Endothelin-1 Predicts Hemodynamically Assessed Pulmonary Arterial Hypertension in HIV Infection.

BackgroundHIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. ET-1 is a robust vasoconstrictor and key mediator of pulmonary vascular homeostasis. Higher levels of ET-1 predict disease severity and mortality in other forms of PAH, and endothelin receptor antagonists are central to treatment, including in HIV-associated PAH. The direct relationship between ET-1 and PAH in HIV-infected individuals is not well described.MethodsWe measured ET-1 and estimated pulmonary artery systolic pressure (PASP) with transthoracic echocardiography (TTE) in 106 HIV-infected individuals. Participants with a PASP ≥ 30 mmHg (n = 65) underwent right heart catheterization (RHC) to definitively diagnose PAH. We conducted multivariable analysis to identify factors associated with PAH.ResultsAmong 106 HIV-infected participants, 80% were male, the median age was 52 years and 77% were on antiretroviral therapy. ET-1 was significantly associated with higher values of PASP [14% per 0.1 pg/mL increase in ET-1, p = 0.05] and PASP ≥ 30 mmHg [PR (prevalence ratio) = 1.24, p = 0.012] on TTE after multivariable adjustment for PAH risk factors. Similarly, among the 65 individuals who underwent RHC, ET-1 was significantly associated with higher values of mean pulmonary artery pressure and PAH (34%, p = 0.003 and PR = 2.43, p = 0.032, respectively) in the multivariable analyses.ConclusionsHigher levels of ET-1 are independently associated with HIV-associated PAH as hemodynamically assessed by RHC. Our findings suggest that excessive ET-1 production in the setting of HIV infection impairs pulmonary endothelial function and contributes to the development of PAH

Hybrid endoscopic thymectomy : combined transesophageal and transthoracic approach in a survival porcine model with cadaver assessment

BACKGROUND: Video-assisted thoracoscopic surgery thymectomy has been used in the treatment of Myastenia Gravis and thymomas (coexisting or not). In natural orifice transluminal endoscopic surgery, new approaches to the thorax are emerging as alternatives to the classic transthoracic endoscopic surgery. The aim of this study was to assess the feasibility and reliability of hybrid endoscopic thymectomy (HET) using a combined transthoracic and transesophageal approach. METHODS: Twelve consecutive in vivo experiments were undertaken in the porcine model (4 acute and 8 survival). The same procedure was assessed in a human cadaver afterward. For HET, an 11-mm trocar was inserted in the 2nd intercostal space in the left anterior axillary line. A 0° 10-mm thoracoscope with a 5-mm working channel was introduced. Transesophageal access was created through a submucosal tunnel using a flexible gastroscope with a single working channel introduced through the mouth. Using both flexible (gastroscope) and rigid (thoracoscope) instruments, the mediastinum was opened; the thymus was dissected, and the vessels were ligated using electrocautery alone. RESULTS: Submucosal tunnel creation and esophagotomy were performed safely without incidents in all animals. Complete thymectomy was achieved in all experiments. All animals in the survival group lived for 14 days. Thoracoscopic and postmortem examination revealed pleural adhesions on site of the surgical procedure with no signs of infection. Histological analysis of the proximal third of the esophagus revealed complete cicatrization of both mucosal defect and myotomy site. In the human cadaver, we were able to replicate all the procedure even though we were not able to identify the thymus. CONCLUSIONS: Hybrid endoscopic thymectomy is feasible and reliable. HET could be regarded as a possible alternative to classic thoracoscopic approach for patients requiring thymectomy.This project was funded by the FCT Grants project PTDC/SAU-OSM/105578/2008

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

The need to promote behaviour change at the cultural level: one factor explaining the limited impact of the MEMA kwa Vijana adolescent sexual health intervention in rural Tanzania. A process evaluation

