen), 10 poäng / 15 hpStudentuppsats (Examensarbete)
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  • 242.
    Bengtsson, Sara K. S.
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Nyberg, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Hedström, Helena
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Zingmark, Elisabeth
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Jonsson, Bjorn
    Bäckström, Torbjörn
    Bixo, Marie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi.
    Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans2015Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 52, s. 22-31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of gamma-amino-butyric acid (GABA) on the GABA type A (GABA(A)) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABA(A) receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

  • 243.
    Benhalima, Katrien
    et al.
    Department of Endocrinology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium.
    Jendle, Johan
    Örebro universitet, Institutionen för medicinska vetenskaper. Diabetes Endocrinology and Metabolism Research Centre, School of Medicine, Örebro University, Örebro, Sweden.
    Beunen, Kaat
    Department of Endocrinology, University Hospital Gasthuisberg, KU Leuven, Leuven, Belgium.
    Ringholm, Lene
    Center for Pregnant Women with Diabetes, Department of Endocrinology and Metabolism, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
    Automated Insulin Delivery for Pregnant Women With Type 1 Diabetes: Where do we stand?2024Ingår i: Journal of Diabetes Science and Technology, E-ISSN 1932-2968, artikel-id 19322968231223934Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Automated insulin delivery (AID) systems mimic an artificial pancreas via a predictive algorithm integrated with continuous glucose monitoring (CGM) and an insulin pump, thereby providing AID. Outside of pregnancy, AID has led to a paradigm shift in the management of people with type 1 diabetes (T1D), leading to improvements in glycemic control with lower risk for hypoglycemia and improved quality of life. As the use of AID in clinical practice is increasing, the number of women of reproductive age becoming pregnant while using AID is also expected to increase. The requirement for lower glucose targets than outside of pregnancy and for frequent adjustments of insulin doses during pregnancy may impact the effectiveness and safety of AID when using algorithms for non-pregnant populations with T1D. Currently, the CamAPS® FX is the only AID approved for use in pregnancy. A recent randomized controlled trial (RCT) with CamAPS® FX demonstrated a 10% increase in time in range in a pregnant population with T1D and a baseline glycated hemoglobin (HbA1c) ≥ 48 mmol/mol (6.5%). Off-label use of AID not approved for pregnancy are currently also being evaluated in ongoing RCTs. More evidence is needed on the impact of AID on maternal and neonatal outcomes. We review the current evidence on the use of AID in pregnancy and provide an overview of the completed and ongoing RCTs evaluating AID in pregnancy. In addition, we discuss the advantages and challenges of the use of current AID in pregnancy and future directions for research.

  • 244. Bennet, L.
    et al.
    Lindblad, U.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    A family history of diabetes determines poorer glycaemic control and younger age of diabetes onset in immigrants from the Middle East compared with native Swedes2015Ingår i: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 41, nr 1, s. 45-54Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims. - Immigrant populations from the Middle East develop diabetes earlier than indigenous European populations; however, the underlying etiology is poorly understood. This study looked at the risk factors associated with early diabetes onset and, in non-diabetics, glycaemic control in immigrants from Iraq compared with native Swedes.

    Methods. - This cross-sectional population-based study comprised 1398 Iraqi immigrants and 757 Swedes (ages 30-75 years) residing in the same area of Malmo, Sweden. Outcomes were age at diabetes onset and glycaemic control (HbA(1c)) as assessed by Cox proportional hazards and linear regression, respectively.

    Results. - In Iraqis vs Swedes, clustering in the family history (in two or more relatives) was more prevalent (23.2% vs 3.6%, P<0.001) and diabetes onset occurred earlier (47.6 years vs 53.4 years, P=0.001). Having an Iraqi background independently raised the hazard ratio (HR) for diabetes onset. Diabetes risk due to family history was augmented by obesity, with the highest HRs observed in obese participants with clustering in the family history (HR: 5.1, 95% CI: 3.2-8.2) after adjusting for country of birth and gender. In participants without previously diagnosed diabetes (Iraqis: n=1270; Swedes: n=728), HbA(1c), levels were slightly higher in Iraqis than in Swedes (4.5% vs 4.4%, P=0.038). This difference was explained primarily by clustering in the family history rather than age, obesity, lifestyle or socioeconomic status.

    Conclusion. - The study shows that the greater predisposition to diabetes in Middle Eastern immigrants may be explained by a more extensive family history of the disorder; clinical interventions tailored to Middle Eastern immigrants with such a family history are thus warranted.

