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  • 51.
    Bhandage, Amol K.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Korol, Sergiy V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi. Uppsala University.
    Shen, Qiujin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Pei, Yu
    Karolinska Institute, Stockholm, Sweden.
    Deng, Qiaolin
    Karolinska Institute, Stockholm, Sweden.
    Espes, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes2018Ingår i: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, s. 283-294Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

  • 52.
    Birkeland, Kare I.
    et al.
    Univ Oslo, Inst Clin Med.; Oslo Univ Hosp, Dept Transplantat Med..
    Jorgensen, Marit E.
    Steno Diabet Ctr Copenhagen.;Southern Denmark Univ, Natl Inst Publ Hlth..
    Carstensen, Bendix
    Steno Diabet Ctr Copenhagen..
    Persson, Frederik
    Steno Diabet Ctr Copenhagen..
    Gulseth, Hanne L.
    Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med..
    Thuresson, Marcus
    Statisticon AB..
    Fenici, Peter
    AstraZeneca..
    Nathanson, David
    Karolinska Inst, Dept Clin Sci & Educ..
    Nyström, Thomas
    Karolinska Inst, Dept Clin Sci & Educ..
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Bodegard, Johan
    AstraZeneca Nord Baltic, Med Dept..
    Norhammar, Anna
    Karolinska Inst, Södersjukhuset, Dept Med.;Capio St Görans Hosp.
    Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A Multinational Observational Analysis2017Ingår i: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, nr 9, s. 709-717Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.

  • 53.
    Biskup, Izabela
    et al.
    Swedish Univ Agr Sci, BioCtr, Dept Food Sci, Uppsala, Sweden.;Wroclaw Med Univ, Dept Pharmacognosy, Wroclaw, Poland..
    Kyro, Cecilie
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Marklund, Matti
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Olsen, Anja
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    van Dam, Rob M.
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Natl Univ Hlth Syst, Singapore, Singapore.;Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Tjonneland, Anne
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Overvad, Kim
    Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark..
    Lindahl, Bernt
    Umea Univ, Dept Publ Hlth, Umea, Sweden.;Umea Univ, Dept Clin Med, Umea, Sweden..
    Johansson, Ingegerd
    Umea Univ, Dept Odontol & Cariol, Umea, Sweden..
    Landberg, Rikard
    Swedish Univ Agr Sci, BioCtr, Dept Food Sci, Uppsala, Sweden.;Karolinska Inst, Inst Environm Med, Nutr Epidemiol Unit, Stockholm, Sweden..
    Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and risk of type 2 diabetes in Scandinavian men and women2016Ingår i: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, nr 1, s. 88-96Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Studies that use dietary biomarkers to investigate the association between whole-grain intake and the risk of developing type 2 diabetes (T2D) are lacking. Objective: We examined the association between plasma total alkylresorcinols and the alkylresorcinol C17:0-to-C21:0 ratio, biomarkers of whole-grain wheat and rye intake and relative whole grain rye over whole-grain wheat intake, respectively, and the risk of T2D among Scandinavian men and women. Design: A nested case-control study was established within the Northern Sweden Health and Disease Study and the Danish Diet, Cancer and Health cohort. Alkylresorcinol concentrations and the ratios of C17:0 to C21:0 were determined in plasma samples from 931 case-control pairs. ORs for T2D were calculated for plasma total alkylresorcinol concentration or C17:0-to-C21:0 ratio in quartiles with the use of conditional logistic regression that was adjusted for potential confounders. Additional analyses with whole-grain wheat and rye intake estimated from food-frequency questionnaires (FFQs) as exposures were also performed. Results: The plasma total alkylresorcinol concentration was not associated with T2D risk (OR: 1.34; 95% CI: 0.95, 1.88) for the highest compared with the lowest quartiles in multivariable adjusted models. However, the C17:0-to-C21:0 ratio was associated with a lower diabetes risk (OR: 0.54; 95% CI: 0.37, 0.78). Analyses with whole-grain intake estimated from FFQs yielded similar results. Conclusions: Total whole-grain wheat and rye intake, reflected by alkylresorcinols in plasma, was not associated with a lower risk of T2D in a population with high whole-grain intake. In contrast, the proportion of whole-grain rye to whole-grain wheat intake, indicated by the plasma C17:0-to-C21:0 ratio, was inversely associated with T2D. This suggests that whole-grain intake dominated by rye may be favorable for T2D prevention.

  • 54.
    Bjermo, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Dietary Fatty Acids and Inflammation: Observational and Interventional Studies2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Dietary fat quality influences the risk of type 2 diabetes and cardiovascular disease. A low-grade inflammation is suggested to contribute to the disease development, often accompanied by obesity. Whereas n-3 polyunsaturated fatty acids (PUFA) have been considered anti-inflammatory, n-6 PUFA have been proposed to act pro-inflammatory. Saturated fatty acids (SFA) act pro-inflammatory in vitro.

    This thesis aimed to investigate effects of different fatty acids on low-grade inflammation in observational and interventional studies. In Paper I and II, fatty acid composition in serum cholesterol esters was used as objective marker of dietary fat quality and related to serum C-reactive protein (CRP) and other circulating inflammatory markers in two population-based cohorts, conducted in middle-aged men and elderly men and women, respectively. In Paper III and IV, the impact of diets differing in fat quality on inflammation and oxidative stress was investigated in randomised controlled studies, in subjects with metabolic syndrome and abdominal obesity.

    In Paper I and II, a low proportion of linoleic acid (18:2 n-6) in serum was associated with higher CRP concentrations, indicating that a low intake of vegetable fats may be related to low-grade inflammation. High CRP concentrations were also associated with high proportions of palmitoleic (16:1) and oleic (18:1) acids and high stearoyl coenzymeA desaturase index, possibly reflecting altered fat metabolism and/or high SFA intake in this population. When comparing two high-fat diets rich in either saturated or monounsaturated fat, and two low-fat diets with or without long-chain n-3 PUFA supplementation during 12 weeks (Paper III), no differences in inflammation or oxidative stress markers were observed. Moreover, a 10-week intervention (Paper IV) with high linoleic acid intake showed no adverse effects on inflammation or oxidative stress. Instead, interleukin-1 receptor antagonist and tumor necrosis factor receptor-2 decreased after linoleic acid intake compared with a diet high in SFA.

    The results in this thesis indicate that dietary n-6 PUFA found in vegetable fats is associated with lower inflammation marker levels, and to some extent reduces systemic inflammation when compared with SFA. Supplementation of n-3 PUFA did not exert any systemic anti-inflammatory effects, maybe due to a relatively low dose.

    Delarbeten
    1. Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men
    Öppna denna publikation i ny flik eller fönster >>Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men
    2008 (Engelska)Ingår i: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 99, nr 6, s. 1186-1189Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Altered fatty acid (FA) composition is related to insulin resistance and CVD. One possible mediator may be inflammation, but longitudinal data relating FA composition to inflammation taking insulin resistance into account are limited. We investigated the long-term association between FA composition and C-reactive protein (CRP) concentrations in a large population-based cohort study in 767 men followed for 20 years. The association between FA composition in serum cholesteryl esters at age 50 and CRP concentrations at age 70 was investigated using linear regression. In addition, desaturase activities (stearoyl-CoA desaturase-1 (SCD-1), Delta 5- and Delta 6-desaturase) were estimated using FA product-to-precursor ratios. Insulin resistance was measured directly at follow-up by euglycaemic clamp. After adjusting for confounders (smoking, physical activity, alcohol intake, obesity and erythrocyte sedimentation rate) CRP concentrations were inversely associated with the proportion of 18:2n-6 (P=0.002) and positively associated with 16:1n-7 (P=0.008), 18: 1n-9 (P=0.0003), 20:5n-3 (P=0.04) and estimated SCD-1 (P=0.005) and Delta 6-desaturase (P=0.02) activities. After adding insulin resistance to the model, 18: 1n-9, 18:2n-6 and SCD-1 remained significant predictors of CRP. A FA composition indicating low intake of 18:2n-6, high intake of SFA and high SCD-1 activity is, in a Swedish population of middle-aged men, associated with CRP concentrations 20 years later, even independently of obesity and insulin resistance.

    Nyckelord
    C-reactive protein, fatty acids, SCD-1, inflammation
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-17694 (URN)10.1017/S0007114507871674 (DOI)000255955500006 ()18062827 (PubMedID)
    Tillgänglig från: 2008-08-15 Skapad: 2008-08-15 Senast uppdaterad: 2018-02-22Bibliografiskt granskad
    2. Relationships between serum fatty acid composition and multiple markers of inflammation and endothelial function in an elderly population
    Öppna denna publikation i ny flik eller fönster >>Relationships between serum fatty acid composition and multiple markers of inflammation and endothelial function in an elderly population
    Visa övriga...
    2009 (Engelska)Ingår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 203, nr 1, s. 298-303Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Fatty acid (FA) composition in serum has been associated with C-reactive protein (CRP), but associations with other markers of inflammation and endothelial function, e.g. adhesion molecules are unknown. We recently suggested a possible role of the lipogenic enzyme stearoyl coenzymeA desaturase-1 (SCD-1) in inflammation. This study investigates the associations between serum FA composition, including SCD-1 index, and various inflammatory and endothelial function markers. METHODS: 264 Swedish men and women aged 70 years participated in this cross-sectional population-based study. FA composition was measured in serum cholesteryl esters and was correlated to inflammatory markers (CRP, interleukin [IL]-2, IL-6, IL-8, tumor necrosis factor [TNF]-alpha, vascular cellular adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1, E-selectin, P-selectin, L-selectin, interferon-gamma, and monocyte chemoattractant protein [MCP]-1), using linear regression analysis. SCD-1 activity was estimated by FA product-to-precursor ratio (16:1/16:0). RESULTS: Serum FA composition was significantly associated with CRP and E-selectin but not with other inflammatory markers. After adjusting for BMI, smoking, physical activity, alcohol consumption and lipid-lowering therapy, the proportion of palmitoleic acid and SCD-1 index were positively correlated with CRP concentrations (P=0.003 and P=0.001, respectively). CONCLUSION: A FA composition reflecting high intake of saturated fat and a high SCD-1 index is independently related to CRP concentrations, but not to other markers of inflammation and endothelial function in this population of elderly men and women. Given the absent association between FA composition and the other markers, CRP may be the preferable marker to use when investigating potential relationships between FAs and low-grade inflammation.

    Nyckelord
    Fatty acids, Inflammation, Endothelial function, SCD-1, C-reactive protein, Adhesion molecules
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-103687 (URN)10.1016/j.atherosclerosis.2008.06.020 (DOI)000264510700045 ()18687433 (PubMedID)
    Tillgänglig från: 2009-05-20 Skapad: 2009-05-20 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study
    Öppna denna publikation i ny flik eller fönster >>Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study
    Visa övriga...
    2010 (Engelska)Ingår i: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 104, nr 9, s. 1357-1362Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Subjects with the metabolic syndrome (MetS) have enhanced oxidative stress and inflammation. Dietary fat quality has been proposed to be implicated in these conditions. We investigated the impact of four diets distinct in fat quantity and quality on 8-iso-PGF2α (a major F2-isoprostane and oxidative stress indicator), 15-keto-13,14-dihydro-PGF2α (15-keto-dihydro-PGF2α, a major PGF2α metabolite and marker of cyclooxygenase-mediated inflammation) and C-reactive protein (CRP). In a 12-week parallel multicentre dietary intervention study (LIPGENE), 417 volunteers with the MetS were randomly assigned to one of the four diets: two high-fat diets (38 % energy (%E)) rich in SFA or MUFA and two low-fat high-complex carbohydrate diets (28 %E) with (LFHCC n-3) or without (LFHCC) 1·24 g/d of very long chain n-3 fatty acid supplementation. Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α were determined by RIA and adjusted for urinary creatinine levels. Serum concentration of CRP was measured by ELISA. Neither concentrations of 8-iso-PGF2α and 15-keto-dihydro-PGF2α nor those of CRP differed between diet groups at baseline (P>0·07) or at the end of the study (P>0·44). Also, no differences in changes of the markers were observed between the diet groups (8-iso-PGF2α, P = 0·83; 15-keto-dihydro-PGF2α, P = 0·45; and CRP, P = 0·97). In conclusion, a 12-week dietary fat modification did not affect the investigated markers of oxidative stress and inflammation among subjects with the MetS in the LIPGENE study.

