| 1. |
- Kalis, Martins, et al.
(författare)
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Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12, s. e29166-
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Tidskriftsartikel (refereegranskat)abstract
- Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.
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| 2. |
- Alanentalo, Tomas, et al.
(författare)
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Quantification and 3-D imaging of the insulitis-induced destruction of β-cells in murine type 1 diabetes
- 2010
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 59:7, s. 1756-1764
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to refine the information regarding the quantitative and spatial dynamics of infiltrating lymphocytes and remaining beta-cell volume during the progression of type 1 diabetes in the NOD mouse model of the disease.Research design and methods: Using an ex vivo technique, optical projection tomography (OPT), we quantified and assessed the 3D spatial development and progression of insulitis and beta-cell destruction in pancreas from diabetes prone NOD and non-diabetes prone congenic NOD.H-2b mice between 3 and 16 weeks of age.Results: Together with results showing the spatial dynamics of the insulitis process we provide data of beta-cell volume distributions down to the level of the individual islets and throughout the pancreas during the development and progression of type 1 diabetes. Our data provide evidence for a compensatory growth potential of the larger insulin(+) islets during the later stages of the disease around the time point for development of clinical diabetes. This is in contrast to smaller islets, which appear less resistant to the autoimmune attack. We also provide new information on the spatial dynamics of the insulitis process itself, including its apparently random distribution at onset, the local variations during its further development, and the formation of structures resembling tertiary lymphoid organs at later phases of insulitis progression.Conclusions: Our data provides a powerful tool for phenotypic analysis of genetic and environmental effects on type 1 diabetes etiology as well as for evaluating the potential effect of therapeutic regimes.
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| 3. |
- Bergsten, Eva L., 1969-, et al.
(författare)
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Physical and psychosocial work conditions among baggage handlers in six Swedish airports
- 2012
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Konferensbidrag (refereegranskat)abstract
- Introduction Flight baggage handlers are mainly engaged in sorting luggage or cargo, loading and unloading it to and from the airplanes. The Vocational Training and Working Environment Council, TYA - formed by employer’s and employee’s organizations in the transportation sector - initiated a scientific study in 2009 to investigate the prevalence of musculoskeletal disorders and their suspected determinants in six Swedish airports involving a total of about 1000 handlers in 14 cargo- and handling companies. Encouraged by an initial literature review, the present field study was designed to contain qualitative, questionnaire-based, and observational surveys of working conditions, as well as extensive direct measurements of postures using full-shift inclinometry. This paper reports the design and results of the questionnaire part of the study.MethodAll baggage handlers working at least half-time (n=1044) were encouraged to fill in an extensive questionnaire handed out at the workplace by a research team member. In general the researcher collected the questionnaires at the same occasion. The questionnaire addressed general health, work capacity and physical exposures in relevant handling tasks. It also included a modified version of the Copenhagen Psychosocial Questionnaire (COPSOQ), the Nordic Council of Minister’s Questionnaire (NMQ) on disorders, and the SOFI-questionnaire measuring perceived fatigue.ResultsThe response rate was 73%. The prevalence of musculoskeletal disorders in the back, shoulders and wrists during the last 12 months was 70%, 60% and 45%. Positive effects of devices used for reducing perceived physical load were confirmed. The handlers expressed a low confidence in the leadership, and insufficient feedback, information and influence at work. Fatigue particularly occurred in the dimensions lack of energy and physical discomfort.DiscussionThe observed prevalence of low back pain (70%) is high, and in parity with results among nurses in Sweden (64%; Josephson et al. 1997) and China (56%; Smith et al. 2004). Further examination of questionnaires, interviews and direct posture measurements will identify determinants to consider for intervention to reduce the prevalence of disorders among the baggage handlers.Josephson M, et al. Occup Environ Med 1997;54:681-685.Smith DR, et al. Occup Med 2004;54:579-582
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| 4. |
- Brauner, Hanna, et al.
(författare)
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Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice.