  • 245. Bennet, L.
    et al.
    Udumyan, R.
    Östgren, C.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Jansson, S.
    Wändell, P.
    Mortality in first- and second- generation immigrants to Sweden diagnosed with type 2 diabetes2020Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, nr SUPPL 1, s. S43-S43, artikel-id 84Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background and aims: Non-western immigrants to Europe are at high risk for type 2 diabetes (T2D). In this nationwide study including incident cases of T2D, the aim was to compare mortality in first- and second generation immigrants with native Swedes.

    Materials and methods: Patients living in Sweden diagnosed with a new-onset pharmacologically treated T2D between 2006 to 2012 were identified through the Swedish Prescription Drug Register. Patients were followed until December 31, 2016 for all-cause mortality (ACM) and until December 31, 2012 for cause-specific mortality (CSM). Analyses were adjusted for age at diagnosis, sex, year of diagnosis, socioeconomy, education, treatment and region. Comparisons were assessed using coxregression analysis.

    Results: In total, 169 300 individuals (129 533 (76.3%) native Swedes; 31 988 (18.9%) first-generation immigrants, and 7 799 (4.8%) secondgeneration immigrants with either one or both parents born outside Sweden) were diagnosed with T2D between 2006 and 2012 and fulfilled inclusion criteria. First-generation immigrants had lower ACM rate [hazard ratio (HR): 0.85, 95% CI 0.82 to 0.89] compared with native Swedes.The mortality was particularly low in persons born in the Middle East [0.45,0.40 to 0.51], Asia [0.56, 0.46 to 0.68], and Africa [0.88. 0.82 to 0.95]. Mortality rates decreased with older age at migration and shorter stay in Sweden, with the lowest rate in those originating from the Middle East living in Sweden <25 years [0.40, 0.34 to 0.46]. Firstgeneration immigrants born in the Middle East (0.43; 0.30-0.62), and Asia (0.38; 0.19- 0.77) had lower cardiovascular disease related mortality rates compared with native Swedes. Middle Eastern immigrants further displayed lower cancer related mortality rate (0.59, 0.42 to 0.84) compared with native Swedes. Second generation immigrants displayed similar survival rates as native Swedes.

    Conclusion: Our data indicate that in T2D patients, exposure to the Swedish environment seems to have a larger impact on mortality risk than region of origin. This study indicates protecting mechanisms on mortality related to the non-western environment.

  • 246.
    Bennet, L.
    et al.
    Lund University, Malmö, Sweden.
    Udumyan, Ruzan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Östgren, C.
    Linköping University, Linköping, Sweden.
    Rolandsson, O.
    Umeå University, Umeå, Sweden.
    Jansson, S.
    Örebro University, Örebro, Sweden.
    Wandell, P.
    Karolinska Institute, Stockholm, Sweden.
    Mortality in first- and second- generation immigrants to Sweden diagnosed with type 2 diabetes2020Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, nr Suppl. 1, s. S43-S43Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    Background and aims: Non-western immigrants to Europe are at high risk for type 2 diabetes (T2D). In this nationwide study including incident cases of T2D, the aim was to compare mortality in first- and second generation immigrants with native Swedes.

    Materials and methods: Patients living in Sweden diagnosed with a new-onset pharmacologically treated T2D between 2006 to 2012 were identified through the Swedish Prescription Drug Register. Patients were followed until December 31, 2016 for all-cause mortality (ACM) and until December 31, 2012 for cause-specific mortality (CSM). Analyses were adjusted for age at diagnosis, sex, year of diagnosis, socioeconomy, education, treatment and region. Comparisons were assessed using coxregression analysis.

    Results: In total, 169 300 individuals (129 533 (76.3%) native Swedes; 31 988 (18.9%) first-generation immigrants, and 7 799 (4.8%) second-generation immigrants with either one or both parents born outside Sweden) were diagnosed with T2D between 2006 and 2012 and fulfilled inclusion criteria. First-generation immigrants had lower ACM rate [hazard ratio (HR): 0.85, 95% CI 0.82 to 0.89] compared with native Swedes. The mortality was particularly low in persons born in the Middle East [0.45,0.40 to 0.51], Asia [0.56, 0.46 to 0.68], and Africa [0.88. 0.82 to 0.95]. Mortality rates decreased with older age at migration and shorter stay in Sweden, with the lowest rate in those originating from the Middle East living in Sweden <25 years [0.40, 0.34 to 0.46]. First-generation immigrants born in the Middle East (0.43; 0.30-0.62), and Asia (0.38; 0.19- 0.77) had lower cardiovascular disease related mortality rates compared with native Swedes. Middle Eastern immigrants further displayed lower cancer related mortality rate (0.59, 0.42 to 0.84) compared with native Swedes. Second generation immigrants displayed similar survival rates as native Swedes.