    Nyckelord
    Dietary fat; Oxidative stress; Inflammation; Metabolic syndrome; LIPGENE study
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-133408 (URN)10.1017/S000711451000228X (DOI)000284015300012 ()20569506 (PubMedID)
    Tillgänglig från: 2010-11-09 Skapad: 2010-11-09 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    4. Dietary fat modification and liver fat content in abdominal obesity
    Öppna denna publikation i ny flik eller fönster >>Dietary fat modification and liver fat content in abdominal obesity
    Visa övriga...
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Identifikatorer
    urn:nbn:se:uu:diva-156073 (URN)
    Tillgänglig från: 2011-08-02 Skapad: 2011-07-11 Senast uppdaterad: 2011-11-10
  • 55. Bjornsdottir, Sigridur
    et al.
    Oksnes, Marianne
    Isaksson, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    Methlie, Paal
    Nilsen, Roy M.
    Hustad, Steinar
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    Hulting, Anna-Lena
    Husebye, Eystein S.
    Lovas, Kristian
    Nystrom, Thomas
    Bensing, Sophie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet.
    Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy2015Ingår i: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, nr 1, s. 28-35Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ContextConventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). ObjectiveThe aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. Design and settingAn open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. PatientsTen Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. InterventionThrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. Main outcome measureWe measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. ResultsContinuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. ConclusionContinuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD.

  • 56.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Mellström, Dan
    Ohlsson, Claes
    Karlsson, Magnus
    ljunggren, Östen
    Kindmark, Andreas
    Johansson, Gunnar
    POLYMORPHIC VARIATIONS IN THE GENE FOR CYP2R1 IS ASSOCIATED WITH CIRCULATING LEVELS OF 25OHD3, BUT NOT WITH CALCIUM – PHOSPHATE CONCENTRATIONS (MROS SWEDEN)Manuskript (preprint) (Övrigt vetenskapligt)
  • 57.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Mellström, Dan
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Geriatr Med, Gothenburg, Sweden.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Karlsson, Magnus
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped Surg, Malmo, Sweden.
    Mallmin, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Haplotypes in the CYP2R1 gene are associated with levels of 25(OH)D and bone mineral density, but not with other markers of bone metabolism (MrOS Sweden)2018Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, nr 12, artikel-id e0209268Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective: Polymorphisms in the CYP2R1 gene encoding Vitamin D 25-hydroxylase have been reported to correlate with circulating levels of 25-OH vitamin D3 (25(OH)D). It is unknown whether these variations also affect overall bone metabolism. In order to elucidate the overall associations of polymorphisms in the CYP2R1, we studied haplotype tagging single nucleotide polymorphisms (SNPs) in the gene and serum levels of 25(OH)D, calcium, phosphate, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23), as well as bone mineral density (BMD).

    Methods: Baseline data on serum parameters and BMD from MrOS Sweden, a prospective population-based cohort study of elderly men (mean age 75 years, range 69-81), were analyzed. Genotyping was performed for eight SNPs covering the CYP2R1 gene in 2868 men with available samples of DNA. Subjects were followed up concerning incidence of fracture during five years.

    Results: There was a significant genetic association with circulating levels of 25(OH)D (4.6-18.5% difference in mean values between SNP alleles), but there were no correlations with levels of calcium, phosphate, PTH or FGF23 for any genetic variant. No differences were found in fracture incidence between the variants. There was an inverse relationship between lower BMD and concomitant higher 25(OH)D for three of the haplotypes (p < 0.005).

    Conclusions: Common variants in the CYP2R1 gene encoding Vitamin D 25-hydroxylase correlate with levels of circulating 25(OH)D but do not otherwise associate with measures of calcium and phosphate homeostasis. Presence of the specific haplotypes may be an indicator of risk for low 25(OH)D levels, and may in addition be correlated to bone mineral density.

  • 58.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Ribom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Ortopedi.
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Scragg, R.
    Univ Auckland, Sch Populat Hlth, Sect Epidemiol & Biostat, Auckland, New Zealand.
    Mellstrom, D.
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin, Geriatr Med,Nutr, Gothenburg, Sweden.
    Grundberg, E.
    McGill Univ, Dept Human Genet, Montreal, PQ, Canada;McGill Univ, Genome Quebec Innovat Ctr, Montreal, PQ, Canada.
    Ohlsson, C.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Ctr Bone & Arthrit Res, Gothenburg, Sweden.
    Karlsson, M.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci & Orthoped Surg, Malmo, Sweden.
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Variations in the vitamin D receptor gene are not associated with measures of muscle strength, physical performance, or falls in elderly men: Data from MrOS Sweden2019Ingår i: Journal of Steroid Biochemistry and Molecular Biology, ISSN 0960-0760, E-ISSN 1879-1220, Vol. 187, s. 160-165Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The vitamin D receptor (VDR) has been proposed as a candidate gene for several musculoskeletal phenotypes. However, previous results on the associations between genetic variants of the VDR with muscle strength and falls have been contradictory. The MrOS Sweden survey, a prospective population-based cohort study of 3014 elderly men (mean age 75 years, range 69-81) offered the opportunity to further investigate these associations. At baseline, data were collected on muscle strength and also the prevalence of falls during the previous 12 months. Genetic association analysis was performed for 7 Single Nucleotide Polymorphisms (SNPs), covering the genetic region surrounding the VDR gene in 2924 men with available samples of DNA. Genetic variations in the VDR were not associated with five different measurements of muscle strength or physical performance (hand grip strength right and left, 6 m walking test (easy and narrow) and timed-stands test). However, one of the 7 SNPs of the gene for the VDR receptor, rs7136534, was associated with prevalence of falls (33.6% of the AA, 14.6% of the AG and 16.5% of the GG allele). In conclusion, VDR genetic variants are not related to muscle strength or physical performance in elderly Swedish men. The role of the rs7136534 SNP for the occurrence of falls is not clear.

  • 59. Björk, Anne
    et al.
    Ribom, Eva
    Johansson, Gunnar
    Scragg, Robert
    Mellström, Dan
    Grundberg, Elin
    Ohlsson, Claes
    Karlsson, Magnus
    Ljunggren, Östen
    Kindmark, Andreas
    Genetic variation in the vitamin D receptor gene is not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.Manuskript (preprint) (Övrigt vetenskapligt)
  • 60.
    Björk, Anne
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Ribom, Eva
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Johansson, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Scragg, Robert
    Section of Epidemiology & Biostatistics, School of Population Health, University of Auckland, Auckland, New Zeeland.
    Mellström, Dan
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Grundberg, Elin
    Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada.
    Ohlsson, Claes
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Magnus
    Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Malmö..
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Kindmark, Andreas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Genetic variation in the vitamin D receptor gene is not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.Manuskript (preprint) (Övrigt vetenskapligt)
  • 61.
    Björklund, Peyman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Backman, Samuel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Experimentell kirurgi.
    Epigenetics of pheochromocytoma and paraganglioma2018Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 469, s. 92-97Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors arising in the medullae of the adrenal glands or in paraganglia. The knowledge of the tumor biology of these lesions has increased dramatically during the past two decades and more than a dozen recurrently mutated genes have been identified. Different clusters have been described that share epigenetic signatures. Mutations in the succinate dehydrogenase complex subunit genes play a pivotal role in reprogramming the epigenetic state of these tumors by inhibiting epigenetic regulators such as TET enzymes and histone demethylases. Another subgroup of tumors carries hypomethylated genomes, and overexpression of several microRNAs has been described. While much remains to be investigated regarding the epigenetics of PPGLs, it is clear that it plays an important role in PPGL biology.

  • 62.
    Björklund, Peyman
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Krajisnik, Tijana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Åkerström, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Westin, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Larsson, Tobias E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Medicin.
    Type I membrane Klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism2008Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, nr 10, s. 4152-4157Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: The type I membrane protein Klotho was recently shownto mediate PTH secretion in parathyroid cells in response tolow extracellular calcium. In contrast, Klotho inhibits PTHsecretion indirectly through the action of fibroblast growthfactor-23. Abnormal Klotho expression in parathyroid disordersremains to be elucidated.

    Objective: The aim of the study was to determine: 1) Klothoexpression in parathyroid adenomas from patients with primaryhyperparathyroidism (pHPT) compared to normal tissue; and 2)its relation to the serum calcium and PTH levels.

    Design: Surgically removed parathyroid glands (n = 40) and fournormal parathyroid tissue specimens were analyzed for KlothomRNA and protein levels by quantitative real-time PCR and immunohistochemistry.In vitro effects of calcium on Klotho mRNA expression were studiedin bovine parathyroid cells.

    Results: Klotho mRNA levels were significantly decreased (n= 23) or undetectable (n = 17) in parathyroid adenomas comparedto normal tissues (P < 0.001). Reduced Klotho protein expressionwas confirmed by immunohistochemistry. Klotho mRNA levels wereinversely correlated to serum calcium (r = –0.97; P <0.0001), and calcium dose-dependently decreased Klotho mRNAexpression in normal parathyroid cells in vitro (P < 0.01).Serum calcium was the only significant marker of Klotho expressionin multivariate analysis with calcium, phosphate, PTH, and adenomaweight as independent variables.

    Conclusions: Parathyroid Klotho expression is decreased or undetectablein pHPT. We provide evidence that 1) serum calcium is stronglyassociated with parathyroid Klotho expression in pHPT; and 2)abnormal PTH secretion in hypercalcemic pHPT subjects is mediatedby Klotho-independent mechanisms.

  • 63.
    Blixt, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    The bank vole (Myodes glareolus) – a novel animal model for the study of diabetes mellitus2010Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The bank vole (Microtus arvalis) develops glucose intolerance both when kept in captivity and in the wild state. Glucose intolerant bank voles kept in captivity exhibited polydipsia, polyuria, hyperglycemia, hyperinsulinemia, islet autoantibodies and a markedly changed islet structure resembling so–called hydropic degeneration. Islets showing hydropic degeneration have reduced β–cell mass. However, the relative islet size to total pancreas area was not changed.

    Pancreatic islet isolated from glucose intolerant bank voles had an altered islet function showing signs of being exposed to an increased functional demand on their β–cells. Also, islets from male bank voles seem more affected than the islets from females. Islets isolated from glucose tolerant male bank voles cultured for 5 days at 28 mM glucose did not reveal any change in insulin gene expression or insulin biosynthesis rate. However, islets from female bank voles displayed a glucose concentration dependent response. This suggests that there is gender difference in that, islets of female more easily than islets of males adapt to elevated glucose concentration. Furthermore, islets isolated from glucose tolerant males had reduced insulin gene expression after exposure to proinflammatory cytokines for 48 hrs. This effect seemed to be NO-independent since only a minor elevation of nitrite accumulation in the medium was seen, and the use of iNOS inhibitor could not counteract the cytokine effect. The observed response seen in bank vole islets upon exposure to various glucose concentrations or proinflammatory cytokines is similar to those seen in studies of human islets. The bank vole may therefore represent a novel animal model for the study of diabetes. An unresolved issue is the role of the Ljungan virus which is found in the bank vole colony.

    Bank voles developing glucose intolerance display features of both human type 1 and type 2 diabetes, where environmental factors seems to play an important role as determinant. Our findings suggest that bank voles bred in the laboratory may develop more of a type 2 diabetes. However, bank voles caught in nature instead may rather develop a type 1 form of the disease.

