| 1. |
- Friederich, Malou, 1983-, et al.
(author)
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Identification and distribution of uncoupling protein isoforms in the normal and diabetic rat kidney
- 2009
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In: Advances in Experimental Medicine and Biology. - New York : Springer. - 0065-2598 .- 2214-8019. - 9780387859972 ; 645, s. 205-212
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Journal article (peer-reviewed)abstract
- Uncoupling protein (UCP)-2 and -3 are ubiquitously expressed throughout the body but there is currently no information regarding the expression and distribution of the different UCP isoforms in the kidney. Due to the known cross-reactivity of the antibodies presently available for detection of UCP-2 and -3 proteins, we measured the mRNA expression of UCP-1, -2 and -3 in the rat kidney in order to detect the kidney-specific UCP isoforms. Thereafter, we determined the intrarenal distribution of the detected UCP isoforms using immunohistochemistry. Thereafter, we compared the protein levels in control and streptozotocin-induced diabetic rats using Western blot. Expressions of the UCP isoforms were also performed in brown adipose tissue and heart as positive controls for UCP-1 and 3, respectively. UCP-2 mRNA was the only isoform detected in the kidney. UCP-2 protein expression in the kidney cortex was localized to proximal tubular cells, but not glomerulus or distal nephron. In the medulla, UCP-2 was localized to cells of the medullary thick ascending loop of Henle, but not to the vasculature or parts of the nephron located in the inner medulla. Western blot showed that diabetic kidneys have about 2.5-fold higher UCP-2 levels compared to controls. In conclusion, UCP-2 is the only isoform detectable in the kidney and UCP-2 protein can be detected in proximal tubular cells and cells of the medullary thick ascending loop of Henle. Furthermore, diabetic rats have increased UCP-2 levels compared to controls, but the mechanisms underlying this increase and its consequences warrants further studies.
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| 2. |
- Johansson, Magnus, 1976-, et al.
(author)
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Prolactin treatment improves engraftment and function of transplanted pancreatic islets
- 2009
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In: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 150:4, s. 1646-1653
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Journal article (peer-reviewed)abstract
- Transplantation of pancreatic islets is clinically used to treat type 1 diabetes, but requires multiple donors. Previous experimental studies have demonstrated that transplanted islets have a low blood vessel density, which leads to a hypoxic microenvironment. The present study tested the hypothesis that experimental prolactin pretreatment, a substance which seems to stimulate angiogenesis in endogenous islets, would increase graft blood vessel density, thereby improving transplantation outcome. Pancreatic islets from C57BL/6 mice were incubated with prolactin (500 ng/ml) or vehicle during the last 24 h of culture before syngeneic transplantation beneath the renal capsule, or recipients were injected with prolactin or vehicle for the first 7 days after transplantation. One month post-transplantation, graft vascular density, blood flow, oxygen tension, endocrine volume and function was evaluated. Also human islets were incubated with prolactin or vehicle before experimental transplantation and investigated for vascular engraftment. Vascular engraftment of syngeneically transplanted mouse islets was improved by both in vivo and in vitro prolactin pretreatment. Moreover, prolactin pretreatment in vitro of islets used for transplantation improved recovery from diabetes in a minimal islet mass model. Interestingly, also human islets subjected to prolactin treatment before experimental transplantation demonstrated improved revascularization, blood perfusion and oxygen tension when evaluated one month post-transplantation. We conclude that prolactin may improve engraftment of transplanted pancreatic islets. The protocol with pretreatment of islets ex vivo could minimize the risk of side effects when used in the clinical setting.
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| 3. |
- Johansson, Åsa, 1981-, et al.
(author)
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Angiostatic factors normally restrict islet endothelial cell proliferation and migration : implications for islet transplantation
- 2009
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In: Transplant International. - : Frontiers Media SA. - 0934-0874 .- 1432-2277. ; 22:12, s. 1182-1188
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Journal article (peer-reviewed)abstract
- New blood vessel formation in transplanted islets occurs within 7-14 days posttransplantation through both the expansion of donor islet endothelium and ingrowth of blood vessels from the implantation organ. However, several studies indicate that although the islets attract recipient blood vessels, the formed intra-islet vascular network is insufficient, which affects islet posttransplant function. This study aimed to develop an in vitro model to investigate the migration and proliferation properties of isolated liver and islet endothelium. Rat islet or liver endothelium was purified using Bandeiraea simplicifolia (BS-1)-coated Dynabeads. The liver endothelium displayed an increased migration towards islet-conditioned medium, and this chemo-attractant effect was fully prevented by adding a neutralizing vascular endothelial growth factor (VEGF)-antibody. In contrast, islet-produced VEGF failed to induce islet endothelial cell migration and only had marginal effects on islet endothelial cell proliferation. These properties could, however, be activated through blocking the effects of either endostatin, thrombospondin-1 or α1-antitrypsin. In conclusion, VEGF may attract recipient blood vessels towards intrahepatically transplanted islets, but intra-islet vascular expansion is hampered by angiostatic factors present within the islets and the islet endothelium. Inhibition of these early after transplantation may provide a strategy to restore the islet vascular network and improve islet graft function.
