An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.Peer reviewe

Maternal Enterovirus Infection during Pregnancy as a Risk Factor in Offspring Diagnosed with Type 1 Diabetes between 15 and 30 Years of Age

Maternal enterovirus infections during pregnancy may increase the risk of offspring developing type 1 diabetes during childhood. The aim of this study was to investigate whether gestational enterovirus infections increase the offspring's risk of type 1 diabetes later in life. Serum samples from 30 mothers without diabetes whose offspring developed type 1 diabetes between 15 and 25 years of age were analyzed for enterovirus-specific immunoglobulin M (IgM) antibodies and enterovirus genome (RNA), and compared to a control group. Among the index mothers, 9/30 (30%) were enterovirus IgM-positive, and none was positive for enterovirus RNA. In the control group, 14/90 (16%) were enterovirus IgM-positive, and 4/90 (4%) were positive for enterovirus RNA (n.s.). Boys of enterovirus IgM-positive mothers had approximately 5 times greater risk of developing diabetes (OR 4.63; 95% CI 1.22–17.6), as compared to boys of IgM-negative mothers (P < .025). These results suggest that gestational enterovirus infections may be related to the risk of offspring developing type 1 diabetes in adolescence and young adulthood

A Nested Case-Control Study of Intrauterine Exposure to Persistent Organochlorine Pollutants in Relation to Risk of Type 1 Diabetes

BACKGROUND: The incidence of type 1 diabetes in Europe is increasing at a rate of about 3% per year and there is also an increasing incidence throughout the world. Type 1 diabetes is a complex disease caused by multiple genetic and environmental factors. Persistent organochlorine pollutants (POPs) have been suggested as a triggering factor for developing childhood type 1 diabetes. The aim of this case-control study was to assess possible impacts of in utero exposure to POPs on type 1 diabetes. METHODOLOGY/ PRINCIPAL FINDINGS: The study was performed as a case-control study within a biobank in Malmö, a city located in the Southern part of Sweden. The study included 150 cases (children who had their diagnosis mostly before 18 years of age) and 150 controls, matched for gender and day of birth. 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) and the major DDT metabolite 1,1-dichloro-2,2-bis (p-chlorophenyl)-ethylene (p,p'-DDE) were used as a biomarkers for POP exposure. When comparing the quartile with the highest maternal serum concentrations of PCB-153 with the other quartiles, an odds ratio (OR) of 0.73 (95% confidence interval [CI] 0.42, 1.27) was obtained. Similar results was obtained for p,p'-DDE (OR 0.56, 95% CI 0.29, 1.08). CONCLUSIONS: The hypothesis that in utero exposure to POPs will trigger the risk for developing type 1 diabetes was not supported by the results. The risk estimates did, although not statistically significant, go in the opposite direction. However, it is not reasonable to believe that exposure to POPs should protect against type 1 diabetes

Veterans walk to beat back pain: study rationale, design and protocol of a randomized trial of a pedometer-based Internet mediated intervention for patients with chronic low back pain

<p>Abstract</p> <p>Background</p> <p>Chronic back pain is a significant problem worldwide and may be especially prevalent among patients receiving care in the U.S. Department of Veterans Affairs healthcare system. Back pain affects adults at all ages and is associated with disability, lost workplace productivity, functional limitations and social isolation. Exercise is one of the most effective strategies for managing chronic back pain. Yet, there are few clinical programs that use low cost approaches to help patients with chronic back pain initiate and maintain an exercise program.</p> <p>Methods/Design</p> <p>We describe the design and rationale of a randomized controlled trial to assess the efficacy of a pedometer-based Internet mediated intervention for patients with chronic back pain. The intervention uses an enhanced pedometer, website and e-community to assist these patients with initiating and maintaining a regular walking program with the primary aim of reducing pain-related disability and functional interference. The study specific aims are: 1) To determine whether a pedometer-based Internet-mediated intervention reduces pain-related functional interference among patients with chronic back pain in the short term and over a 12-month timeframe. 2) To assess the effect of the intervention on walking (measured by step counts), quality of life, pain intensity, pain related fear and self-efficacy for exercise. 3) To identify factors associated with a sustained increase in walking over a 12-month timeframe among patients randomized to the intervention.</p> <p>Discussion</p> <p>Exercise is an integral part of managing chronic back pain but to be effective requires that patients actively participate in the management process. This intervention is designed to increase activity levels, improve functional status and make exercise programs more accessible for a broad range of patients with chronic back pain.</p> <p>Trial Registration Number</p> <p>NCT00694018</p