    Conclusion: Our data indicate that in T2D patients, exposure to the Swedish environment seems to have a larger impact on mortality risk than region of origin. This study indicates protecting mechanisms on mortality related to the non-western environment.

  • 247. Bennet, Louise
    et al.
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin. Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Department of Diabetes and Endocrinology/Lund University Diabetes Centre, Skåne University Hospital, Malmö, Sweden; Genetic and Molecular Epidemiology Unit, Lund University, Malmö, Sweden; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Zöller, Bengt
    Groop, Leif
    Family history of diabetes and its relationship with insulin secretion and insulin sensitivity in Iraqi immigrants and native Swedes: a population-based cohort study2018Ingår i: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 55, nr 3, s. 233-242Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims Middle Eastern immigrants to western countries are at high risk of developing type 2 diabetes. However, the heritability and impact of rst-degree family history (FH) of type 2 diabetes on insulin secretion and action have not been adequately described. Methods Citizens of Malmö, Sweden, aged 30–75 years born in Iraq or Sweden were invited to participate in this population- based study. Insulin secretion (corrected insulin response and oral disposition index) and action (insulin sensitivity index) were assessed by oral glucose tolerance tests.

    Results In total, 45.7% of Iraqis (616/1348) and 27.4% of native Swedes (201/733) had FH in parent(s), sibling(s) or single parent and sibling, i.e., FH+. Approximately 8% of Iraqis and 0.7% of Swedes had ≥ 3 sibling(s) and parent(s) with diabetes, i.e., FH++. Irrespective of family size, prediabetes and diabetes increased with family burden (FH− 29.4%; FH+ 38.8%; FH++ 61.7%) without signi cant di erences across ethnicities. With increasing level of family burden, insulin secretion rather than insulin action decreased. Individuals with a combination of ≥ 3 siblings and parents with diabetes presented with the lowest levels of insulin secretion.

    Conclusions The Iraqi immigrant population often present with a strong familial burden of type 2 diabetes with the worst glycemic control and highest diabetes risk in individuals with ≥ 3 siblings and parents with diabetes. Our data show that in a population still free from diabetes familial burden in uences insulin secretion to a higher degree than insulin action and may be a logical target for intervention. 

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  • 248. Bennet, Louise
    et al.
    Groop, Leif
    Franks, Paul W.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Department of Nutrition, Harvard School of Public Health, Boston, MA, USA; Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden; Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Malmö, Sweden.
    Country of birth modifies the association of fatty liver index with insulin action in Middle Eastern immigrants to Sweden2015Ingår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 110, nr 1, s. 66-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: Non-alcohol fatty liver disease (NAFLD) is a strong risk factor for insulin resistance and type 2 diabetes. The prevalence of NAFLD varies across populations of different ethnic backgrounds but the prevalence in Middle Eastern populations, which are at high risk of type 2 diabetes, is largely unknown. Using fatty liver index (FLI) as a proxy for NAFLD the aim was to calculate the odds of NAFLD (FLI >= 70) given country of origin and further to investigate the associations between ISI and FLI. Methods: In 2010-2012 we conducted a population-based study of individuals aged 30-75 years born in Iraq or Sweden, in whom anthropometrics, fasting blood samples and oral glucose tolerance tests were performed and sociodemography and lifestyle behaviors characterized. Results: A higher proportion of Iraqis (N = 1085) than Swedes (N = 605) had a high probability of NAFLD (FLI >= 70, 32.5 vs. 22.6%, p < 0.001, age-and sex-adjusted data) and ISI was more severely impaired (70.7 vs. 95.9%, p < 0.001). Independently of traditional risk factors for NAFLD, being born in Iraqi increased the risk of FLI >= 70 (OR 1.59: 95% CI 1.15, 2.20). Furthermore, country of birth presented a stronger association between ISI and FLI >= 70 in Iraqis than in Swedes (P-interaction = 0.019). Conclusions: Our data indicate that immigrants from Iraq are at higher risk of NAFLD. The finding that country of birth modifies the relationship of FLI with ISI, suggests that liver fat may be a stronger determinant of impaired insulin action and increased risk of type 2 diabetes in Iraqis than in Swedes.