    Delarbeten
    1. Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
    Öppna denna publikation i ny flik eller fönster >>Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
    2007 (Engelska)Ingår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 154, nr 1-3, s. 41-47Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Bank voles (Clethrionomys glareolus) kept in captivity develop diabetes mellitus to a significant extent. Also in wild bank voles, elevated blood glucose has been observed. A newly isolated picornavirus named Ljungan virus (LV) has been found in the pancreas of these bank voles. Moreover, LV infection in combination with environmental factors may cause glucose intolerance/diabetes (GINT/D) in normal mice. The aim of the present study was to investigate the functional characteristics of pancreatic islets, isolated from bank voles, bred in the laboratory but considered LV infected. About 20% of all males and females were classified as GINT/D following a glucose tolerance test. Of these animals the majority had become diabetic by 20 weeks of age, with a tendency towards an earlier onset in the males. GINT/D animals had increased serum insulin levels. Islets were tested on the day of isolation (day 0) and after 1 week of culture for their insulin content and their capacity to synthesize (pro)insulin, secrete insulin and metabolize glucose. Functional differences could be observed between normal and GINT/D animals as well as between genders. An elevated basal insulin secretion was observed on day 0 indicating β-cell dysfunction among islets isolated from diabetic males. In vitro culture could reverse some functional changes. The increased serum insulin level and the increased basal islet insulin secretion may suggest that the animals had developed a type 2 diabetes-like condition. It is likely that the putative stress imposed in the laboratory, maybe in combination with LV infection, can lead to an increased functional demand on the β-cells.

    Nyckelord
    Bank vole, Clethrionomys glareolus, Diabetes mellitus, Insulin release, Ljungan virus, Pancreatic islets
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-17170 (URN)10.1016/j.ygcen.2007.06.019 (DOI)000249641100006 ()17686482 (PubMedID)
    Tillgänglig från: 2008-06-17 Skapad: 2008-06-17 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. Suppression of bank vole pancreatic islet function by proinflammatory cytokines
    Öppna denna publikation i ny flik eller fönster >>Suppression of bank vole pancreatic islet function by proinflammatory cytokines
    2009 (Engelska)Ingår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 305, nr 1-2, s. 1-5Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Bank voles kept in captivity may develop diabetes. We recently characterized beta-cell function of pancreatic islets from normal and glucose intolerant/diabetic bank voles. These animals had features of both human type 1 and type 2 diabetes. Cytokines may impair β-cell function in both types of diabetes. Presently, we studied how pancreatic islets isolated from normal, i.e. glucose tolerant bank voles are affected by proinflammatory cytokines in vitro. Islets were exposed to hIL-1β (25U/ml) alone or in combination with hTNF-α (1000U/ml)+mIFN-γ (1000U/ml) for 48h, whereupon islet functions were assessed. Cytokines markedly reduced insulin gene expression and the (pro)insulin biosynthesis rate, which was accompanied by a profound depletion of the islet insulin content. The cytokines did not affect the culture medium insulin accumulation and the glucose oxidation rate, but caused a modest increase in medium nitrite, an indicator of nitric oxide (NO) generation. Cytokine-induced decrease in islet insulin content was not prevented by the preferential inducible NO synthase inhibitor aminoguanidine. These findings suggest that the reduction in islet insulin content is not attributed to enhanced exocytosis or related to altered glucose metabolism, but is rather due to a decline in insulin production. The suppressive effects of islet functions elicited by cytokines seem to be mediated by an NO-independent mechanism. In relation to previous studies on cytokine effects on islets from various species, the bank vole islets show a pattern which more resembles human islets than rat or murine islets.

    Nyckelord
    Bank vole, pancreatic islet, proinflammatory cytokines, interleukin-1β, tumor necrosis factor-α, interferon-γ
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-122700 (URN)10.1016/j.mce.2009.02.010 (DOI)000266750200001 ()19433255 (PubMedID)
    Tillgänglig från: 2010-04-16 Skapad: 2010-04-16 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    3. Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
    Öppna denna publikation i ny flik eller fönster >>Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Bank vole, pancreatic islet, glucose culture, diabetes mellitus
    Nationell ämneskategori
    Endokrinologi och diabetes Endokrinologi och diabetes
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-122713 (URN)
    Tillgänglig från: 2010-04-16 Skapad: 2010-04-16 Senast uppdaterad: 2010-05-12
    4. Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
    Öppna denna publikation i ny flik eller fönster >>Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Nyckelord
    Bank vole, hydropic degeneration, pancreatic islet, hyperinsulinemia, diabetes mellitus
    Nationell ämneskategori
    Endokrinologi och diabetes Endokrinologi och diabetes
    Forskningsämne
    Medicinsk cellbiologi
    Identifikatorer
    urn:nbn:se:uu:diva-122714 (URN)
    Tillgänglig från: 2010-04-16 Skapad: 2010-04-16 Senast uppdaterad: 2010-05-12
  • 64.
    Blixt, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Niklasson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.Manuskript (preprint) (Övrigt vetenskapligt)
  • 65.
    Blixt, Martin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Niklasson, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.Manuskript (preprint) (Övrigt vetenskapligt)
  • 66.
    Bodegard, J.
    et al.
    AstraZeneca, Sodertalje, Sweden..
    Nathanson, D.
    Karolinska Inst, Dept Clin Sci & Educa, Stockholm, Sweden..
    Nystrom, T.
    Karolinska Inst, Stockholm, Sweden..
    Thuresson, M.
    Statisticon AB, Uppsala, Sweden..
    Norhammar, A.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Second-line treatment with sulfonylurea compared to DPP4 inhibitors demonstrated associations with earlier treatment intensification with insulin2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S189-S189Artikel i tidskrift (Övrigt vetenskapligt)
  • 67. Bodei, Lisa
    et al.
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för radiologi.
    Kidd, Mark
    Prasad, Vikas
    Modlin, Irvin M
    The Status of Neuroendocrine Tumor Imaging: From Darkness to Light?2015Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, nr 1, s. 1-17Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Diagnostic imaging plays a pivotal role in the diagnosis, staging, treatment selection and follow-up for neuroendocrine tumors. The available diagnostic strategies are morphologic imaging, including computed tomography, magnetic resonance imaging (MRI) and ultrasound techniques, and molecular imaging, including scintigraphy with 111In-pentetreotide and positron emission tomography with 68Ga-DOTA-peptides, 18F-DOPA and 11C-5-HTP. A combination of anatomic and functional techniques is routinely performed to optimize sensitivity and specificity. The introduction of diffusion-weighted MRI and dynamic contrast-enhanced techniques represents a promising advance in radiologic imaging, whereas new receptor-binding peptides, including somatostatin agonists and antagonists, represent the recent most favorable innovation in molecular imaging. Future development includes the short-term validation of these techniques, but in extension also a more comprehensive multilevel integration of biologic information pertaining to a specific tumor and patient, possibly encompassing genomic considerations, currently evolving as a new entity denoted ‘precision medicine'. The ideal is a diagnostic sequence that captures the global status of an individual's tumor and encompasses a multidimensional characterization of tumor location, metabolic performance and target identification. To date, advances in imagery have focused on increasing resolution, discrimination and functional characterization. In the future, the fusion of imagery with the parallel analysis of biological and genomic information has the potential to considerably amplify diagnosis.

  • 68.
    Boersma, Greta J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johansson, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lau Börjesson, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Skrtic, S.
    AstraZeneca, R&D, Gothenburg, Sweden.;AstraZeneca, Dept Med, Gothenburg, Sweden..
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Jan W
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Glucose uptake in skeletal muscle, brain and visceral adipose tissue assessed with PET/MR strongly predicts whole body glucose uptake during hyperinsulinaemia2017Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, s. S80-S80Artikel i tidskrift (Övrigt vetenskapligt)
  • 69.
    Boersma, Greta J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johansson, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pereira, Maria J
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Heurling, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Wallenberg Centre for Molecular and Translational Medicine and the Department of Psychiatry and Neurochemistry, University of Gothenburg, Sweden.
    Skrtic, Stanko
    Lau, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Panagiotou, Grigorios
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal, Sweden.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical, Mölndal, Sweden.
    Eriksson, Jan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Altered Glucose Uptake in Muscle, Visceral Adipose Tissue, and Brain Predict Whole-Body Insulin Resistance and may Contribute to the Development of Type 2 Diabetes: A Combined PET/MR Study2018Ingår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 50, nr 8, s. 627-639Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We assessed glucose uptake in different tissues in type 2 diabetes (T2D), prediabetes, and control subjects to elucidate its impact in the development of whole-body insulin resistance and T2D. Thirteen T2D, 12 prediabetes, and 10 control subjects, matched for age and BMI, underwent OGTT and abdominal subcutaneous adipose tissue (SAT) biopsies. Integrated whole-body 18F-FDG PET and MRI were performed during a hyperinsulinemic euglycemic clamp to asses glucose uptake rate (MRglu) in several tissues. MRglu in skeletal muscle, SAT, visceral adipose tissue (VAT), and liver was significantly reduced in T2D subjects and correlated positively with M-values (r=0.884, r=0.574, r=0.707 and r=0.403, respectively). Brain MRglu was significantly higher in T2D and prediabetes subjects and had a significant inverse correlation with M-values (r=-0.616). Myocardial MRglu did not differ between groups and did not correlate with the M-values. A multivariate model including skeletal muscle, brain and VAT MRglu best predicted the M-values (adjusted r2=0.85). In addition, SAT MRglu correlated with SAT glucose uptake ex vivo (r=0.491). In different stages of the development of T2D, glucose uptake during hyperinsulinemia is elevated in the brain in parallel with an impairment in peripheral organs. Impaired glucose uptake in skeletal muscle and VAT together with elevated glucose uptake in brain were independently associated with whole-body insulin resistance, and these tissue-specific alterations may contribute to T2D development.

  • 70.
    Boersma, Greta J.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Johansson, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Pereira, Maria J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Skrtic, S.
    AstraZeneca, R&D, Gothenburg, Sweden.;Univ Gothenburg, Dept Med, Gothenburg, Sweden..
    Lau Börjesson, Joey
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Katsogiannos, Petros
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Panagiotou, G.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Jan W.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Skeletal muscle and liver, but not brain, account for impaired glucose utilisation in type 2 diabetes: whole-body PET/MR during hyperinsulinaemic euglycaemic clamp2016Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, s. S33-S33Artikel i tidskrift (Refereegranskat)
  • 71.
    Bokrantz, Tove
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg.
    Ohlsson, Claes
    Univ Gothenburg, Sahlgrenska Acad, CBAR, Gothenburg.
    Lorentzon, Mattias
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Geriatr Med, Gothenburg.
    Karlsson, Magnus
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg.
    Ljunggren, Sten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Manhem, Karin
    Univ Gothenburg, Sahlgrenska Acad, Inst Med, Dept Mol & Clin Med, Gothenburg.
    Mellstrom, Dan
    Univ Gothenburg, Dept Geriatr, Inst Med, Sahlgrenska Acad, CBAR, Gothenburg.
    Peripheral Arterial Disease Predicts Hip Fracture in Men. Results from the MrOS Sweden Study2017Ingår i: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 32, nr S1, s. S95-S95, artikel-id Meeting Abstract: FR0229Artikel i tidskrift (Övrigt vetenskapligt)
  • 72.
    Borgström, F.
    et al.
    Quantify Res, Stockholm, Sweden..
    Olafsson, G.
    Quantify Res, Stockholm, Sweden..
    Jonsson, E.
    Quantify Res, Stockholm, Sweden..
    Ström, O.
    Quantify Res, Stockholm, Sweden..
    Ljunggren, Östen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Akesson, K.
    Skane Univ Hosp, Dept Orthoped, Lund, Sweden.;Lund Univ, Clin Sci Malmo, Lund, Sweden..
    Spangeus, A.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Kanis, J. A.
    Univ Sheffield, Sch Med, Ctr Metab Bone Dis, Sheffield, S Yorkshire, England..
    A Simulation Model For The Treatment Pathway Of Osteoporosis2016Ingår i: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 27, s. S60-S60Artikel i tidskrift (Övrigt vetenskapligt)
  • 73.
    Brandhorst, Daniel
    et al.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Parnaud, Geraldine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Friberg, Andrew
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lavallard, Vanessa
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Demuylder-Mischler, Sandrine
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Hughes, Stephen
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Saphoerster, Julia
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Kurfuerst, Manfred
    SERVA Electrophoresis GmbH, Uetersen, Germany..
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Berney, Thierry
    Geneva Univ Hosp, Dept Surg, Cell Isolat & Transplantat Ctr, Geneva, Switzerland..
    Johnson, Paul R. V.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England.;Churchill Hosp, OCDEM, Oxford, England..
    Multicenter Assessment of Animal-free Collagenase AF-1 for Human Islet Isolation2017Ingår i: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 26, nr 10, s. 1688-1693Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Animal-free (AF) SERVA Collagenase AF-1 and Neutral Protease (NP) AF GMP Grade have recently become available for human islet isolation. This report describes the initial experiences of 3 different islet transplant centers. Thirty-four human pancreases were digested using 1 vial of the 6 different lots of Collagenase AF-1 (2,000-2,583 PZ-U/vial) supplemented with 4 different lots of NP AF in a range of 50 to 160 DMC-U per pancreas. Isolation, culture, and quality assessment were performed using standard techniques as previously described. All data are presented as mean +/- standard error of the mean (SEM). Variability of pancreas weight was associated with a wide range of collagenase and NP activities, ranging from 12.7 to 46.6 PZ-U/g (26.0 +/- 1.5 PZ-U/g) and 0.4 to 3.0 DMC-U/g (1.5 +/- 0.1 DMC-U/g), respectively. Postpurification islet yield was 296,494 +/- 33,620 islet equivalents (IEQ) equivalent to 3,274 +/- 450 IEQ/g with a purity of 55.9% +/- 3.2%. Quality assessment performed after 2 to 4 d of culture demonstrated a viability of 88.1% +/- 1.5% and a stimulation index of 3.7 +/- 0.7. Eighteen of the 34 preparations were transplanted into type 1 diabetic patients equivalent to a transplantation rate of 52.9%. Six preparations, which were infused into patients as first transplant, could be analyzed and increased the fasting C-peptide level from 0.11 +/- 0.08 pretransplant to 1.23 +/- 0.24 and 2.27 +/- 0.31 ng/mL 3 and 6 mo posttransplant (P < 0.05), respectively. Insulin requirements were simultaneously reduced at the same time from 39.2 +/- 3.8 IU/d before transplantation to 10.8 +/- 4.1 and 4.0 +/- 2.3 IU/d, after 3 and 6 mo posttransplant (P < 0.05), respectively. This study demonstrates the efficiency of AF SERVA Collagenase AF-1 and NP AF for clinical islet isolation and transplantation. The new plant-based production process makes these products a safe new option for the islet field.