Background - Few of the many behavioral sexual health interventions in Africa have been rigorously evaluated. Where biological outcomes have been measured, improvements have rarely been found. One of the most rigorous trials was of the multi-component MEMA kwa Vijana adolescent sexual health programme, which showed improvements in knowledge and reported attitudes and behaviour, but none in biological outcomes. This paper attempts to explain these outcomes by reviewing the process evaluation findings, particularly in terms of contextual factors. Methods - A large-scale, primarily qualitative process evaluation based mainly on participant observation identified the principal contextual barriers and facilitators of behavioural change. Results - The contextual barriers involved four interrelated socio-structural factors: culture (i.e. shared practices and systems of belief), economic circumstances, social status, and gender. At an individual level they appeared to operate through the constructs of the theories underlying MEMA kwa Vijana - Social Cognitive Theory and the Theory of Reasoned Action – but the intervention was unable to substantially modify these individual-level constructs, apart from knowledge. Conclusion - The process evaluation suggests that one important reason for this failure is that the intervention did not operate sufficiently at a structural level, particularly in regard to culture. Recently most structural interventions have focused on gender or/and economics. Complementing these with a cultural approach could address the belief systems that justify and perpetuate gender and economic inequalities, as well as other barriers to behaviour change

Chemoattractant Receptor Homologous to the T Helper 2 Cell (CRTH2) Is Not Expressed in Human Amniocytes and Myocytes

BACKGROUND: 15-deoxy-Δ 12,14- Prostaglandin J2 (15dPGJ2) inhibits Nuclear factor kappa B (NF-κB) in human myocytes and amniocytes and delays inflammation induced preterm labour in the mouse. 15dPGJ2 is a ligand for the Chemoattractant Receptor Homologous to the T helper 2 cell (CRTH2), a G protein-coupled receptor, present on a subset of T helper 2 (Th2) cells, eosinophils and basophils. It is the second receptor for Prostaglandin D2, whose activation leads to chemotaxis and the production of Th2-type interleukins. The cellular distribution of CRTH2 in non-immune cells has not been extensively researched, and its identification at the protein level has been limited by the lack of specific antibodies. In this study we explored the possibility that CRTH2 plays a role in 15dPGJ2-mediated inhibition of NF-κB and would therefore represent a novel small molecule therapeutic target for the prevention of inflammation induced preterm labour. METHODS: The effect of a small molecule CRTH2 agonist on NF-κB activity in human cultured amniocytes and myocytes was assessed by detection of p65 and phospho-p65 by immunoblot. Endogenous CRTH2 expression in amniocytes, myocytes and peripheral blood mononuclear cells (PBMCs) was examined by PCR, western analysis and flow cytometry, with amniocytes and myocytes transfected with CRTH2 acting as a positive control in flow cytometry studies. RESULTS: The CRTH2 agonist had no effect on NF-κB activity in amniocytes and myocytes. Although CRTH2 mRNA was detected in amniocytes and myocytes, CRTH2 was not detectable at the protein level, as demonstrated by western analysis and flow cytometry. 15dPGJ2 inhibited phospho-65 in PBMC'S, however the CRTH2 antagonist was not able to attenuate this effect. In conclusion, CRTH2 is not expressed on human amniocytes or myocytes and plays no role in the mechanism of 15dPGJ2-mediated inhibition of NF-κB

Cardiac biomarkers of acute coronary syndrome: from history to high-sensitivity cardiac troponin

The role of cardiac troponins as diagnostic biomarkers of myocardial injury in the context of acute coronary syndrome (ACS) is well established. Since the initial 1st-generation assays, 5th-generation high-sensitivity cardiac troponin (hs-cTn) assays have been developed, and are now widely used. However, its clinical adoption preceded guidelines and even best practice evidence. This review summarizes the history of cardiac biomarkers with particular emphasis on hs-cTn. We aim to provide insights into using hs-cTn as a quantitative marker of cardiomyocyte injury to help in the differential diagnosis of coronary versus non-coronary cardiac diseases. We also review the recent evidence and guidelines of using hs-cTn in suspected ACS

Obesity-Related Oxidative Stress: the Impact of Physical Activity and Diet Manipulation

