Ablation of integrin-mediated cell-collagen communication alleviates fibrosis

Objectives Activation of fibroblasts is a hallmark of fibrotic processes. Besides cytokines and growth factors, fibroblasts are regulated by the extracellular matrix environment through receptors such as integrins, which transduce biochemical and mechanical signals enabling cells to mount appropriate responses according to biological demands. The aim of this work was to investigate the in vivo role of collagen–fibroblast interactions for regulating fibroblast functions and fibrosis. Methods Triple knockout (tKO) mice with a combined ablation of integrins α1β1, α2β1 and α11β1 were created to address the significance of integrin-mediated cell–collagen communication. Properties of primary dermal fibroblasts lacking collagen-binding integrins were delineated in vitro. Response of the tKO mice skin to bleomycin induced fibrotic challenge was assessed. Results Triple integrin-deficient mice develop normally, are transiently smaller and reveal mild alterations in mechanoresilience of the skin. Fibroblasts from these mice in culture show defects in cytoskeletal architecture, traction stress generation, matrix production and organisation. Ablation of the three integrins leads to increased levels of discoidin domain receptor 2, an alternative receptor recognising collagens in vivo and in vitro. However, this overexpression fails to compensate adhesion and spreading defects on collagen substrates in vitro. Mice lacking collagen-binding integrins show a severely attenuated fibrotic response with impaired mechanotransduction, reduced collagen production and matrix organisation. Conclusions The data provide evidence for a crucial role of collagen-binding integrins in fibroblast force generation and differentiation in vitro and for matrix deposition and tissue remodelling in vivo. Targeting fibroblast–collagen interactions might represent a promising therapeutic approach to regulate connective tissue deposition in fibrotic diseases

Probabilistic Model-Based Safety Analysis

Model-based safety analysis approaches aim at finding critical failure combinations by analysis of models of the whole system (i.e. software, hardware, failure modes and environment). The advantage of these methods compared to traditional approaches is that the analysis of the whole system gives more precise results. Only few model-based approaches have been applied to answer quantitative questions in safety analysis, often limited to analysis of specific failure propagation models, limited types of failure modes or without system dynamics and behavior, as direct quantitative analysis is uses large amounts of computing resources. New achievements in the domain of (probabilistic) model-checking now allow for overcoming this problem. This paper shows how functional models based on synchronous parallel semantics, which can be used for system design, implementation and qualitative safety analysis, can be directly re-used for (model-based) quantitative safety analysis. Accurate modeling of different types of probabilistic failure occurrence is shown as well as accurate interpretation of the results of the analysis. This allows for reliable and expressive assessment of the safety of a system in early design stages

Presence and Persistence of Ebola or Marburg Virus in Patients and Survivors: A Rapid Systematic Review

Background: The 2013-15 Ebola outbreak was unprecedented due to sustainedtransmission within urban environments and thousands of survivors. In 2014 the World Health Organization stated that there was insufficient evidence to give definitive guidance about which body fluids are infectious and when they pose a risk to humans. We report a rapid systematic review of published evidence on the presence of filoviruses in body fluids of infected people and survivors. Methods: Scientific articles were screened for information about filovirus in human body fluids. The aim was to find primary data that suggested high likelihood of actively infectious filovirus in human body fluids (viral RNA). Eligible infections were from Marburg virus (MARV or RAVV) and Zaire, Sudan, Taï Forest and Bundibugyo species of Ebola. [1] Cause of infection had to be laboratory confirmed (in practice either tissue culture or RT-PCR tests), or evidenced by compatible clinical history with subsequent positivity for filovirus antibodies or inflammatory factors. Data were extracted and summarized narratively. Results: 6831 unique articles were found, and after screening, 33 studies were eligible. For most body fluid types there were insufficient patients to draw strong conclusions, and prevalence of positivity was highly variable. Body fluids taken >16 days after onset were usually negative. In the six studies that used both assay methods RT-PCR tests for filovirus RNA gave positive results about 4 times more often than tissue culture. Conclusions: Filovirus was reported in most types of body fluid, but not in every sample from every otherwise confirmed patient. Apart from semen, most non-blood, RT-PCR positive samples are likely to be culture negative and so possibly of low infectious risk. Nevertheless, it is not apparent how relatively infectious many body fluids are during or after illness, even when culture-positive, not least because most test results come from more severe cases. Contact with blood and blood-stained body fluids remains the major risk for disease transmission because of the known high viral loads in blood

A longitudinal study of risk factors for the occurrence, duration and severity of menstrual cramps in a cohort of college women

To describe how menstrual cramps vary from cycle to cycle within a woman over time. To examine the influence of weight and lifestyle factors on occurrence, duration, and severity of menstrual pain. Design A one-year prospective menstrual diary study. Participants One hundred and sixty-five women aged 17 to 19 years entering a local university in 1985. Main outcome measures The occurrence, length, and maximum severity of pain during a menstrual period. Results Menstrual pain occurred during 71.6% of observed menstrual bleeds, most commonly beginning the first day of menses. The median duration was two days. Sixty percent of women reported at least one episode of severe pain, while 13% reported severe pain more than half the time. Earlier age at menarche and long menstrual periods increased the occurrence, duration and severity of pain. In smokers, cramps tended to last longer. Being overweight was an important risk factor for menstrual cramps and doubled the odds of having a long pain episode. Frequent alcohol consumption decreased the probability of having menstrual cramps, but in women who had pain it increased duration and severity. Physical activity was not associated with any pain parameter. Conclusions Women who have pain lasting three days are an important target group for prophylactic therapy. The occurrence and severity of menstrual cramps is influenced by potentially modifiable characteristics including weight, smoking, and alcohol consumption. Doctors may wish to counsel women presenting with dysmenorrhoea about the importance of healthy lifestyles and about the inefficacy of alcohol consumption as a treatment for dysmenorrhoea.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73220/1/j.1471-0528.1996.tb09597.x.pd

Inhibition of Intestinal Bile Acid Transporter Slc10a2 Improves Triglyceride Metabolism and Normalizes Elevated Plasma Glucose Levels in Mice

Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2) and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c). Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF) 15 mRNA and normalized bile acid synthesis in Slc10a2−/− mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2 - Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC

OBJECTIVE The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS The strongest associations in the MHC class II region (rs3957146, beta [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (beta [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, beta [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.Peer reviewe