  • 74.
    Brandhorst, Heide
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Johnson, Paul R.
    Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England;Oxford NIHR Biomed Res Ctr, Oxford, England.
    Moench, Johanna
    Nordmark Arzneimittel, Uetersen, Germany.
    Kurfuerst, Manfred
    Nordmark Arzneimittel, Uetersen, Germany.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Brandhorst, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Univ Oxford, Nuffield Dept Surg Sci, Oxford, England;Oxford Ctr Diabet Endocrinol & Metab, Oxford, England.
    Comparison of Clostripain and Neutral Protease as Supplementary Enzymes for Human Islet Isolation2019Ingår i: Cell Transplantation, ISSN 0963-6897, E-ISSN 1555-3892, Vol. 28, nr 2, s. 176-184Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although human islet transplantation has been established as valid and safe treatment for patients with type 1 diabetes, the utilization rates of human pancreases for clinical islet transplantation are still limited and substantially determined by the quality and composition of collagenase blends. While function and integrity of collagenase has been extensively investigated, information is still lacking about the most suitable supplementary neutral proteases. The present study compared islet isolation outcome after pancreas digestion by means of collagenase used alone or supplemented with either neutral protease (NP), clostripain (CP), or both proteases. Decent amounts of islet equivalents (IEQ) were isolated using collagenase alone (3090 +/- 550 IEQ/g), or in combination with NP (2340 +/- 450 IEQ/g) or CP (2740 +/- 280 IEQ/g). Nevertheless, the proportion of undigested tissue was higher after using collagenase alone (21.1 +/- 1.1%, P < 0.05) compared with addition of NP (13.3 +/- 2.2%) or CP plus NP (13.7 +/- 2.6%). Likewise, the percentage of embedded islets was highest using collagenase only (13 +/- 2%) and lowest adding NP plus CP (4 +/- 1%, P < 0.01). The latter combination resulted in lowest post-culture overall survival (42.7 +/- 3.9%), while highest survival was observed after supplementation with CP (74.5 +/- 4.8%, P < 0.01). An insulin response toward glucose challenge was present in all experimental groups, but the stimulation index was significantly decreased using collagenase plus NP (2.0 +/- 0.12) compared with supplementation with CP (3.16 +/- 0.4, P < 0.001). This study demonstrates for the first time that it is possible to isolate significant numbers of human islets combining collagenase only with CP. The supplementation with CP is an effective means to substantially reduce NP activity, which significantly decreases survival and viability after culture. This will facilitate the manufacturing of enzyme blends with less harmful characteristics.

  • 75. Brandt, A. -S
    et al.
    de Portu, S.
    Medtron Int Sarl, Tolochenaz, Switzerland..
    Hellman, Jarl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Cost savings associated with CSII therapy compared to MDI in a Swedish setting2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S477-S477Artikel i tidskrift (Övrigt vetenskapligt)
  • 76.
    Breedh, Julia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Comasco: Neuropsykofarmakologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Comasco, Erika
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Comasco: Neuropsykofarmakologi.
    Hellgren, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Papadopoulos, Fotios C.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Ekselius: Psykiatri.
    Skalkidou, Alkistis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Obstetrisk och reproduktiv hälsoforskning.
    Sundström Poromaa, Inger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktiv hälsa.
    Hypothalamic-pituitary-adrenal axis responsiveness, startle response, and sensorimotor gating in late pregnancy2019Ingår i: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 106, s. 1-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response (ASR) and the prepulse inhibition (PPI) of the startle response are neurophysiological research tools and objective measures of an individual's response to an emotional context or stressor. The ASR and PPI are influenced by psychiatric diseases characterized by anxiety symptoms and are sensitive to cortisol. Hence, the ASR and the PPI can be used to investigate the effects of pregnancy-induced endocrine changes and their contribution to affective disorders. The present study sought to investigate the association between measures of HPA-axis responsiveness, startle reactivity and sensorimotor gating during pregnancy that to date remains unknown. The eye-blink component of the ASR, and its prepulse inhibition, were measured in 107 late third trimester pregnant women. Saliva samples were collected to assess the cortisol awakening response (CAR), a measure of HPA-axis activity. Blood was sampled to measure serum levels of cortisol, cortisone and the cortisone to cortisol ratio. Ongoing anxiety disorders, sleep duration, smoking, and age were considered as potential confounders in the statistical analyses. CAR reactivity, measured as area under the curve (AUC) increase and above baseline, was positively associated with baseline startle magnitude [Cohen's d = 0.27; F (1, 105) = 4.99; p = 0.028, and Cohen's d = 0.30; F (1, 105) = 6.25; p = 0.014, respectively] as well as PPI at 86 dB [Cohen's d = 0.29; F (1, 105) = 5.93; p = 0.017; and Cohen's d = 0.34; F (1, 105) = 8.38; p = 0.005, respectively]. The observed positive correlation between startle magnitude in pregnant women and greater increase in cortisol during the awakening response may be interpreted as heightened neurophysiological reactivity, likely associated with dysregulation of the stress system.

  • 77.
    Brozzetti, Annalisa
    et al.
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Alimohammadi, Mohammad
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morelli, Silvia
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Minarelli, Viviana
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy..
    Hallgren, Asa
    Karolinska Inst, Dept Med Solna, Ctr Mol Med, S-17176 Stockholm, Sweden..
    Giordano, Roberta
    Univ Turin, Dept Med Sci, Div Endocrinol Diabetol & Metab, I-10126 Turin, Italy..
    De Bellis, Annamaria
    Univ Naples 2, Endocrinol Unit, Dept Cardiothorac & Resp Sci, I-80132 Naples, Italy..
    Perniola, Roberto
    V Fazzi Reg Hosp, Dept Pediat Neonatal Intens Care, I-73100 Lecce, Italy..
    Kämpe, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Falorni, Alberto
    Univ Perugia, Dept Internal Med, I-06126 Perugia, Italy.
    Autoantibody Response Against NALP5/MATER in Primary Ovarian Insufficiency and in Autoimmune Addison's Disease2015Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 5, s. 1941-1948Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. Objectives: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. Methods: Autoantibodies against NALP5/MATER and inhibin chains-alpha and -beta A were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. Results: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-alpha/beta A autoantibodies. Conclusions: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

  • 78.
    Brue, Thierry
    et al.
    Aix Marseille Univ, Inst Natl Sante & Rech Med INSERM, U1251, MMG, F-13005 Marseille, France;Hop Conception, AP HM, Ctr Reference Malad Rares Hypophyse HYPO, Dept Endocrinol, F-13005 Marseille, France.
    Lindberg, Anders
    Pfizer Hlth AB, Sollentuna, Sweden.
    van der Lely, Aart Jan
    Erasmus Univ MC, Dept Med, Rotterdam, Netherlands.
    Akerblad, Ann Charlotte
    Pfizer Hlth AB, Sollentuna, Sweden.
    Koltowska-Häggström, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Gomez, Roy
    Pfizer, European Med Affairs, B-1050 Brussels, Belgium.
    Droste, Michael
    Hey-Hadavi, Judith
    Pfizer Inc, Endocrine Care, New York, NY USA.
    Strasburger, Christian J.
    Campus Charite Mitte, Dept Med, Div Clin Endocrinol, Berlin, Germany.
    Camacho-Hubner, Cecilia
    Pfizer Inc, Endocrine Care, New York, NY USA.
    Diabetes in patients with acromegaly treated with pegvisomant: observations from acrostudy2019Ingår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 63, nr 3, s. 563-572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PurposeTo explore the effects of pegvisomant (PEGV) on glucose metabolism in patients with acromegaly within ACROSTUDY, an international, observational, prospective safety surveillance study.MethodsPatients were retrospectively divided into two cohorts, with (DM group) or without diabetes mellitus (no-DM). Parameters of glucose metabolism and IGF-I values were analyzed yearly both cross-sectionally for 4 years (yrs) and longitudinally at 1 and 4-5yrs of PEGV treatment.ResultsAmong 1762 patients, 510 (28.9%) had DM before PEGV start. At cross-sectional analyses, in the DM group mean blood glucose was 140.058.7mg/dl at baseline, 116.4 +/- 44.8mg/dl at year 1 and 120.0 +/- 44.3mg/dl at yr 4. Mean HbA1c was 6.6 +/- 1.2 % at yr 1 vs. 7.0 +/- 1.4 % at baseline. HbA1c was above 6.5% in 61.9% at baseline and ranged from 45.4 to 53.8% at subsequent yearly time points. At the 4-yr longitudinal analysis, in the DM group (n=109), mean blood glucose decreased by 20.2mg/dl at yr 4, mean HbA1c was 7.0 +/- 1.5% at baseline vs. 6.8 +/- 1.4%. Patients achieved IGF-I normalization in 52.1% and 57.4% of cases in the DM and no-DM groups, respectively at 1 year. The mean daily PEGV dose (mg/day) was higher in the DM group (18.2 vs. 15.3) while the absolute change of IGF-I values from baseline was similar in both groups. PEGV was well tolerated in both groups without any unexpected AEs.Conclusions p id=Par4 Patients with DM had a moderate decrease in mean fasting glucose values during PEGV treatment.