- 2010
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Ingår i: Journal of Immunology. - : American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 184:5, s. 2272-2280
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about target organ-infiltrating NK cells in type 1 diabetes and other autoimmune diseases. In this study, we identified NK cells with a unique phenotype in the pancreas of NOD mice. Pancreatic NK cells, localized to the endocrine and exocrine parts, were present before T cells during disease development and did not require T cells for their infiltration. Furthermore, NK cells, or NK cell precursors, from the spleen could traffic to the pancreas, where they displayed the pancreatic phenotype. Pancreatic NK cells from other mouse strains shared phenotypic characteristics with pancreatic NK cells from NOD mice, but displayed less surface killer cell lectin-like receptor G1, a marker for mature NK cells that have undergone proliferation, and also did not proliferate to the same extent. A subset of NOD mouse pancreatic NK cells produced IFN-gamma spontaneously, suggesting ongoing effector responses. However, most NOD mouse pancreatic NK cells were hyporesponsive compared with spleen NK cells, as reflected by diminished cytokine secretion and a lower capacity to degranulate. Interestingly, such hyporesponsiveness was not seen in pancreatic NK cells from the nonautoimmune strain C57BL/6, suggesting that this feature is not a general property of pancreatic NK cells. Based on our data, we propose that NK cells are sentinel cells in a normal pancreas. We further speculate that during inflammation, pancreatic NK cells initially mediate proinflammatory effector functions, potentially contributing to organ-specific autoimmunity, but later become hyporesponsive because of exhaustion or regulation.
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| 5. |
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| 6. |
- Ganachaud, C., et al.
(författare)
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An anomalous behavior of trypsin immobilized in alginate network
- 2013
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Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 1432-0614 .- 0175-7598. ; 97:10, s. 4403-4414
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Tidskriftsartikel (refereegranskat)abstract
- Alginate is a biopolymer used in drug formulations and for surgical purposes. In the presence of divalent cations, it forms solid gels, and such gels are of interest for immobilization of cells and enzymes. In this work, we entrapped trypsin in an alginate gel together with a known substrate, N (alpha)-benzoyl-l-arginine-4-nitroanilide hydrochloride (l-BAPNA), and in the presence or absence of d-BAPNA, which is known to be a competitive inhibitor. Interactions between alginate and the substrate as well as the enzyme were characterized with transmission electron microscopy, rheology, and nuclear magnetic resonance spectroscopy. The biocatalysis was monitored by spectrophotometry at temperatures ranging from 10 to 42 A degrees C. It was found that at 37 and 42 A degrees C a strong acceleration of the reaction was obtained, whereas at 10 A degrees C and at room temperature, the presence of d-BAPNA leads to a retardation of the reaction rate. The same effect was found when the reaction was performed in a non-cross-linked alginate solution. In alginate-free buffer solution, as well as in a solution of carboxymethylcellulose, a biopolymer that resembles alginate, the normal behavior was obtained; however, with d-BAPNA acting as an inhibitor at all temperatures. A more detailed investigation of the reaction kinetics showed that at higher temperature and in the presence of alginate, the curve of initial reaction rate versus l-BAPNA concentration had a sigmoidal shape, indicating an allosteric behavior. We believe that the anomalous behavior of trypsin in the presence of alginate is due to conformational changes caused by interactions between the positively charged trypsin and the strongly negatively charged alginate.
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| 7. |
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| 8. |
- Gupta, Shashank, et al.
(författare)
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Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis.
- 2013
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10
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Tidskriftsartikel (refereegranskat)abstract
- Multiple Sclerosis (MS) is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS). T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE) animal models for the disease. A technology for quantitative and 3 dimensional (3D) spatial assessment of inflammation in this and other CNS inflammatory conditions is much needed. Here we present a procedure for 3D spatial assessment and global quantification of the development of neuroinflammation based on Optical Projection Tomography (OPT). Applying this approach to the analysis of rodent models of MS, we provide global quantitative data of the major inflammatory component as a function of the clinical course. Our data demonstrates a strong correlation between the development and progression of neuroinflammation and clinical disease in several mouse and a rat model of MS refining the information regarding the spatial dynamics of the inflammatory component in EAE. This method provides a powerful tool to investigate the effect of environmental and genetic forces and for assessing the therapeutic effects of drug therapy in animal models of MS and other neuroinflammatory/neurodegenerative disorders.