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  • 249. Bennet, Louise
    et al.
    Groop, Leif
    Franks, Paul W
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Ethnic differences in the contribution of insulin action and secretion to type 2 diabetes in immigrants from the Middle East compared to native Swedes2014Ingår i: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 105, nr 1, s. 79-87Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims: We investigated insulin action (insulin sensitivity index, ISI) and insulin secretion (oral disposition indices, DIo) and studied metabolic, demographic and lifestyle-related risk factors for type 2 diabetes and insulin action, in the largest non-European immigrant group to Sweden, immigrants from Iraq and native Swedes.

    Methods: Population-based, cross-sectional study conducted 2010-2012 including residents 30-75 years of age born in Iraq or Sweden, in whom oral glucose tolerance tests were performed and sociodemography and lifestyle behaviors were characterized.

    Results: In Iraqis compared to Swedes, ISI was more impaired (76.9 vs. 102.3, p < .001) whereas corrected insulin response CIR was higher (226.6 vs. 188.6, p = .016). However, insulin secretion was inadequate given the substantial insulin resistance, as indicated by lower DIo indices in Iraqis than in Swedes (DIo 12,712.9 vs. 14,659.2, p < .001). The crude ethnic difference in ISI was not offset by traditional risk factors like waist circumference, body mass index or family history of diabetes. In Iraqis, ISI conveyed somewhat higher odds of type 2 diabetes than in Swedes (odds ratio OR 0.98, 95% CI 0.97-0.99) vs. OR 0.95, 0.92-0.99), as indicated by an interaction between country of birth and ISI (P-interaction = .044).

    Conclusion: This study reports ethnic differences in the contribution of insulin action to type 2 diabetes. Our data suggests that the impaired insulin action observed in immigrants from the Middle East to Sweden is not fully explained by established risk factors.

    (C) 2014 The Authors. Published by Elsevier Ireland Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

  • 250. Bennet, Louise
    et al.
    Udumyan, Ruzan
    Ostgren, Carl Johan
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Jansson, Stefan P. O.
    Wandell, Per
    Mortality in first- and second-generation immigrants to Sweden diagnosed with type 2 diabetes: a 10 year nationwide cohort study2020Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 64, nr 1, s. 95-108Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aims/hypothesis: Non-Western immigrants to Europe are at high risk for type 2 diabetes. In this nationwide study including incident cases of type 2 diabetes, the aim was to compare all-cause mortality (ACM) and cause-specific mortality (CSM) rates in first- and second-generation immigrants with native Swedes.

    Methods: People living in Sweden diagnosed with new-onset pharmacologically treated type 2 diabetes between 2006 and 2012 were identified through the Swedish Prescribed Drug Register. They were followed until 31 December 2016 for ACM and until 31 December 2012 for CSM. Analyses were adjusted for age at diagnosis, sex, socioeconomic status, education, treatment and region. Associations were assessed using Cox regression analysis.

    Results: In total, 138,085 individuals were diagnosed with type 2 diabetes between 2006 and 2012 and fulfilled inclusion criteria. Of these, 102,163 (74.0%) were native Swedes, 28,819 (20.9%) were first-generation immigrants and 7103 (5.1%) were second-generation immigrants with either one or both parents born outside Sweden. First-generation immigrants had lower ACM rate (HR 0.80 [95% CI 0.76, 0.84]) compared with native Swedes. The mortality rates were particularly low in people born in non-Western regions (0.46 [0.42, 0.50]; the Middle East, 0.41 [0.36, 0.47]; Asia, 0.53 [0.43, 0.66]; Africa, 0.47 [0.38, 0.59]; and Latin America, 0.53 [0.42, 0.68]). ACM rates decreased with older age at migration and shorter stay in Sweden. Compared with native Swedes, first-generation immigrants with <= 24 years in Sweden (0.55 [0.51, 0.60]) displayed lower ACM rates than those spending >24 years in Sweden (0.92 [0.87, 0.97]). Second-generation immigrants did not have better survival rates than native Swedes but rather displayed higher ACM rates for people with both parents born abroad (1.28 [1.05, 1.56]).

    Conclusions/interpretation: In people with type 2 diabetes, the lower mortality rate in first-generation non-Western immigrants compared with native Swedes was reduced over time and was equalised in second-generation immigrants. These findings suggest that acculturation to Western culture may impact ACM and CSM in immigrants with type 2 diabetes but further investigation is needed.

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