  • 79. Bruenner, Yvonne F.
    et al.
    Kofoet, Anja
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Freiherr, Jessica
    Central Insulin Administration Improves Odor-Cued Reactivation of Spatial Memory in Young Men2015Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 100, nr 1, s. 212-219Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. Objective: The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. Design: We applied a double-blind, placebo-controlled, counterbalanced within-subject design. Setting: The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled similar to 10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Results: Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. Conclusions: These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

  • 80.
    Brunner, Fabian J.
    et al.
    Univ Heart & Vasc Ctr Hamburg, Dept Cardiol, D-20246 Hamburg, Germany.
    Waldeyer, Christoph
    Univ Heart & Vasc Ctr Hamburg, Dept Cardiol, D-20246 Hamburg, Germany.
    Ojeda, Francisco
    Univ Heart & Vasc Ctr Hamburg, Dept Cardiol, D-20246 Hamburg, Germany.
    Salomaa, Veikko
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Kee, Frank
    Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland.
    Sans, Susana
    Catalan Dept Hlth, Barcelona, Spain.
    Thorand, Barbara
    German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany.
    Giampaoli, Simona
    Natl Inst Hlth ISS, Dept Cardiovasc Endocrine Metab Dis & Ageing, Rome, Italy.
    Brambilla, Paolo
    Univ Milano Bicocca, Dept Med & Surg, Milan, Italy.
    Tunstall-Pedoe, Hugh
    Univ Dundee, Cardiovasc Epidemiol Unit, Inst Cardiovasc Res, Dundee, Scotland.
    Moitry, Marie
    Univ Hosp Strasbourg, Dept Epidemiol & Publ Hlth, Strasbourg, France.
    Iacoviello, Licia
    IRCCS Neuromed, Dept Epidemiol & Prevent, Pozzilli, Italy;Univ Insubria, Dept Med & Surg, Res Ctr Epidemiol & Prevent Med, Varese, Italy.
    Veronesi, Giovanni
    Univ Insubria, Dept Med & Surg, Res Ctr Epidemiol & Prevent Med, Varese, Italy.
    Grassi, Guido
    Univ Milano Bicocca, Med Clin, Dept Med & Surg, Milan, Italy.
    Mathiesen, Ellisiv B.
    Univ Tromso, Univ Tromso Arctic, Dept Clin Med, Tromso, Norway;Univ Hosp North Norway, Dept Neurol & Neurophysiol, Tromso, Norway.
    Soderberg, Stefan
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden;Umea Univ, Ctr Heart, Umea, Sweden.
    Linneberg, Allan
    Bispebjerg & Frederiksberg Hosp, Ctr Clin Res & Prevent, Copenhagen, Denmark;Univ Copenhagen, Fac Hlth & Med Sci, Dept Clin Med, Copenhagen, Denmark.
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.
    Amouyel, Philippe
    Univ Lille, Risk Factors & Mol Determinants Aging Dis, Lille, France;INSERM, Lille, France;CHU Lille, Lille, France;Inst Pasteur, Lille, France.
    Ferrieres, Jean
    Toulouse Univ, Sch Med, Toulouse, France.
    Tamosiunas, Abdonas
    Lithuanian Univ Hlth Sci, Inst Cardiol, Kaunas, Lithuania.
    Nikitin, Yuriy P.
    Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Res Inst Internal & Prevent Med,Branch Fed Res Ct, Novosibirsk, Russia.
    Drygas, Wojciech
    Natl Inst Cardiol, Dept Epidemiol Cardiovasc Dis Prevent & Hlth Prom, Warsaw, Poland.
    Melander, Olle
    Lund Univ, Dept Clin Sci, Malmo, Sweden.
    Joeckel, Karl-Heinz
    Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
    Leistner, David M.
    Charite Berlin Univ Med, Dept Cardiol, Campus Benjamin Franklin, Berlin, Germany;German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany.
    Shaw, Jonathan E.
    Baker Heart & Diabet Inst, Melbourne, Vic, Australia.
    Panagiotakos, Demosthenes B.
    Harokopio Univ, Sch Hlth Sci & Educ, Dept Nutr & Dietet, Athens, Greece.
    Simons, Leon A.
    Univ New South Wales, Sydney, NSW, Australia;St Vincents Hosp, Sydney, NSW, Australia.
    Kavousi, Maryam
    Univ Med Ctr Rotterdam, Erasmus Med Ctr, Dept Epidemiol, Rotterdam, Netherlands.
    Vasan, Ramachandran S.
    Boston Univ, Framingham, MA USA;NHLBI, Framingham Study, Framingham, MA USA.
    Dullaart, Robin P. F.
    Univ Groningen, Dept Endocrinol, Univ Med Ctr Groningen, Groningen, Netherlands.
    Wannamethee, S. Goya
    UCL, Dept Primary Care & Populat Hlth, London, England.
    Risérus, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Klinisk nutrition och metabolism.
    Shea, Steven
    Columbia Univ, Dept Med, New York, NY USA;Columbia Univ, Dept Epidemiol, New York, NY USA.
    de Lemos, James A.
    Univ Texas Southwestern Med Ctr Dallas, Div Cardiol, Dallas, TX 75390 USA.
    Omland, Torbjorn
    Akershus Univ Hosp, Dept Cardiol, Div Med, Lorenskog, Norway;Univ Oslo, Inst Clin Med, Ctr Heart Failure Res, Oslo, Norway.
    Kuulasmaa, Kari
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Landmesser, Ulf
    Charite Berlin Univ Med, Dept Cardiol, Campus Benjamin Franklin, Berlin, Germany;German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany;Berlin Inst Hlth, Berlin, Germany.
    Blankenberg, Stefan
    Univ Heart & Vasc Ctr Hamburg, Dept Cardiol, D-20246 Hamburg, Germany;German Ctr Cardiovasc Res, Partner Site Hamburg Kiel Lubeck, Hamburg, Germany.
    Zeller, T.
    Lackner, K.
    Wild, P.
    Peters, A.
    Meisinger, C.
    Voelzke, H.
    Doerr, M.
    Nauck, M.
    Schoettker, B.
    Lorenz, T.
    Makarova, N.
    Schmidt, B.
    Klotsche, J.
    Koenig, W.
    Kontto, J.
    Mannisto, S.
    Jaaskelainen, T.
    Niiranen, T.
    Jousilahti, P.
    Metspalu, A.
    Alver, M.
    Donfrancesco, C.
    Signorini, S. G.
    Gianfagna, F.
    Costanzo, S.
    Woodward, M.
    Dobson, A.
    Giles, G.
    Hodge, A.
    Magliano, D. J.
    Wilsgaard, T.
    Lyngbakken, M. N.
    Hveem, K.
    Eliasson, M.
    Engstrom, G.
    Ingelsson, M.
    Jorgensen, T.
    Twerenbold, R.
    Dallongeville, J.
    Malyutina, S.
    Pajak, A.
    Bobak, M.
    Whincup, P.
    Pitsavos, C.
    Benjamin, E. J.
    Bakker, S. J. L.
    Ikram, M. K.
    Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium2019Ingår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 394, nr 10215, s. 2173-2183Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. Methods In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. Findings Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48.7%] women; median age 51.0 years [IQR 40.7-59.7]). 199 415 individuals were included in the derivation cohort (91 786 [48.4%] women) and 199 431 (92 269 [49.1%] women) in the validation cohort. During a maximum follow-up of 43.6 years (median 13.5 years, IQR 7.0-20.1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease eventrates for increasing non-HDL cholesterol categories (from 7.7% for non-HDL cholesterol <2.6 mmol/L to 33.7% for >= 5.7 mmol/L in women and from 12.8% to 43.6% in men; p<0.0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2.6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1.1, 95% CI 1.0-1.3 for nonHDL cholesterol 2.6 to <3.7 mmol/L to 1.9, 1.6-2.2 for >= 5.7 mmol/L in women and from 1.1, 1.0-1.3 to 2.3, 2.0-2.5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. Interpretation Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies.

  • 81.
    Bruserud, Oyvind
    et al.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Oftedal, Bergithe E.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Landegren, Nils
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Autoimmunitet. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden..
    Erichsen, Martina M.
    Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Bratland, Eirik
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Lima, Kari
    Akershus Univ Hosp, Dept Med, N-1747 Nordbyhagen, Norway.;Oslo Univ Hosp, Dept Endocrinol, N-0372 Oslo, Norway..
    Jorgensen, Anders P.
    Oslo Univ Hosp, Dept Endocrinol, N-0372 Oslo, Norway..
    Myhre, Anne G.
    Oslo Univ Hosp, Dept Pediat, N-0424 Oslo, Norway..
    Svartberg, Johan
    Univ Hosp North Norway, Div Internal Med, N-9019 Tromso, Norway.;Artic Univ Norway, Univ Tromso, Inst Clin Med, N-9019 Tromso, Norway..
    Fougner, Kristian J.
    St Olavs Hosp, Dept Endocrinol, N-7006 Trondheim, Norway..
    Bakke, Asne
    Stavanger Univ Hosp, Dept Med, N-4011 Stavanger, Norway..
    Nedrebo, Bjorn G.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haugesund Hosp, Dept Med, N-5504 Haugesund, Norway..
    Mella, Bjarne
    Ostfold Hosp, Dept Med, N-1603 Fredrikstad, Norway..
    Breivik, Lars
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Viken, Marte K.
    Oslo Univ Hosp, Dept Immunol, N-0372 Oslo, Norway.;Univ Oslo, N-0372 Oslo, Norway..
    Knappskog, Per M.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Ctr Med Genet & Mol Med, N-5021 Bergen, Norway..
    Marthinussen, Mihaela C.
    Univ Bergen, Fac Med & Dent, Dept Clin Dent, N-5021 Bergen, Norway.;Oral Hlth Ctr Expertise Western Norway, N-5021 Bergen, Norway..
    Lovas, Kristian
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    Kampe, Olle
    Karolinska Inst, Dept Med Solna, S-17176 Stockholm, Sweden..
    Wolff, Anette B.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway..
    Husebye, Eystein S.
    Univ Bergen, Dept Clin Sci, N-5012 Bergen, Norway.;Haukeland Hosp, Dept Med, N-5021 Bergen, Norway..
    A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 12016Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, nr 8, s. 2975-2983Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Autoimmune polyendocrine syndrome type 1 (APS1) is a childhood-onset monogenic disease defined by the presence of two of the three major components: hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis (CMC). Information on longitudinal follow-up of APS1 is sparse. Objective: To describe the phenotypes of APS1 and correlate the clinical features with autoantibody profiles and autoimmune regulator (AIRE) mutations during extended follow-up (1996-2016). Patients: All known Norwegian patients with APS1. Results: Fifty-two patients from 34 families were identified. The majority presented with one of the major disease components during childhood. Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. With age, most patients presented three to five disease manifestations, although some had milder phenotypes diagnosed in adulthood. Fifteen of the patients died during follow-up (median age at death, 34 years) or were deceasedsiblingswithahighprobability of undisclosed APS1. All except three had interferon-omega) autoantibodies, and allhadorgan-specific autoantibodies. The most common AIRE mutation was c.967_979del13, found in homozygosity in 15 patients. A mild phenotype was associated with the splice mutation c.879+1G>A. Primary adrenocortical insufficiency and type 1 diabetes were associated with protective human leucocyte antigen genotypes. Conclusions: Multiple presumable autoimmune manifestations, in particular hypoparathyroidism, CMC, and enamel hypoplasia, should prompt further diagnostic workup using autoantibody analyses (eg, interferon-omega) and AIRE sequencing to reveal APS1, even in adults. Treatment is complicated, and mortality is high. Structured follow-up should be performed in a specialized center.

  • 82.
    Bucci, M.
    et al.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Huovinen, V.
    Turku Univ, Turku Pet Ctr, Turku, Finland.;Turku Univ, Dept Radiol Med Imaging Ctr Southwest Finland, Turku, Finland. Turku Univ Hosp, Turku, Finland..
    Guzzardi, M. A.
    CNR, Inst Clin Physiol, PET Ctr, Pisa, Italy..
    Koskinen, S.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Raiko, J.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Lipponen, H.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Badeau, R. M.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Sarja, N.
    Turku Univ, Turku Pet Ctr, Turku, Finland..
    Salonen, M.
    Folkhalsan Res Ctr, Helsinki, Finland..
    Andersson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sandboge, S.
    Folkhalsan Res Ctr, Helsinki, Finland..
    Iozzo, P.
    CNR, Inst Clin Physiol, PET Ctr, Pisa, Italy..
    Eriksson, J. G.
    Folkhalsan Res Ctr, Helsinki, Finland.;Univ Helsinki, FIN-00014 Helsinki, Finland..
    Nuutila, P.
    Turku Univ, Turku Pet Ctr, Turku, Finland.;Univ Turku, Dept Med, SF-20500 Turku, Finland.;Turku Univ Hosp, Turku, Finland..
    Maternal obesity and telomere length associate with skeletal muscle insulin resistance which is reversed by exercise training in elderly womenM2015Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S16-S17Artikel i tidskrift (Övrigt vetenskapligt)
  • 83. Bucci, Marco
    et al.
    Huovinen, Ville
    Guzzardi, Maria Angela
    Koskinen, Suvi
    Raiko, Juho R
    Lipponen, Heta
    Ahsan, Shaila
    Badeau, Robert M
    Honka, Miikka-Juhani
    Koffert, Jukka
    Savisto, Nina
    Salonen, Minna K
    Andersson, Jonathan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Kullberg, Joel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sandboge, Samuel
    Iozzo, Patricia
    Eriksson, Johan G
    Nuutila, Pirjo
    Resistance training improves skeletal muscle insulin sensitivity in elderly offspring of overweight and obese mothers.2016Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, nr 1, s. 77-86Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS/HYPOTHESIS: Maternal obesity predisposes offspring to adulthood morbidities, including type 2 diabetes. Type 2 diabetes and insulin resistance have been associated with shortened telomere length. First, we aimed to investigate whether or not maternal obesity influences insulin sensitivity and its relationship with leucocyte telomere length (LTL) in elderly women. Second, we tested whether or not resistance exercise training improves insulin sensitivity in elderly frail women.

