Thrombin increases inflammatory cytokine and angiogenic growth factor secretion in human adipose cells in vitro

<p>Abstract</p> <p>Background</p> <p>Abdominal obesity is associated with pro-thrombotic and inflammatory states. Therefore, the purpose of this study was to examine the expression of thrombin receptors (PAR1 and PAR4) human adipose tissue and whether thrombin stimulates an inflammatory cytokine and growth factor profile in human adipose tissue.</p> <p>Methods</p> <p>Human adipose tissue, isolated preadipocytes and differentiated adipocytes were used in this study. PAR1 and PAR4 mRNA and protein were detected by RT-PCR and immunoblot analysis in both adipose tissue and adipose microvessels. In separate studies, IL-1β, IL-6, MCP-1, TNF-α, IL-10, FGF-2, VEGF, and PDGF production were measured from adipose tissue (n = 5), adipocytes (n = 5), and preadipocytes (n = 3) supernatants with and without thrombin (1 or 10 U/ml; 24 hrs) treatment.</p> <p>Results</p> <p>Thrombin increased cytokine secretion of IL-1β, IL-6, MCP-1 and TNF-α and growth factor secretion of VEGF from adipocytes along with MCP-1 and VEGF from preadipocytes. The direct thrombin inhibitor lepirudin given in conjunction with thrombin prevented the thrombin-mediated increase in cytokine and growth factor secretion.</p> <p>Conclusion</p> <p>Here we show that thrombin PAR1 and PAR4 receptors are present and that thrombin stimulates inflammatory cytokine generation and growth factor release in human adipose tissue and cells <it>in vitro</it>. These data suggest that thrombin may represent a molecular link between obesity and associated inflammation.</p

Vascular dysfunction and exercise

The endothelium regulates vascular permeability and actively controls the exchange of molecules in response to environmental and molecular signals. Endothelial cells regulate vascular tone by releasing a number of soluble mediators, including nitric oxide, prostaglandin I2, and endothelium-derived hyperpolarizing factor. Misbalance between pro-oxidants and antioxidants results in increased production of reactive oxygen species, increased oxidative stress and endothelial dysfunction. Endothelium dysfunction is characterized by an impaired nitric oxide bioavailability due to reduced production of nitric oxide, reduced endothelium-dependent hyper-polarization and enhanced production of contracting factors. Endothelium dysfunction leads to vascular remodeling by vascular smooth muscle cells proliferation, migration and extracellular matrix remodeling. The presence of impaired endotheliumdependent vasodilation is a marker of endothelial dysfunction. The benefits of exercise on the cardiovascular system have long been recognized. Most clinical and experimental studies have reported beneficial effects of regular physical activity in increasing nitric oxide bioavailability and reducing oxidative stress. Therefore, regular physical exercise may be a protective factor against vascular dysfunction induced by acute exertion

Vascular dysfunction and exercise

The endothelium regulates vascular permeability and actively controls the exchange of molecules in response to environmental and molecular signals. Endothelial cells regulate vascular tone by releasing a number of soluble mediators, including nitric oxide, prostaglandin I2, and endothelium-derived hyperpolarizing factor. Misbalance between pro-oxidants and antioxidants results in increased production of reactive oxygen species, increased oxidative stress and endothelial dysfunction. Endothelium dysfunction is characterized by an impaired nitric oxide bioavailability due to reduced production of nitric oxide, reduced endothelium-dependent hyper-polarization and enhanced production of contracting factors. Endothelium dysfunction leads to vascular remodeling by vascular smooth muscle cells proliferation, migration and extracellular matrix remodeling. The presence of impaired endotheliumdependent vasodilation is a marker of endothelial dysfunction. The benefits of exercise on the cardiovascular system have long been recognized. Most clinical and experimental studies have reported beneficial effects of regular physical activity in increasing nitric oxide bioavailability and reducing oxidative stress. Therefore, regular physical exercise may be a protective factor against vascular dysfunction induced by acute exertion

Exercise training in group 2 pulmonary hypertension: which intensity and what modality

