Gap junction reduction in cardiomyocytes following transforming growth factor- beta treatment and Trypanosoma cruzi infection

Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-beta (TGF-beta). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-beta T. cruzi, or SB-431542, an inhibitor of TGF-beta receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-beta signalling had been shown previously to be highly activated. We demonstrated that TGF-beta treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-beta secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-beta levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease

Small area estimation strategy for the 2011 Census in England and Wales

© 2018-IOS Press and the authors. All rights reserved. The use of model-based small area estimation for adjusting census results in the UK was first introduced in the 2001 Census. The aim was to obtain local level population estimates by age-sex groups, adjusted for the level of undercount that combined results from the Census and the Census Coverage Survey. A similar approach was adopted for the 2011 Census but with new features and this paper describes the work carried out to arrive at the chosen small area strategy. Simulation studies are used to investigate three proposed small area estimation methods: a local fixed effects model (the 2001 Census approach), a direct estimator and a synthetic estimator. The results indicate that both the synthetic and the local fixed effect models constitute good options to produce accurate and reliable local authority population estimates. A proposal is made to implement a small area estimation procedure that accommodates both the synthetic and local fixed models, as in some selected areas with differing local authority under-coverage rates a local fixed effects model may perform best. We examine this strategy under real census conditions based on the final results from the 2011 census

MS Prevalence and Patients' Characteristics in the District of Braga, Portugal

Multiple Sclerosis (MS) is a chronic autoimmune disease of the Central Nervous System causing inflammation and neurodegeneration. There are only 3 epidemiological studies in Portugal, 2 in the Centre and 1 in the North, and there is the need to further study MS epidemiology in this country. The objective of this work is to contribute to the MS epidemiological knowledge in Portugal, describing the patients' epidemiological, demographic, and clinical characteristics in the Braga district of Portugal. This is a cross-sectional study of 345 patients followed in two hospitals of Braga district. These hospitals cover a resident population of 866,012 inhabitants. The data was collected from the clinical records, and 31/12/2009 was established as the prevalence day. For all MS patients, demographic characteristics and clinical outcomes are reported. We have found an incidence of 2.74/100,000 and a prevalence of 39.82/100,000 inhabitants. Most patients have an EDSS of 3 or lower and a mean age of 42 years. The diagnosis was done at mean age of 35, with RRMS being the disease type in more than 80% of patients. In this cohort, we found a female : male ratio of 1.79. More than 50% of patients are treated with Interferon β-1b IM or IFNβ-1a SC 22 μg

Genetic mapping of a new heart rate QTL on chromosome 8 of spontaneously hypertensive rats

BACKGROUND: Tachycardia is commonly observed in hypertensive patients, predominantly mediated by regulatory mechanisms integrated within the autonomic nervous system. The genetic loci and genes associated with increased heart rate in hypertension, however, have not yet been identified. METHODS: An F2 intercross of Spontaneously Hypertensive Rats (SHR) × Brown Norway (BN) linkage analysis of quantitative trait loci mapping was utilized to identify candidate genes associated with an increased heart rate in arterial hypertension. RESULTS: Basal heart rate in SHR was higher compared to that of normotensive BN rats (365 ± 3 vs. 314 ± 6 bpm, p < 0.05 for SHR and BN, respectively). A total genome scan identified one quantitative trait locus in a 6.78 cM interval on rat chromosome 8 (8q22–q24) that was responsible for elevated heart rate. This interval contained 241 genes, of which 65 are known genes. CONCLUSION: Our data suggest that an influential genetic region located on the rat chromosome 8 contributes to the regulation of heart rate. Candidate genes that have previously been associated with tachycardia and/or hypertension were found within this QTL, strengthening our hypothesis that these genes are, potentially, associated with the increase in heart rate in a hypertension rat model