    METHODS: Forty-six elderly women, of whom 20 were frail offspring of lean/normal weight mothers (OLM, BMI ≤26.3 kg/m(2)) and 17 were frail offspring of overweight/obese mothers (OOM, BMI ≥28.1 kg/m(2)), were studied before and after a 4 month resistance training (RT) intervention. Muscle insulin sensitivity of glucose uptake was measured using (18)F-fluoro-2-deoxyglucose and positron emission tomography with computed tomography during a hyperinsulinaemic-euglycaemic clamp. Muscle mass and lipid content were measured using magnetic resonance and LTL was measured using real-time PCR.

    RESULTS: The OOM group had lower thigh muscle insulin sensitivity compared with the OLM group (p = 0.048) but similar whole body insulin sensitivity. RT improved whole body and skeletal muscle insulin sensitivity in the OOM group only (p = 0.004 and p = 0.013, respectively), and increased muscle mass in both groups (p < 0.01). In addition, in the OOM group, LTL correlated with different thigh muscle groups insulin sensitivity (ρ ≥ 0.53; p ≤ 0.05). Individuals with shorter LTL showed a higher increase in skeletal muscle insulin sensitivity after training (ρ ≥ -0.61; p ≤ 0.05).

    CONCLUSIONS/INTERPRETATION: Maternal obesity and having telomere shortening were associated with insulin resistance in adult offspring. A resistance exercise training programme may reverse this disadvantage among offspring of obese mothers.

    TRIAL REGISTRATION: ClinicalTrials.gov NCT01931540.

  • 84. Burman, P.
    et al.
    Mattsson, A. F.
    Johannsson, G.
    Höybye, C.
    Holmer, H.
    Dahlqvist, P.
    Berinder, K.
    Edén Engström, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Ekman, B.
    Erfurth, E. M.
    Svensson, J.
    Wahlberg, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Karlsson, F. A.
    Deaths Among Adult Patients With Hypopituitarism: Hypocortisolism During Acute Stress, and De Novo Malignant Brain Tumors Contribute to an Increased Mortality2013Ingår i: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, nr 4, s. 1466-1475Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context: Patients with hypopituitarism have an increased standardized mortality rate. The basis for this has not been fully clarified. Objective: To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up. Design and Methods: All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospectively monitored in KIMS (Pfizer International Metabolic Database) 1995-2009 were compared to general population data in the Swedish National Cause of Death Registry. In addition, events reported in KIMS, medical records, and postmortem reports were reviewed. Main Outcome Measures: Standardized mortality ratios (SMR) were calculated, with stratification for gender, attained age, and calendar year during follow-up. Results: An excess mortality was found, 120 deaths vs 84.3 expected, SMR 1.42 (95% confidence interval: 1.18-1.70). Infections, brain cancer, and sudden death were associated with significantly increased SMRs (6.32, 9.40, and 4.10, respectively). Fifteen patients, all ACTH-deficient, died from infections. Eight of these patients were considered to be in a state of adrenal crisis in connection with death (medical reports and post-mortem examinations). Another 8 patients died from de novo malignant brain tumors, 6 of which had had a benign pituitary lesion at baseline. Six of these 8 subjects had received prior radiation therapy. Conclusion: Two important causes of excess mortality were identified: first, adrenal crisis in response to acute stress and intercurrent illness; second, increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy. Both of these causes may be in part preventable by changes in the management of pituitary disease.

  • 85.
    Burman, Pia
    et al.
    Lund Univ, Skane Univ Hosp Malmo, Dept Endocrinol, S-20502 Malmo, Sweden..
    Edén-Engström, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrinologi och mineralmetabolism.
    Ekman, Bertil
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Karlsson, Anders F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk diabetologi och metabolism.
    Schwarcz, Erik
    Univ Orebro, Fac Med & Hlth, Dept Internal Med, SE-70182 Orebro, Sweden..
    Wahlberg, Jeanette
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Limited value of cabergoline in Cushing's disease: a prospective study of a 6-week treatment in 20 patients2016Ingår i: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, nr 1, s. 17-24Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Context and objective: The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after >= 1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. Design: Twenty patients (19 naive and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. Methods: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. Results: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. Conclusions: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

  • 86.
    Busse, N.
    et al.
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Paroni, F.
    Richardson, S. J.
    Univ Exeter, Sch Med, Islet Biol Exeter IBEx, Exeter, Devon, England..
    Frisk, Gun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Laiho, J. E.
    Univ Tampere, Dept Virol, Tampere, Finland..
    Oikarinen, M.
    Univ Tampere, Dept Virol, Tampere, Finland..
    Hyoty, H.
    Univ Tampere, Dept Virol, Tampere, Finland..
    Morgan, N. G.
    Univ Exeter, Sch Med, Islet Biol Exeter IBEx, Exeter, Devon, England..
    Maedler, K.
    Univ Bremen, Islet Biol Lab, Bremen, Germany..
    Detection of beta cell virus infection in type 1 diabetes by short fluorescently labelled oligonucleotide probes2016Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, s. S170-S171Artikel i tidskrift (Refereegranskat)
  • 87. Butwicka, Agnieszka
    et al.
    Frisen, Louise
    Almqvist, Catarina
    Zethelius, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lichtenstein, Paul
    Risks of Psychiatric Disorders and Suicide Attempts in Children and Adolescents With Type 1 Diabetes: A Population-Based Cohort Study2015Ingår i: Diabetes Care, ISSN 0149-5992, E-ISSN 1935-5548, Vol. 38, nr 3, s. 453-459Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE To assess the risk of psychiatric disorders and suicide attempts in children with type 1 diabetes and their healthy siblings. RESEARCH DESIGN AND METHODS We performed a population-based case-cohort study of individuals born in Sweden between 1973 and 2009. Children with type 1 diabetes (n = 17,122) and their healthy siblings (n = 18,847) were identified and followed until their 18th birthday. Their risk of psychiatric disorders was compared with that of matched control subjects. RESULTS The risk of psychiatric morbidity in children with type 1 diabetes compared with the general population was tripled within 6 months after the onset of diabetes (hazard ratio [HR] 3.0 [95% CI 2.7-3.4]) and doubled within the total observation period (HR 2.1 [95% CI 2.0-2.2]). An increased risk was noted in suicide attempts (HR 1.7 [95% CI 1.4-2.0]) and in most categories of psychiatric disorders. The risk of psychiatric disorders in probands declined from HR 2.7 (95% CI 2.2-3.3) for those in the cohort born 1973-1986 to 1.9 (95% CI 1.8-2.0) in those born 1997-2009. The risk for any psychiatric disorders among siblings of patients with type 1 diabetes was estimated to be HR 1.1 (95% CI 1.0-1.1), and there was no increased risk in any of the specific category of disorders. CONCLUSIONS Children with type 1 diabetes are at high risk of psychiatric disorders, which seems to be a consequence of the disease rather than due to a common familial etiology. The results support recommendations on comprehensive mental health surveillance in children with type 1 diabetes, especially in recently diagnosed children.

  • 88. Byberg, L
    et al.
    Siegbahn, A
    Berglund, L
    McKeigue, P
    Reneland, R
    Lithell, H
    Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglycerides in 70-year-old men.1998Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 18, nr 2, s. 258-64Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been discussed as a part of the insulin resistance syndrome. However, it is not clear whether the relationship between PAI-1 and insulin resistance is independent of or mediated by increased triglycerides levels. The aim of this study was to investigate whether PAI-1 activity is associated with insulin sensitivity independently of serum triglycerides (sTG) and of other potential confounders. Seventy-year-old men (n=871), participating in a cohort study undergoing extensive metabolic investigations, had blood samples taken for determination of PAI-1 activity. Insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp. In multivariate correlation and regression analyses, insulin sensitivity was a statistically significant determinant of PAI-1 activity (partial r=-.12; P<.001), independent of sTG, body mass index, waist-hip ratio, and other potential confounders. The levels of sTG were also independently related to PAI-1 activity (partial r=.18; P<.001). The relationships between PAI-1 and insulin sensitivity and sTG were independent of fasting glucose levels. Aggregation of risk factors of the insulin resistance syndrome was associated with increased activity of PAI-1 in men with normal glucose tolerance. We conclude that PAI-1 activity is related to insulin sensitivity and sTG, independently of each other and of other potential confounders, and that increased levels of PAI-1 should be regarded as a component of the insulin resistance syndrome.

  • 89.
    Bysani, Madhusudhan
    et al.
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Agren, Rasmus
    Chalmers Univ Technol, Sci Life Lab, Natl Bioinformat Infrastruct Sweden, Dept Biol & Biol Engn, Gothenburg, Sweden.
    Davegardh, Cajsa
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Volkov, Petr
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Ronn, Tina
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Unneberg, Per
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Molekylär evolution. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bacos, Karl
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    Ling, Charlotte
    Lund Univ, Scania Univ Hosp, Diabet Ctr, Dept Clin Sci,Epigenet & Diabet Unit, Malmo, Sweden.
    ATAC-seq reveals alterations in open chromatin in pancreatic islets from subjects with type 2 diabetes2019Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikel-id 7785Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Impaired insulin secretion from pancreatic islets is a hallmark of type 2 diabetes (T2D). Altered chromatin structure may contribute to the disease. We therefore studied the impact of T2D on open chromatin in human pancreatic islets. We used assay for transposase-accessible chromatin using sequencing (ATAC-seq) to profile open chromatin in islets from T2D and non-diabetic donors. We identified 57,105 and 53,284 ATAC-seq peaks representing open chromatin regions in islets of nondiabetic and diabetic donors, respectively. The majority of ATAC-seq peaks mapped near transcription start sites. Additionally, peaks were enriched in enhancer regions and in regions where islet-specific transcription factors (TFs), e.g. FOXA2, MAFB, NKX2.2, NKX6.1 and PDX1, bind. Islet ATAC-seq peaks overlap with 13 SNPs associated with T2D (e.g. rs7903146, rs2237897, rs757209, rs11708067 and rs878521 near TCF7L2, KCNQ1, HNF1B, ADCY5 and GCK, respectively) and with additional 67 SNPs in LD with known T2D SNPs (e.g. SNPs annotated to GIPR, KCNJ11, GLIS3, IGF2BP2, FTO and PPARG). There was enrichment of open chromatin regions near highly expressed genes in human islets. Moreover, 1,078 open chromatin peaks, annotated to 898 genes, differed in prevalence between diabetic and non-diabetic islet donors. Some of these peaks are annotated to candidate genes for T2D and islet dysfunction (e.g. HHEX, HMGA2, GLIS3, MTNR1B and PARK2) and some overlap with SNPs associated with T2D (e.g. rs3821943 near WFS1 and rs508419 near ANK1). Enhancer regions and motifs specific to key TFs including BACH2, FOXO1, FOXA2, NEUROD1, MAFA and PDX1 were enriched in differential islet ATAC-seq peaks of T2D versus non-diabetic donors. Our study provides new understanding into how T2D alters the chromatin landscape, and thereby accessibility for TFs and gene expression, in human pancreatic islets.

