CGRP and migraine

Migraine has been estimated to be the seventh highest cause of disability worldwide, and the third most common disease worldwide after dental caries and tension type headache. However, the use of currently available acute and prophylactic medications to control this condition, such as 5-HT1 agonists (triptans) and beta-blockers, is limited by side effects and efficacy so that alternative and more specific treatments are required. More recently, an improved understanding of the pathophysiology of disease has allowed investigation of new therapeutic targets. The 37 amino acid neuropeptide calcitonin gene-related peptide (CGRP) has been shown to play a crucial role in the trigeminocervical complex pathway for nociception in the head. Studies have demonstrated elevated levels in the external jugular vein during the headache phase of migraine, with reduction following headache resolution. Furthermore, CGRP infusion triggers migraine type headache and subsequent treatment with triptans results in normalization of CGRP levels. This neuropeptide is therefore thought to have a central role in pain modulation as it participates in the neurovascular pathway and contributes to the vasodilation and neurogenic inflammation, which leads to migrainous attacks. Targeting CGRP may provide the ideal therapeutic tool needed for control of this common and debilitating illness. The three studies chosen for this month’s journal club are a small sample of the large amount of research being performed on CGRP. The first investigates whether its measurement can be used to classify migraine. The second and third articles are phase II clinical trials which investigate the use of CGRP antagonists and a monoclonal antibody CGR

Sudden bilateral loss of vision in a 19-year-old man

Introduction: Posterior Reversible Leukoencephalopathy Syndrome (PRES) is caused by ischaemia commonly affecting the posterior cerebral vasculature. It presents with sudden decreased vision, headaches, nausea, vomiting, seizures, and altered mental status. Case presentation: A 19-year-old male presented to the ophthalmic emergency complaining of sudden bilateral loss of vision, which was down to light perception He reported headaches, nausea, and drowsiness since the previous day. He was a known case of hypertension secondary to IgA nephropathy. Magnetic resonance imaging (MRI) with STIR and FLAIR sequences showed foci of hyperintensity within the occipital lobes bilaterally. This confirmed the suspected diagnosis of PRES. Discussion: Aetiological factors of PRES include sudden increase in blood pressure, eclampsia, porphyria, renal disease, and Cushing syndrome. These lead to blood-brain barrier injury either by hyper- or hypoperfusion, endothelial dysfunction, changes in blood vessel morphology, hypocapnea, or immune system activation. Histopathological changes in PRES include activated astrocytes, scattered macrophages and lymphocytes, often in the absence of inflammation or neuronal damage. Conclusion: PRES is usually a reversible neuroophthalmological condition, however prompt recognition and appropriate management is important to prevent permanent brain injury or even death.peer-reviewe

Environmental components of childhood obesity prevention interventions: an overview of systematic reviews.

Childhood obesity has a complex multi-factorial aetiology grounded in environmental and individual level factors that affect behaviour and outcomes. An ecological, systems-based approach to addressing childhood obesity is increasingly being advocated. The primary aim of this review is to summarize the evidence reported in systematic reviews on the effectiveness of population-level childhood obesity prevention interventions that have an environmental component. We conducted a systematic review of reviews published since 1995, employing a standardized search strategy in nine databases. Inclusion criteria required that reviews be systematic and evaluated at least one population-level, environmental intervention in any setting aimed at preventing or reducing obesity in children (5-18 years). Sixty-three reviews were included, ten of which were of high quality. Results show modest impact of a broad range of environmental strategies on anthropometric outcomes. Systematic reviews vary in methodological quality, and not all relevant primary studies may be included in each review. To ensure relevance of our findings to practice, we also report on relevant underlying primary studies, providing policy-relevant recommendations based on the evidence reviewed. Greater standardization of review methods and reporting structures will benefit policymakers and public health professionals seeking informed decision-making

Smooth-muscle-associated contractile protein in renal mesenchymal tumour cells and in transformed cells from DMN-injected rats.

Cryostat sections and established in vitro cultures of dimethylnitrosamine(DMN)-induced renal mesenchymal tumours and monolayer cultures of transformed kidney cells derived from rats treated with a carcinogenic dose of DMN were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Eight mesenchymal tumours examined showed filamentous cytoplasmic staining of spindle cells infiltrating between renal tubules, whilst in normal kidneys interstitial cells were only weakly positive. In established in vitro cultures from 6 mesenchymal tumours, different patterns of staining were observed in morphologically different cell forms, ranging from fine filamentous staining in giant cells to diffuse cytoplasmic fluorescence in small bipolar cells, and cell outline staining in polygonal cells. In addition filamentous staining of microvillous projections and nucleolar staining were observed in some tumour cells. Monolayer cultures of transformed kidney cells showed strong staining of coarse, randomly-orientated cytoplasmic filaments, whilst fibroblasts cultured from normal rat kidney demonstrated an ordered array of fine, parallel filaments. Specificity of the immunofluorescent staining reaction was established by failure to obtain staining with normal serum, with smooth muscle antibody serum neutralized by homogenates of smooth muscle or extracts containing actin derived from smooth muscle. These results indicate that there is an apparent increase of actin-like contractile microfilaments in transformed cells and in renal mesenchymal tumours. The cytoplasmic contracile microfilaments in these cells may play a role in tumour cell mobility and invasion