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| 4. |
- Olerud, Johan, 1977-
(author)
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Role of Thrombospondin-1 in Endogenous and Transplanted Pancreatic Islets
- 2009
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Doctoral thesis (other academic/artistic)abstract
- Type 1 diabetes mellitus is a severe life-long disease with a pronounced risk of developing secondary complications. One way to avoid the latter is to restore the fine tuning of blood glucose homeostasis by transplantation of pancreatic islets. However, isolated islets need to be properly engrafted and to re-establish a vascular network in order to regain function. Earlier studies have shown that pancreatic islets experimentally transplanted to e.g. the liver or the kidney become poorly revascularized. In the present thesis, mice deficient of the angiostatic factor thrombospondin-1 (TSP-1) were found to have an impaired beta-cell function. Development of this beta-cell dysfunction was prevented by treatment of TSP-1 deficient mice from birth with the TGFbeta-1 activating sequence of TSP-1. TSP-1 in islets was predominantly expressed in the endothelial cells. Isolated islet endothelial cells was observed to have a low proliferatory and migratory capacity towards angiogenic stimuli, but this could be reversed by neutralizing antibodies to the angiostatic factors alpha1-antitrypsin, endostatin or TSP-1. Transient downregulation of TSP-1 expression in mouse islet cells prior to transplantation improved graft revascularization, blood perfusion, oxygenation and function when evaluated one-month post-transplantation. The same result was achieved when islets or recipients of islets were pre-treated with the hormone prolactin one-month post-transplantation. The present study illustrates the importance of the angiostatic factor TSP-1 for islet beta-cell function and engraftment of islets following transplantation. Interference with TSP-1 can possibly be used to improve the results of clinical islet transplantation.
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| 5. |
- Robinson, Yohan, 1977-, et al.
(author)
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Do biological disease-modifying antirheumatic drugs reduce the spinal fracture risk related to ankylosing spondylitis? : A longitudinal multiregistry matched cohort study
- 2017
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In: BMJ Open. - London, UK : BMJ Publishing Group Ltd. - 2044-6055. ; 7:12
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Journal article (peer-reviewed)abstract
- Objectives: Ankylosing spondylitis (AS) is associated with an increased spinal fracture risk due to the loss of elasticity in spinal motion segments. With the introduction of biological disease-modifying antirheumatic drug (bDMARD) treatment for AS, the individual course of the disease has been ameliorated. This study aims to examine the association of bDMARD treatment and risk of spinal fracture.Design: Longitudinal population-based multiregistry observational matched cohort study.Setting: Swedish Patient Registry 1987-2014 and Swedish Prescribed Drugs Registry 2005-2014.Participants: Included were patients ≥18 years of age receiving treatment at a healthcare facility for the primary diagnosis of AS. About 1352 patients received more than one prescription of bDMARD from 2005 to 2014. An untreated control group was created by propensity score matching for age, sex, comorbidity, antirheumatic prescriptions and years with AS (n=1352).Main Outcome Measures: Spinal fracture-free survival.Results: No bDMARD treatment-related effect on spinal fracture-free survival was observed in the matched cohorts. Male gender (HR=2.54, 95% CI 1.48 to 4.36) and Charlson Comorbidity Index score (HR=3.02, 95% CI 1.59 to 5.75) contributed significantly to spinal fracture risk.Conclusion: bDMARD had no medium-term effect on the spinal fracture-free survival in patients with AS.Trial Registration Number: NCT02840695
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| 6. |
- Robinson, Yohan, 1977-, et al.
(author)
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Surgical Stabilization Improves Survival of Spinal Fractures Related to Ankylosing Spondylitis
- 2015
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In: Spine. - 0362-2436 .- 1528-1159. ; 40:21, s. 1697-1702
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Journal article (peer-reviewed)abstract
- Study Design. National registry cohort study. Objective. The aim of this study was to investigate the effect of surgical stabilization on survival of spinal fractures related to ankylosing spondylitis (AS). Summary of Background Data. Spinal fractures related to AS are associated with considerable morbidity and mortality. Multiple studies suggest a beneficial effect of surgical stabilization in these patients. Methods. In the Swedish patient registry, all patients treated in an inpatient facility are registered with diagnosis and treatment codes. The Swedish mortality registry collects date and cause of death for all fatalities. Registry extracts of all patients with AS and spinal fractures including date of death and treatment were prepared and analyzed for epidemiological purposes. Results. Seventeen thousand two hundred ninety-seven individual patients with AS were admitted to treatment facilities in Sweden between 1987 and 2011. Nine hundred ninety patients with AS (age 66 +/- 14 years) had 1131 spinal fractures, of which 534 affected cervical, 352 thoracic, and 245 lumbar vertebrae. Thirteen percent had multiple levels of injuries during the observed period. Surgically treated patients had a greater survival than those treated nonsurgically [hazard ratio (HR) 0.79, P = 0.029]. Spinal cord injury was the major factor contributing to mortality in this cohort (HR 1.55, P< 0.001). The proportion of surgically treated spinal fractures increased linearly during the last decades (r = 0.92, P< 0.001) and was 64% throughout the observed years. Conclusions. Spinal cord injury threatened the survival of patients with spinal fractures related to AS. Even though surgical treatment is associated with a considerable complication rate, it improved the survival of spinal fractures related to AS.
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