  • 90.
    Caballero-Corbalán, José
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Islet Transplantation a Technical Challenge: Studies on Human Pancreas Preservation and Enzymatic Digestion2011Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Islet transplantation has found its niche in diabetes treatment. It has contributed to a better quality of life and better glycemic control of patients with diabetes suffering from severe hypoglycemia that are not eligible for vascularized pancreas transplantation. Islet isolation is a technically challenging procedure. The different studies within this doctoral thesis aim to improve and standardize different steps in the isolation procedure. They are in particular looking to improve human pancreas preservation during cold storage, to optimize islet release from the exocrine tissue and to assess whether the isolated islet yield can be predicted from a biopsy.

    We found that pancreas preservation with pre-oxygenated perfluorodecalin (two-layer method) did not improve the ischemic tolerance of the human pancreas as compared to cold storage with the University of Wisconsin (UW) solution. Furthermore, in pancreas with long cold ischemia time (CIT) (>10 hours), Histidine-Tryptophan-Ketoglutarate (HTK) had a limited preservation capacity as compared with the UW solution with respect to isolation outcome. We also found that during enzymatic pancreas digestion, Vitacyte HA was able to provide a similar islet yield and quality as Serva NB1 with less collagenase activity and shorter digestion time. We further describe the first experience with a new GMP manufactured enzyme called Liberase MTF-S for successful human islet isolation. Finally, we found that the isolated islet yield could not be predicted from a biopsy taken from the head of the pancreas concerning solely morphological parameters of the islets tissue.

    The improvement of pancreas preservation will allow for marginal organs with prolonged cold ischemia time to expand the donor pool. Better knowledge of how the pancreatic extracellular matrix is digested by collagenase will lead to a fast and predictable islet release from the exocrine tissue. By standardizing the isolation procedure and improving organ selection we will increase the success rate in human islet isolation, thereby making islet transplantation available for more patients.

    Delarbeten
    1. No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation
    Öppna denna publikation i ny flik eller fönster >>No beneficial effect of two-layer storage compared with UW-storage on human islet isolation and transplantation
    Visa övriga...
    2007 (Engelska)Ingår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 84, nr 7, s. 864-869Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Background. Shipment of pancreata between distant centers is frequently associated with prolonged cold ischemia time (CIT) that leads to poorer outcomes for islet transplantation. Clinical pilot trials have indicated that oxygenation of explanted human pancreata utilizing the two-layer method (TLM) allows the use of marginal donor pancreata for islet transplantation. The present study aimed to clarify whether TLM enhances the ischemic tolerance of human pancreata. Methods. We analyzed retrospectively the outcome of 200 human islet isolations performed after TLM preservation or storage in University of Wisconsin solution (UWS). Results. Donor characteristics and digestion parameters did not vary significantly between TLM-preserved and UWS-stored pancreata. No differences were observed between experimental groups with regard to islet yield, purity, or dynamic glucose stimulation index after either short or prolonged CIT. However, CIT and stimulation index were negatively correlated in each experimental group. The isolation outcome in donors aged ≥60 years was not increased after TLM preservation when compared to UWS storage. No effect was observed regarding islet posttransplant function in recipients with established kidney grafts. Conclusions. The present study suggests that the ischemic tolerance of human pancreata cannot be extended by TLM preservation. In addition, TLM does not seem to improve the isolation outcome for pancreata from elderly donors.

    Nyckelord
    Clinical islet transplantation, Cold storage, Marginal donors, Two-layer method
    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-16849 (URN)10.1097/01.tp.0000284584.60600.ab (DOI)000250232600010 ()17984839 (PubMedID)
    Tillgänglig från: 2008-06-05 Skapad: 2008-06-05 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    2. Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation
    Öppna denna publikation i ny flik eller fönster >>Using HTK for Prolonged Pancreas Preservation Prior to Human Islet Isolation
    Visa övriga...
    2012 (Engelska)Ingår i: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 175, nr 1, s. 163-168Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) has been established as an alternative to University-of-Wisconsin solution (UWS) for abdominal organ preservation, but data about HTK efficiency to preserve pancreata during prolonged cold ischemia time (CIT) are conflicting. In human islet transplantation, HTK provided similar isolation outcomes after short CIT. The present study aimed to investigate whether islets can be successfully isolated from HTK-preserved pancreata after prolonged CIT compared with UWS.

    MATERIALS AND METHODS: Sixty-four human pancreata retrieved from donors meeting criteria for kidney donation were perfused utilizing either HTK or UWS and preserved for more or less than 10 h prior to islet isolation. Along with parameters related to isolation and islet quality assessment, the dry-to-wet weight ratio was evaluated.

    RESULTS: Donor- and procurement-related factors did not vary between HTK- and UWS-perfused pancreata. The dry-to-wet weight ratio was lower in HTK-preserved pancreata indicated tissue edema (21.0% ± 3.5% versus 24.8% ± 2.0%, P = 0.007). Isolation-related variables differed between experimental groups after prolonged CIT with respect to purified packed tissue volume (9.1 ± 5.0 versus 17.2 ± 8.1 μL/g, P = 0.004) and islet yield (1910 ± 980 versus 3150 ± 1420 IE/g, P = 0.012). Islet purity and survival after culture were similar after HTK or UWS perfusion. The preservation solution did not affect in vitro function and transplantability of isolated islets.

    CONCLUSIONS: Compared with UWS, HTK has similar efficiency to preserve human pancreata for subsequent islet isolation during <10 h CIT but seems to be limited for prolonged cold storage.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-156890 (URN)10.1016/j.jss.2011.03.012 (DOI)000303472500031 ()21550052 (PubMedID)
    Tillgänglig från: 2011-08-10 Skapad: 2011-08-10 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
    3. Vitacyte Collagenase HA: A Novel Enzyme Blend for Efficient Human Islet Isolation
    Öppna denna publikation i ny flik eller fönster >>Vitacyte Collagenase HA: A Novel Enzyme Blend for Efficient Human Islet Isolation
    Visa övriga...
    2009 (Engelska)Ingår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 88, nr 12, s. 1400-1402Artikel i tidskrift, Letter (Refereegranskat) Published
    Nationell ämneskategori
    Kirurgi Medicin och hälsovetenskap
    Forskningsämne
    Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-111858 (URN)10.1097/TP.0b013e3181bd1441 (DOI)000273200000013 ()20029339 (PubMedID)
    Anmärkning

    Letter. Authors were listed in the wrong order in the original publication (erratum in Transplantation, 2010, vol. 89, issue 7, p. 907)

    Tillgänglig från: 2009-12-28 Skapad: 2009-12-28 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
    4. Mammalian Tissue-Free Liberase: A New GMP-Graded Enzyme Blend for Human Islet Isolation
    Öppna denna publikation i ny flik eller fönster >>Mammalian Tissue-Free Liberase: A New GMP-Graded Enzyme Blend for Human Islet Isolation
    Visa övriga...
    2010 (Engelska)Ingår i: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 90, nr 3, s. 332-333Artikel i tidskrift, Letter (Refereegranskat) Published
    Nationell ämneskategori
    Kirurgi
    Identifikatorer
    urn:nbn:se:uu:diva-135881 (URN)10.1097/TP.0b013e3181e117e3 (DOI)000280581200020 ()
    Tillgänglig från: 2010-12-13 Skapad: 2010-12-09 Senast uppdaterad: 2019-01-24Bibliografiskt granskad
    5. Predicting the outcome of human islet isolation
    Öppna denna publikation i ny flik eller fönster >>Predicting the outcome of human islet isolation
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background. Islet transplantation is currently being explored as a possible treatment to diabetes mellitus. Islet isolation from the human pancreas is a technically demanding process and the success rate even in the most experienced GMP facilities is only about 50%. The aim of this study was to investigate whether isolation outcome can be predicted from a pancreas biopsy taken during organ procurement.

    Methods. The outcome of 29 human islet isolations was retrospectively studied. Biopsies from the pancreatic head were immunostained for insulin to study islet morphology and size distribution utilizing a digital analysis system. Isolations were categorized as successful if they yielded more than 2000 IE/g. 

    Results. Pellet volume after collagenase digestion and islet purity was higher in the successful group. None of the morphology variables, i.e. islet number (IN/mm2), islet equivalent number (IE/IN) and percentage of insulin positive area in the biopsy, differed significantly between the study groups.

    Conclusions. No single morphological feature observed in a biopsy taken from the head of pancreas can predict the outcome of islet isolation from the human pancreas, even if using the same enzyme blend in standardized human islet isolation procedure.

    Identifikatorer
    urn:nbn:se:uu:diva-156891 (URN)
    Tillgänglig från: 2011-08-10 Skapad: 2011-08-10 Senast uppdaterad: 2011-11-03
  • 91. Calissendorff, Jan
    et al.
    Maret, Eva
    Sundin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap.
    Falhammar, Henrik
    Ileal neuroendocrine tumors and heart: not only valvular consequences2015Ingår i: Endocrine (Basingstoke), ISSN 1355-008X, E-ISSN 1559-0100, Vol. 48, nr 3, s. 743-755Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Ileal neuroendocrine tumors (NETs) often progress slowly, but because of their generally nonspecific symptoms, they have often metastasized to local lymph nodes and to the liver by the time the patient presents. Biochemically, most of these patients have increased levels of whole blood serotonin, urinary 5-hydroxyindoleacetic acid, and chromogranin A. Imaging work-up generally comprises computed tomography or magnetic resonance imaging and somatostatin receptor scintigraphy, or in recent years positron emission tomography with Ga-68-labeled somatostatin analogs, allowing for detection of even sub-cm lesions. Carcinoid heart disease with affected leaflets, mainly to the right side of the heart, is a well-known complication and patients routinely undergo echocardiography to diagnose and monitor this. Multitasking surgery is currently recognized as first-line treatment for ileal NETs with metastases and carcinoid heart disease. Open heart surgery and valve replacement are advocated in patients with valvular disease and progressive heart failure. When valvulopathy in the tricuspid valve results in right-sided heart failure, a sequential approach, performing valve replacement first before intra-abdominal tumor-reductive procedures are conducted, reduces the risk of bleeding. Metastases to the myocardium from ileal NETs are seen in <1-4.3% of patients, depending partly on the imaging technique used, and are generally discovered in those affected with widespread disease. Systemic treatment with somatostatin analogs, and sometimes alpha interferon, is first-line medical therapy in metastatic disease to relieve hormonal symptoms and stabilize the tumor. This treatment is also indicated when heart metastases are detected, with the addition of diuretics and fluid restriction in cases of heart failure. Myocardial metastases are rarely treated by surgical resection.

  • 92.
    Capdevila, Jaume
    et al.
    Vall Hebron Univ Hosp, VHIO, Barcelona, Spain.
    Bodei, Lisa
    Mem Sloan Kettering Canc Ctr, New York, NY USA.
    Davies, Philippa
    Royal Free Hosp, Neuroendocrine Tumour Unit, London, England.
    Gorbounova, Vera
    Inst Russian Acad Med Sci, Dept Oncol, Moscow, Russia.
    Jensen, Robert T.
    NIH, Bethesda, MD USA.
    Knigge, Ulrich P.
    Univ Copenhagen, Dept Surg, Copenhagen, Denmark.
    Krejs, Guenter J.
    Med Univ Graz, Graz, Austria.
    Krenning, Eric
    Erasmus MC, Cyclotron Rotterdam BV, Rotterdam, Netherlands.
    O'Connor, Juan Manuel
    Alexander Fleming Inst, Caba, Argentina.
    Peeters, Marc
    Antwerp Univ Hosp, Dept Oncol, Antwerp, Belgium.
    Rindi, Guido
    Univ Cattolica Sacro Cuore, Fdn Policlin Univ A Gemelli IRCCS Roma, Rome, Italy.
    Salazar, Ramon
    Catalan Inst Oncol, Oncobell Program, IDIBELL, Cerca,Ciberonc, Barcelona, Spain.
    Vullierme, Marie-Pierre
    Beaujon Hop Assistance Publ, Radiol Dept, Paris, France.
    Pavel, Marianne E.
    Friedrich Alexander Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Erlangen, Germany.
    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 Metastatic Lung and Digestive Neuroendocrine Neoplasms2019Ingår i: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 108, nr 1, s. 18-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Unmet medical needs are not infrequent in oncology, and these needs are usually of higher magnitude in rare cancers. The field of neuroendocrine neoplasms (NENs) has evolved rapidly during the last decade, and, currently, a new WHO classification is being implemented and several treatment options are available in the metastatic setting after the results of prospective phase III clinical trials. However, several questions are still unanswered, and decisions in our daily clinical practice should be made with limited evidence. In the 2016 meeting of the advisory board of the European Neuroendocrine Tumor Society (ENETS), the main unmet medical needs in the metastatic NENs setting were deeply discussed, and several proposals to try to solve them are presented in this article, including biomarkers, imaging, and therapy.