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes

Members of ENDIA Study Group: Peter Baghurst, Simon Barry, Jodie Dodd, Maria Makrides for the University of Adelaide.BACKGROUND The incidence of type 1 diabetes has increased worldwide, particularly in younger children and those with lower genetic susceptibility. These observations suggest factors in the modern environment promote pancreatic islet autoimmunity and destruction of insulin-producing beta cells. The Environmental Determinants of Islet Autoimmunity (ENDIA) Study is investigating candidate environmental exposures and gene-environment interactions that may contribute to the development of islet autoimmunity and type 1 diabetes. METHODS/DESIGN ENDIA is the only prospective pregnancy/birth cohort study in the Southern Hemisphere investigating the determinants of type 1 diabetes in at-risk children. The study will recruit 1,400 unborn infants or infants less than six months of age with a first-degree relative (i.e. mother, father or sibling) with type 1 diabetes, across five Australian states. Pregnant mothers/infants will be followed prospectively from early pregnancy through childhood to investigate relationships between genotype, the development of islet autoimmunity (and subsequently type 1 diabetes), and prenatal and postnatal environmental factors. ENDIA will evaluate the microbiome, nutrition, bodyweight/composition, metabolome-lipidome, insulin resistance, innate and adaptive immune function and viral infections. A systems biology approach will be used to integrate these data. Investigation will be by 3-monthly assessments of the mother during pregnancy, then 3-monthly assessments of the child until 24 months of age and 6-monthly thereafter. The primary outcome measure is persistent islet autoimmunity, defined as the presence of autoantibodies to one or more islet autoantigens on consecutive tests. DISCUSSION Defining gene-environment interactions that initiate and/or promote destruction of the insulin-producing beta cells in early life will inform approaches to primary prevention of type 1 diabetes. The strength of ENDIA is the prospective, comprehensive and frequent systems-wide profiling from early pregnancy through to early childhood, to capture dynamic environmental exposures that may shape the development of islet autoimmunity. TRIAL REGISTRATION Australia New Zealand Clinical Trials Registry ACTRN12613000794707.Megan AS Penno, Jennifer J Couper, Maria E Craig, Peter G Colman, William D Rawlinson, Andrew M Cotterill, Timothy W Jones, Leonard C Harrison and ENDIA Study Grou

Gestational Islet Autoimmunity, Infections, and Type 1 Diabetes

The intention of this thesis was to investigate autoimmune markers for type 1 diabetes, together with signs of enterovirus infections during the pre- and perinatal period of life, and their possible association with the development of diabetes during childhood, adolescence, and young adulthood. We found that: 1. Newborns with ABO immunization, linked in epidemiological studies with heightened diabetes risk, had an increased prevalence of islet autoantibodies at birth. This was also observed in newborns with neonatal hyperbilirubinemia without blood-group incompatibility, suggesting that intrauterine factors may be associated with islet autoimmunity. 2. The epitope pattern of GAD65 immunoglobulin binding differed between birth and diagnosis of type 1 diabetes, supporting the view that a change in the epitope pattern sometimes occurs between birth and diagnosis. Moreover, the epitope pattern of the child at birth differed from that of its mother; hence it cannot be completely excluded that the fetus may be capable of some antibody production of its own. 3. Children with fewer islet autoantibodies when diagnosed with type 1 diabetes were more likely to have had autoantibodies in their cord blood sample, leading us to conclude that cord blood islet autoimmunity in offspring of non-diabetic mothers may modulate the immunological expression of diabetes, and explain why some type 1 diabetic children are islet autoantibody negative at the time of clinical diagnosis. 4. Adolescents and young adults who developed type 1 diabetes between ages 15 and 25 had no increased prevalence of any of the four islet autoantibodies at birth, in contrast to an earlier study of children under age 15, showing that pre- and perinatal risk factors are less likely to be involved in the development of type 1 diabetes in young adulthood. 5. Mothers whose offspring developed type 1 diabetes between ages 15 and 25 had slightly higher titers of enterovirus-specific IgM compared to a control group, but the difference was insignificant. However, boys of enterovirus IgM positive mothers had a risk of developing diabetes approximately five times greater than boys of enterovirus IgM negative mothers. Our study could not rule out the possibility that gestational infections might also influence the risk of diabetes in adolescence and young adulthood. Our data support the view that islet autoantibodies at birth are markers of an ongoing process in the ?-cells. Gestational factors appear to be of importance for the risk of developing type 1 diabetes in childhood, and may also influence the risk in adolescence and young adulthood. Pre- and perinatal events also seem to modulate the immunological expression of diabetes during childhood