Obesity-related oxidative stress, the imbalance between pro-oxidants and antioxidants (e.g., nitric oxide), has been linked to metabolic and cardiovascular disease, including endothelial dysfunction and atherosclerosis. Reactive oxygen species (ROS) are essential for physiological functions including gene expression, cellular growth, infection defense, and modulating endothelial function. However, elevated ROS and/or diminished antioxidant capacity leading to oxidative stress can lead to dysfunction. Physical activity also results in an acute state of oxidative stress. However, it is likely that chronic physical activity provides a stimulus for favorable oxidative adaptations and enhanced physiological performance and physical health, although distinct responses between aerobic and anaerobic activities warrant further investigation. Studies support the benefits of dietary modification as well as exercise interventions in alleviating oxidative stress susceptibility. Since obese individuals tend to demonstrate elevated markers of oxidative stress, the implications for this population are significant. Therefore, in this review our aim is to discuss (i) the role of oxidative stress and inflammation as associated with obesity-related diseases, (ii) the potential concerns and benefits of exercise-mediated oxidative stress, and (iii) the advantageous role of dietary modification, including acute or chronic caloric restriction and vitamin D supplementation

Imperforate anus with a rectovestibular fistula and pseudotail: a case report

<p>Abstract</p> <p>Introduction</p> <p>Human tails and pseudotails are rare sacrococcygeal lesions that are associated with a wide variety of anomalies and syndromes. Anorectal malformations are also relatively uncommon congenital defects that often occur in conjunction with syndromes or other congenital abnormalities. The anomalies associated with both disorders determine the timing and approach to surgical correction. We present an unusual case of a patient with both imperforate anus and a pseudotail in the absence of a syndrome or other associated anomalies and we emphasize the necessity of a thorough preoperative evaluation.</p> <p>Case presentation</p> <p>A Caucasian girl was born at term after an uncomplicated pregnancy and was noted at birth to have a skin-covered posterior midline mass and imperforate anus with a fistula to the vaginal vestibule. Ultrasound and magnetic resonance imaging revealed a predominately fatty lesion without presacral extension and ruled out associated spinal and cord abnormalities. The patient underwent diversion with colostomy and a mucous fistula in the newborn period as a fistulogram demonstrated a long fistulous tract to normal rectum and it was anticipated that anoplasty and resection of the mass would require extensive posterior dissection. The sacrococcygeal mass was removed during posterior sagittal anorectoplasty at the age of six weeks which was determined to be a pseudotail because of the composition of brown fat and cartilage. The patient is now 14 months old with normal bowel function after a colostomy takedown.</p> <p>Conclusion</p> <p>A comprehensive preoperative assessment and thoughtful operative plan were necessary in this unusual case because of the extensive differential diagnosis for sacrococcygeal masses in the newborn and the frequency of anomalies and syndromes associated with tail variants and imperforate anus. The pediatricians and neonatologists who initially evaluate such patients and the surgeons who correct these disorders must be aware of the potential pitfalls in their management.</p

Groups whose word problem is a Petri net language

There has been considerable interest in exploring the connections between the word problem of a finitely generated group as a formal language and the algebraic structure of the group. However, there are few complete characterizations that tell us precisely which groups have their word problem in a specified class of languages. We investigate which finitely generated groups have their word problem equal to a language accepted by a Petri net and give a complete classification, showing that a group has such a word problem if and only if it is virtually abelian

Metabolic effects of bezafibrate in mitochondrial disease

Mitochondrial disorders affect 1/5,000 and have no cure. Inducing mitochondrial biogenesis with bezafibrate improves mitochondrial function in animal models, but there are no comparable human studies. We performed an open-label observational experimental medicine study of six patients with mitochondrial myopathy caused by the m.3243A>G MTTL1 mutation. Our primary aim was to determine the effects of bezafibrate on mitochondrial metabolism, whilst providing preliminary evidence of safety and efficacy using biomarkers. The participants received 600-1,200 mg bezafibrate daily for 12 weeks. There were no clinically significant adverse events, and liver function was not affected. We detected a reduction in the number of complex IV-immunodeficient muscle fibres and improved cardiac function. However, this was accompanied by an increase in serum biomarkers of mitochondrial disease, including fibroblast growth factor 21 (FGF-21), growth and differentiation factor 15 (GDF-15), plus dysregulation of fatty acid and amino acid metabolism. Thus, although potentially beneficial in short term, inducing mitochondrial biogenesis with bezafibrate altered the metabolomic signature of mitochondrial disease, raising concerns about long-term sequelae