  • 93. Cardoso, Joao C. R.
    et al.
    Larhammar, Dan
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Farmakologi.
    Comparative evolution of peptide hormone-binding GPCRs: A route to understanding functional complexity2014Ingår i: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 209, nr SI, s. 1-2Artikel i tidskrift (Övrigt vetenskapligt)
  • 94.
    Carlbom, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Espes, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes2016Ingår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, nr 9, s. 1968-1972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS/HYPOTHESIS: The aim of this study was to investigate pancreatic perfusion and its response to a glucose load in patients with type 1 diabetes mellitus compared with non-diabetic ('healthy') individuals.

    METHODS: Eight individuals with longstanding type 1 diabetes and ten sex-, age- and BMI-matched healthy controls underwent dynamic positron emission tomography scanning with (15)O-labelled water before and after intravenous administration of glucose. Perfusion in the pancreas was measured. Portal and arterial hepatic perfusion were recorded as references.

    RESULTS: Under fasting conditions, total pancreatic perfusion was on average 23% lower in the individuals with diabetes compared with healthy individuals. Glucose increased total pancreatic and portal hepatic blood perfusion in healthy individuals by 48% and 38%, respectively. In individuals with diabetes there was no significant increase in either total pancreatic or portal hepatic perfusion.

    CONCLUSIONS/INTERPRETATION: Individuals with type 1 diabetes have reduced basal pancreatic perfusion and a severely impaired pancreatic and splanchnic perfusion response to intravenous glucose stimulation.

  • 95.
    Carlbom, Lina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Espes, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Martinell, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Allmänmedicin och preventivmedicin.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    [(11)C]5-Hydroxy-Tryptophan PET for Assessment of Islet Mass During Progression of Type 2 Diabetes2017Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, nr 5, s. 1286-1292Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    [(11)C]5-hydroxy-tryptophan ([(11)C]5-HTP) PET of the pancreas has been shown to be a surrogate imaging biomarker of pancreatic islet mass. The change in islet mass in different stages of type 2 diabetes (T2D) as measured by non-invasive imaging is currently unknown. Here, we describe a cross-sectional study where subjects at different stages of T2D development with expected stratification of pancreatic islet mass were examined in relation to non-diabetic individuals. The primary outcome was the [(11)C]5-HTP uptake and retention in pancreas, as a surrogate marker for the endogenous islet mass.We found that metabolic testing indicated a progressive loss of beta cell function, but that this was not mirrored by a decrease in [(11)C]5-HTP tracer accumulation in the pancreas. This provides evidence of retained islet mass despite decreased beta cell function. The results herein indicates that beta cell dedifferentiation, and not necessarily endocrine cell loss, constitute a major cause of beta cell failure in T2D.

  • 96.
    Carlsen, Esben Andreas
    et al.
    Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark;Univ Copenhagen, Dept Biomed Sci, Cluster Mol Imaging, Copenhagen, Denmark.
    Fazio, Nicola
    European Inst Oncol IRCCS, Div Gastrointestinal Med Oncol & Neuroendocrine T, IEO, Milan, Italy.
    Granberg, Dan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Grozinsky-Glasberg, Simona
    Hadassah Hebrew Univ, Dept Endocrinol & Metab, Neuroendocrine Tumor Unit, Med Ctr, Jerusalem, Israel.
    Ahmadzadehfar, Hojjat
    Univ Hosp Bonn, Dept Nucl Med, Bonn, Germany.
    Grana, Chiara Maria
    European Inst Oncol IRCCS, Div Nucl Med, IEO, Milan, Italy.
    Zandee, Wouter T.
    Erasmus MC, Rotterdam, Netherlands.
    Cwikla, Jaroslaw
    Univ Warmia & Mazury, Med Sch, Olsztyn, Poland.
    Walter, Martin A.
    Univ Hosp Geneva, Dept Nucl Med, Geneva, Switzerland.
    Oturai, Peter Sandor
    Rigshosp, Dept Clin Physiol Nucl Med & PET, Copenhagen, Denmark.
    Rinke, Anja
    Univ Hosp Giess & Marburg, Dept Gastroenterol, Marburg, Germany.
    Weaver, Andrew
    Churchill Hosp, Dept Oncol, Oxford, England.
    Frilling, Andrea
    Imperial Coll London, Dept Surg & Canc, London, England.
    Gritti, Sara
    European Inst Oncol IRCCS, Div Gastrointestinal Med Oncol & Neuroendocrine T, IEO, Milan, Italy.
    Arveschoug, Anne Kirstine
    Aarhus Univ Hosp, Dept Nucl Med & PET, Aarhus, Denmark.
    Meirovitz, Amichay
    Hadassah Hebrew Univ, Med Ctr, Dept Oncol, Jerusalem, Israel;Hadassah Hebrew Univ, Med Ctr, Radiat Therapy Unit, Jerusalem, Israel.
    Knigge, Ulrich
    Univ Copenhagen, Dept Biomed Sci, Cluster Mol Imaging, Copenhagen, Denmark;Rigshosp, Dept Surg Gastroenterol, Copenhagen, Denmark;Rigshosp, Dept Clin Endocrinol, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study2019Ingår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, nr 2, s. 227-239Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 >= 55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

  • 97.
    Carlsson, Axel C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden..
    Östgren, C. J.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Lanne, T.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nyström, F. H.
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. Dalarna Univ, Sch Hlth & Social Studies, Falun, Sweden..
    The association between endostatin and kidney disease and mortality in patients with type 2 diabetes2016Ingår i: Diabetes & Metabolism, ISSN 1262-3636, E-ISSN 1878-1780, Vol. 42, nr 5, s. 351-357Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim. - Circulating endostatin, a biologically active derivate of collagen XVIII, is considered to be a marker of kidney disease and a risk factor for its related mortality. However, less is known of the role of endostatin in diabetes and the development of diabetic nephropathy. For this reason, our study investigated the associations between circulating endostatin and the prevalence and progression of kidney disease, and its mortality risk in patients with type 2 diabetes (T2D). Methods. - This was a cohort study of 607 patients with T2D (mean age: 61 years, 44% women). Estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, was used to assess the patients' kidney function decline and mortality. Results. - Of the total study cohort, 20 patients declined by >= 20% in eGFR over 4 years, and 44 died during the follow-up (mean duration: 6.7 years). At baseline, participants with diabetic nephropathy (defined as eGFR < 60 mL/min/1.73 m(2)) and/or microalbuminuria [defined as a urinary albumin-to-creatinine ratio (ACR) > 3 g/mol] had higher median levels of endostatin than those without nephropathy (62.7 mu g/L vs 57.4 mu g/L, respectively; P = 0.031). In longitudinal analyses adjusted for age, gender, baseline eGFR and ACR, higher endostatin levels were associated with a higher risk of decline (>= 20% in eGFR, OR per 1 SD increase: 1.73, 95% CI: 1.13-2.65) and a higher risk of mortality (HR per 1 SD increase: 1.57, 95% CI: 1.19-2.07). Conclusion. - In patients with T2D, circulating endostatin levels can predict the progression of kidney disease and mortality independently of established kidney disease markers. The clinical usefulness of endostatin as a risk marker in such patients merits further studies.

  • 98.
    Carlsson, Axel C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Östgren, Carl Johan
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Nystrom, Fredrik H
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Länne, Toste
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Jennersjö, Pär
    Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Ärnlöv, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Association of soluble tumor necrosis factor receptors 1 and 2 with nephropathy, cardiovascular events, and total mortality in type 2 diabetes2016Ingår i: Cardiovascular Diabetology, ISSN 1475-2840, E-ISSN 1475-2840, Vol. 15, artikel-id 40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS/HYPOTHESIS: Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and sTNFR2) contribute to experimental diabetic kidney disease, a condition with substantially increased cardiovascular risk when present in patients. Therefore, we aimed to explore the levels of sTNFRs, and their association with prevalent kidney disease, incident cardiovascular disease, and risk of mortality independently of baseline kidney function and microalbuminuria in a cohort of patients with type 2 diabetes. In pre-defined secondary analyses we also investigated whether the sTNFRs predict adverse outcome in the absence of diabetic kidney disease.

    METHODS: The CARDIPP study, a cohort study of 607 diabetes patients [mean age 61 years, 44 % women, 45 cardiovascular events (fatal/non-fatal myocardial infarction or stroke) and 44 deaths during follow-up (mean 7.6 years)] was used.

    RESULTS: Higher sTNFR1 and sTNFR2 were associated with higher odds of prevalent kidney disease [odd ratio (OR) per standard deviation (SD) increase 1.60, 95 % confidence interval (CI) 1.32-1.93, p < 0.001 and OR 1.54, 95 % CI 1.21-1.97, p = 0.001, respectively]. In Cox regression models adjusting for age, sex, glomerular filtration rate and urinary albumin/creatinine ratio, higher sTNFR1 and sTNFR2 predicted incident cardiovascular events [hazard ratio (HR) per SD increase, 1.66, 95 % CI 1.29-2.174, p < 0.001 and HR 1.47, 95 % CI 1.13-1.91, p = 0.004, respectively]. Results were similar in separate models with adjustments for inflammatory markers, HbA1c, or established cardiovascular risk factors, or when participants with diabetic kidney disease at baseline were excluded (p < 0.01 for all). Both sTNFRs were associated with mortality.

    CONCLUSIONS/INTERPRETATIONS: Higher circulating sTNFR1 and sTNFR2 are associated with diabetic kidney disease, and predicts incident cardiovascular disease and mortality independently of microalbuminuria and kidney function, even in those without kidney disease. Our findings support the clinical utility of sTNFRs as prognostic markers in type 2 diabetes.

  • 99.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Espes, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Transplantation och regenerativ medicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sedigh, Amir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Transplantationskirurgi.
    Rotem, Avi
    Zimermann, Baruch
    Grinberg, Helena
    Goldman, Tali
    Barkai, Uriel
    Avni, Yuval
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Carlbom, Lina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Antaros Medical AB, Mölndal, Sweden.
    Eriksson, Olof
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi.
    Olerud, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Transplantation of macroencapsulated human islets within the bioartificial pancreas βAir to patients with type 1 diabetes mellitus2018Ingår i: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, nr 7, s. 1735-1744Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Macroencapsulation devices provide the dual possibility to immunoprotect transplanted cells while also being retrievable; the latter bearing importance for safety in future trials with stem-cell derived cells. However, macroencapsulation entails a problem with oxygen supply to the encapsulated cells. The βAir device solves this with an incorporated refillable oxygen tank. This phase 1 study evaluated the safety and efficacy of implanting the βAir device containing allogeneic human pancreatic islets to patients with type 1 diabetes. Four patients were transplanted with 1-2 βAir devices, each containing 155000-180000 IEQ (i.e. 1800-4600 IEQ per kg body weight), and monitored for 3-6 months, followed by the recovery of devices. Implantation of the βAir device was safe and successfully prevented immunization and rejection of the transplanted tissue. However, although beta cells survived in the device, only minute levels of circulating C-peptide were observed with no impact on metabolic control. Fibrotic tissue with immune cells was formed in capsule surroundings. Recovered devices displayed a blunted glucose-stimulated insulin response, and amyloid formation in the endocrine tissue. We conclude that the βAir device is safe and can support survival of allogeneic islets for several months, although the function of the transplanted cells was limited.

  • 100.
    Carlsson, Per-Ola
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Disruption of Insulin Receptor Signaling in Endothelial Cells Shows the Central Role of an Intact Islet Blood Flow for In Vivo beta-Cell Function2015Ingår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, nr 3, s. 700-702Artikel i tidskrift (Övrigt vetenskapligt)
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