Mode I fracture characterization of human bone using the DCB test

Purpose – Fracture characterization of human cortical bone under pure mode I loading was performed in this work. The purpose of this paper is to validate the proposed test and procedure concerning fracture characterization of human cortical bone under pure mode I loading. Design/methodology/approach – A miniaturized version of the double cantilever beam (DCB) test was used for the experimental tests. A data reduction scheme based on crack equivalent concept and Timoshenko beam theory is proposed to overcome difficulties inherent to crack length monitoring during the test. The application of the method propitiates an easy determination of the Resistance-curves (R-curves) that allow to define the fracture energy under mode I loading from the plateau region. The average value of fracture energy was subsequently used in a numerical analysis with element method involving cohesive zone modelling. Findings – The excellent agreement obtained reveals that the proposed test and associated methodology is quite effective concerning fracture characterization of human cortical bone under pure mode I loading. Originality/value – A miniaturized version of traditional DCB test was proposed for cortical human bone fracture characterization under mode I loading owing to size restrictions imposed by human femur. In fact, DCB specimen propitiates a longer length for self-similar crack propagation without undertaking spurious effects. As a consequence, a R-curve was obtained allowing an adequate characterization of cortical bone fracture under mode I loading

Susceptibility Patterns of Staphylococcus Aureus Biofilms in Diabetic Foot Infections

BACKGROUND: Foot infections are a major cause of morbidity in people with diabetes and the most common cause of diabetes-related hospitalization and lower extremity amputation. Staphylococcus aureus is by far the most frequent species isolated from these infections. In particular, methicillin-resistant S. aureus (MRSA) has emerged as a major clinical and epidemiological problem in hospitals. MRSA strains have the ability to be resistant to most β-lactam antibiotics, but also to a wide range of other antimicrobials, making infections difficult to manage and very costly to treat. To date, there are two fifth-generation cephalosporins generally efficacious against MRSA, ceftaroline and ceftobripole, sharing a similar spectrum. Biofilm formation is one of the most important virulence traits of S. aureus. Biofilm growth plays an important role during infection by providing defence against several antagonistic mechanisms. In this study, we analysed the antimicrobial susceptibility patterns of biofilm-producing S. aureus strains isolated from diabetic foot infections. The antibiotic minimum inhibitory concentration (MIC) was determined for ten antimicrobial compounds, along with the minimum biofilm inhibitory concentration (MBIC) and minimum biofilm eradication concentration (MBEC), followed by PCR identification of genetic determinants of biofilm production and antimicrobial resistance. RESULTS: Results demonstrate that very high concentrations of the most used antibiotics in treating diabetic foot infections (DFI) are required to inhibit S. aureus biofilms in vitro, which may explain why monotherapy with these agents frequently fails to eradicate biofilm infections. In fact, biofilms were resistant to antibiotics at concentrations 10-1000 times greater than the ones required to kill free-living or planktonic cells. The only antibiotics able to inhibit biofilm eradication on 50 % of isolates were ceftaroline and gentamicin. CONCLUSIONS: The results suggest that the antibiotic susceptibility patterns cannot be applied to biofilm established infections. Selection of antimicrobial therapy is a critical step in DFI and should aim at overcoming biofilm disease in order to optimize the outcomes of this complex pathology

Clinical and Bacteriological Survey of Diabetic Foot Infections in Lisbon

AIMS: An epidemiological survey of diabetic foot infections (DFIs) in Lisbon, stratifying the bacterial profile based on patient demographical data, diabetic foot characteristics (PEDIS classification), ulcer duration and antibiotic therapy. METHODS: A transversal observational multicenter study, with clinical data collection using a structured questionnaire and microbiological products (aspirates, biopsies or swabs collected using the Levine method) of clinically infected foot ulcers of patients with diabetes mellitus (DM). RESULTS: Forty-nine hospitalized and ambulatory patients were enrolled in this study, and 147 microbial isolates were cultured. Staphylococcus was the main genus identified, and methicillin-resistant Staphylococcus aureus (MRSA) was present in 24.5% of total cases. In the clinical samples collected from patients undergoing antibiotic therapy, 93% of the antibiotic regimens were considered inadequate based on the antibiotic susceptibility test results. The average duration of an ulcer with any isolated multi-drug resistant (MDR) organism was 29 days, and previous treatment with fluoroquinolones was statistically associated with multi-drug resistance. CONCLUSIONS: Staphylococcus aureus was the most common cause of DFIs in our area. Prevalence and precocity of MDR organisms, namely MRSA, were high and were probably related to previous indiscriminate antibiotic use. Clinicians should avoid fluoroquinolones and more frequently consider the use of empirical anti-MRSA therapy