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| 9. |
- Holmberg, Lars I., et al.
(författare)
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Sexually abused children. Characterization of these girls when adolscents
- 2010
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Ingår i: International Journal of Adolescent Medicine and Health. - 0334-0139 .- 2191-0278. ; 22:2, s. 291-300
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Tidskriftsartikel (refereegranskat)abstract
- AIM: To study associations between sexual abuse of girls in childhood and variables affecting life in adolescence. METHODS: Anonymously, in the class room, all eligible female adolescents 13-18 years old (n = 1,428) in a medium-sized town completed a validated in-depth questionnaire (Q90) with 165 questions. A history of sexual offense was reported by 119 cases (8.3%, mean age 16.0 years). The remaining 1,309 girls (mean age 15.6 years) served as a comparison group. RESULTS: Questions included body perception, health, including psychosomatic symptoms, depression, suicidal thoughts, psychiatric medication, general questions about present life, peer relations, smoking, alcohol use, delinquent behaviors, and sexual behaviors. In most areas, adolescents with a history of sexual offense responded unfavorably compared with the comparison groups. Some examples were that despite a similar body mass index, 47% of the cases felt overweight as against 31% of the remaining adolescents (p = .0001). Among the sexually abused adolescents, self-perceived depression was more common (60% vs. 37%, p = .0001), as was psychiatric medication (10% vs. 2%, p = .0003). Loneliness was reported by 23% of the cases versus 13% (p = .005). Smoking, alcohol use, and minor criminality showed similar results. Sexual risk behaviors, i.e. multiple sexual partners, unwanted pregnancies, and sexually transmitted infections did not differ between the two groups of girls. CONCLUSION: Many adolescents with a history of childhood sexual offense feel unhappy, as is evident from the magnitude of the problems. This includes many aspects of adolescent life. It seems likely that the problems are at least partially related to sexual abuse in childhood.
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| 10. |
- Janunger, Tomas, 1972-
(författare)
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The genetic contribution to stroke in northern Sweden
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Stroke is a common multi factorial cerebrovascular disorder with a large impact on global health. It is a disorder primarily associated with old age but environmental factors, lifestyle choices and medical history are all important for the risk of developing the disorder. It is also known that heritability is important for predisposition to the disorder. The aim of this work has been to identify genetic variations that increase the risk of being affected by stroke in the population of northern Sweden, a population well apt for genetic studies due to well kept church and medical records together with limited genetic diversity. In the first paper we used linkage analysis in families with early onset of stroke. By this approach we identified a region on chromosome 5q to be linked to an increased risk of developing stroke, a region previously identified as a susceptibility locus for stroke in the Icelandic population. In the second study we used genealogy to identify common ancestry and thereby identify common susceptibility to stroke. The seven families we connected showed significant linkage to the chromosome 9q31-33 region and four of the families shared a common haplotype over 2.1 megabases. In the third manuscript we investigated sequence variation of two candidate genes, TNFSF15 and TLR4. Sequencing of the TLR4 gene revealed previously identified variations in affected individuals from two of the families. Further SNP analysis showed five separate haplotypes among the investigated families and four haplotypes for TNFSF15. However none of these co-segregated with stroke among the investigated families. In the final paper we used a case-control stroke cohort to ascertain association for genetic variation in five genes and genetic regions previously suggested to be linked with stroke. Initial analyses showed association for the 9p21 chromosomal region and a variant in Factor 5 that showed protection against stroke, but after adjustments for common risk factors for stroke, the findings were no longer significant. In conclusion, by studying selected families we have been able to show linkage to two chromosomal regions, 5q and 9q31-33, that indicate genetic predisposition for developing stroke. Further we have shown that family based studies are still an important tool in deciphering the underlying mechanisms for complex disease.
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