Computer modelling of high temperature air combustion

Paper presented at the 9th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Malta, 16-18 July, 2012.High Temperature Air Combustion, HiTAC, is an innovative combustion technology which offers improved heat transfer and a reduction in fuel consumption and NOx emissions. This paper describes a project in which a computational fluid dynamic model of a furnace working on high temperature air combustion technology was developed using FLUENT® CFD software. The model was validated against experimental data obtained from KTH in Sweden. The predicted results compared very well with this experimental data, and were also closer than the predictions from the model built by KTH. The model was applied to a steam boiler of Malta’s Delimara Power Station. Two scenarios were considered: the boiler with conventional combustion and the boiler converted to HITAC. To reduce computational time, a 400:1 scaled down version of the boiler was modelled based on NOx scaling. Further reductions were made by taking advantage of the symmetry of the boiler and by obtaining the solution for a single burner, and then prescribing the parameter profiles for the single burner to the full boiler model as boundary conditions. The computer model results showed much lower NOx emission levels when firing the boiler with methane compared to heavy fuel oil. Further reductions in NOx emissions were obtained with HITAC technology and using methane as a fuel.dc201

Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population

Background Recent studies have implicated variants of the transcription factor 7-like 2 (TCF7L2) gene in genetic susceptibility to type 2 diabetes mellitus in several different populations. The aim of this study was to determine whether variants of this gene are also risk factors for type 2 diabetes development in a UK-resident South Asian cohort of Punjabi ancestry. Methods We genotyped four single nucleotide polymorphisms (SNPs) of TCF7L2 (rs7901695, rs7903146, rs11196205 and rs12255372) in 831 subjects with diabetes and 437 control subjects. Results The minor allele of each variant was significantly associated with type 2 diabetes; the greatest risk of developing the disease was conferred by rs7903146, with an allelic odds ratio (OR) of 1.31 (95% CI: 1.11 – 1.56, p = 1.96 × 10-3). For each variant, disease risk associated with homozygosity for the minor allele was greater than that for heterozygotes, with the exception of rs12255372. To determine the effect on the observed associations of including young control subjects in our data set, we reanalysed the data using subsets of the control group defined by different minimum age thresholds. Increasing the minimum age of our control subjects resulted in a corresponding increase in OR for all variants of the gene (p ≤ 1.04 × 10-7). Conclusion Our results support recent findings that TCF7L2 is an important genetic risk factor for the development of type 2 diabetes in multiple ethnic groups

Type 2 Diabetes Susceptibility Gene TCF7L2 and Its Role in β-Cell Function

Type 2 diabetes is associated with impaired insu-lin secretion. Both 1st- and 2nd-phase insulinsecretion are reduced, but the effect is particu-larly pronounced for the 1st phase. The pro-cesses culminating in impaired insulin secretion are not fully understood, but both genetic and environmental factors are thought to play a role. Over the past 2 years, genome-wide association scans have transformed the ge-netic landscape of type 2 diabetes susceptibility, with the current gene count close to 20 (1). A couple of common themes have emerged from these studies. First, the major-ity of the genes identified thus far seem to affect diabetes susceptibility through -cell dysfunction (2). Second, the risk alleles tend to be common in the population, but their effect on diabetes risk is relatively small (3,4). TCF7L2, the susceptibility gene with the largest effect on disease susceptibility discovered to date, was iden-tified pre–genome-wide association by Grant et al. i

Multi-turn losses and cleaning

In the LHC all multi-turn losses should occur at the collimators in the cleaning insertions. The cleaning inefficiency (leakage rate) is the figure of merit to describe the performance. In combination with the quench limit of the superconducting magnets and the instantaneous life time of the beam this defines the cleaning dependent beam intensity limit of the LHC. In addition, limits can arise from radiation-induced effects, like radiation damage and radation to electronics. In this paper the used collimator settings, the required setup time, the reliability of collimation (all multi-turn losses at collimators), and the achieved proton/ion cleaning inefficiency are discussed. Observed and expected losses are compared. The performance evolution during the months of operation is reviewed. In addition, the peak losses during high intensity runs, losses caused by instabilities, and the resulting beam life times are discussed. Taking the observations into account the intensity reach with collimation at 3.5 and 4 TeV is reviewed.peer-reviewe