Hydraulic closed loop control

The purpose of the thesis work is to investigate methods for closedloop control of hydraulic pressure in transmissions to make them bemore precise. This is desirable since it decreases the fuel consumptionas well as emissions, and improves the driving performance.To be able to study the behaviour of the transmission, a Simulink modelis designed with the parts relevant to the problem, and from this a linearmodel is obtained. Three different controllers are designed andimplemented in the Simulink model, to compare and analyze differentsolutions. The controllers implemented are a PI controller, a PIDcontroller and a LQR controller.The results from the simulation with the different controllers showstep responses to be able to evaluate their individual performance. Theresults show that all of the controllers meet the requirements for a stepreponse under better conditions, but under worse ones the LQR controllerperforms best of the three. The LQR controller is therefore themost suitable of the three controllers for this particular problem.Syftet med det här examensarbete är att undersöka olika metoder för återkopplad reglering av hydrauliskt tryck i en transmission för att göra det mer exakt. Detta är önskvärt eftersom det minskar bränsleåt- gången och utsläpp, och gör även körupplevelsen bättre. För att kunna studera transmission tas en Simulink-modell fram in- nehållande de delar som är relevanta för problemet, och från detta kan en linjär modell erhållas. Tre olika regulatorer tas fram och im- plementeras i Simulink-modellen, för att kunna jämföra och analysera de olika lösningarna. De regulatorer som tas fram är PI-regulator, PID- regulator och LQR-regualator. Resultaten från simuleringen med de olika regulatorerna visar stegs- var under varierande förutsättningar för att kunna utvärdera hur de presterar. Resultaten visar att alla regulatorer uppfyller kraven på ett stegsvar under bättre förhållanden, men LQR-regulatorn presterar bäst under svårare förhållanden. LQR-regulatorn är därför den mest relevanta reglerstrategin för det här problemet av de tr

Payment for Environmental Services - A tool for forest conservation and empowerment of the local people in the State of Amazonas, Brazil? : A case study of Programa Bolsa Floresta

This thesis is a result of a research conducted during three months in four State Protected Conservation Units in the State of Amazonas in Brazil. The world‟s largest PES-program - Programa Bolsa Floresta, will serve as case study. The aim of the study is to identify the socio-environmental conditions under which the program is implemented and, to study if the program architecture is in coherence with the livelihood needs of the target group-, and the needs to protect the rain forest. The target group of the program are the river dwellers, “ribeirinhos”, living in extremely isolated areas being excluded from the public safety net of the Brazilian Government.A basic understanding of the livelihood situation was achieved through the use of systematic collection of empirical data. A combination of qualitative semi-structured interviews, quantitative literature reviews and triangulation of data compose the methodological base of the study. The holistic and human centered theoretical framework of Carney‟s Sustainable Livelihood Approach (SLA) laid the theoretical base of the study.Based upon the baseline study made over the local conditions and the context description this study recognizes that the programs architecture is coherent with the most basic needs of the ribeirinhos as well as the need to protect the forest. Due to the programs few years in execution it is hard to determine long-term impacts of the program at this stage. However, even being in an early stage, the program seems to be a potential key mechanism to build the foundation for future sustainable development in the region. The object of the program is to put value on the Environmental Services (ES) provided by the locals and by doing so, compensate them for their loss of capital. The program is designed holistically, i.e. its components include all five capital assets of the SLA framework. The payments given as compensations aim to advocate participatory, social organizational, educative, and self-reliance promoting methods, such as incentives to an alternative income, construction of schools, improved infrastructure, investments in water filters, means for communication, health programs in schools and ambulance boats