Pulmonary hypertension (PH) due to left-sided heart disease (LSHD) is a common and disconcerting occurrence. For example, both heart failure (HF) with preserved and reduced ejection fraction (HFpEF and HFrEF) often lead to PH as a consequence of a chronic elevation in left atrial filling pressure. A wealth of literature demonstrates the value of exercise training (ET) in patients with LSHD, which is particularly robust in patients with HFrEF and growing in patients with HFpEF. While the effects of ET have not been specifically explored in the LSHD–PH phenotype (i.e., composite pathophysiologic characteristics of patients in this advanced disease state), the overall body of evidence supports clinical application in this subgroup. Moderate intensity aerobic ET significantly improves peak oxygen consumption, quality of life and prognosis in patients with HF. Resistance ET significantly improves muscle strength and endurance in patients with HF, which further enhance functional capacity. When warranted, inspiratory muscle training and neuromuscular electrical stimulation are becoming recognized as important components of a comprehensive rehabilitation program. This review will provide a detailed account of ET programing considerations in patients with LSHD with a particular focus on those concomitantly diagnosed with PH

Interpreting ambiguous ‘trace’ results in Schistosoma mansoni CCA Tests: Estimating sensitivity and specificity of ambiguous results with no gold standard

Background The development of new diagnostics is an important tool in the fight against disease. Latent Class Analysis (LCA) is used to estimate the sensitivity and specificity of tests in the absence of a gold standard. The main field diagnostic for Schistosoma mansoni infection, Kato-Katz (KK), is not very sensitive at low infection intensities. A point-of-care circulating cathodic antigen (CCA) test has been shown to be more sensitive than KK. However, CCA can return an ambiguous ‘trace’ result between ‘positive’ and ‘negative’, and much debate has focused on interpretation of traces results. Methodology/Principle findings We show how LCA can be extended to include ambiguous trace results and analyse S. mansoni studies from both Côte d’Ivoire (CdI) and Uganda. We compare the diagnostic performance of KK and CCA and the observed results by each test to the estimated infection prevalence in the population. Prevalence by KK was higher in CdI (13.4%) than in Uganda (6.1%), but prevalence by CCA was similar between countries, both when trace was assumed to be negative (CCAtn: 11.7% in CdI and 9.7% in Uganda) and positive (CCAtp: 20.1% in CdI and 22.5% in Uganda). The estimated sensitivity of CCA was more consistent between countries than the estimated sensitivity of KK, and estimated infection prevalence did not significantly differ between CdI (20.5%) and Uganda (19.1%). The prevalence by CCA with trace as positive did not differ significantly from estimates of infection prevalence in either country, whereas both KK and CCA with trace as negative significantly underestimated infection prevalence in both countries. Conclusions Incorporation of ambiguous results into an LCA enables the effect of different treatment thresholds to be directly assessed and is applicable in many fields. Our results showed that CCA with trace as positive most accurately estimated infection prevalence

The Outer Disks of Early-Type Galaxies. I. Surface-Brightness Profiles of Barred Galaxies

We present a study of 66 barred, early-type (S0-Sb) disk galaxies, focused on the disk surface brightness profile outside the bar region and the nature of Freeman Type I and II profiles, their origins, and their possible relation to disk truncations. This paper discusses the data and their reduction, outlines our classification system, and presents $R$-band profiles and classifications for all galaxies in the sample. The profiles are derived from a variety of different sources, including the Sloan Digital Sky Survey (Data Release 5). For about half of the galaxies, we have profiles derived from more than one telescope; this allows us to check the stability and repeatability of our profile extraction and classification. The vast majority of the profiles are reliable down to levels of mu_R ~ 27 mag arcsec^-2; in exceptional cases, we can trace profiles down to mu_R > 28. We can typically follow disk profiles out to at least 1.5 times the traditional optical radius R_25; for some galaxies, we find light extending to ~ 3 R_25. We classify the profiles into three main groups: Type I (single-exponential), Type II (down-bending), and Type III (up-bending). The frequencies of these types are approximately 27%, 42%, and 24%, respectively, plus another 6% which are combinations of Types II and III. We further classify Type II profiles by where the break falls in relation to the bar length, and in terms of the postulated mechanisms for breaks at large radii ("classical trunction" of star formation versus the influence of the Outer Lindblad Resonance of the bar). We also classify the Type III profiles by the probable morphology of the outer light (disk or spheroid). Illustrations are given for all cases. (Abridged)Comment: 41 pages, 26 PDF figures. To appear in the Astronomical Journal. Version with full-resolution figures available at http://www.mpe.mpg.de/~erwin/research

Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology

<p>Abstract</p> <p>Background</p> <p>Low-fat (LF) and high-fat (HF) weight loss diets improve brachial artery flow-mediated dilation (FMD) in obese individuals, although results are conflicting. Moreover, the role that adipose tissue plays in mediating these diet-related effects are unknown.</p> <p>Objective</p> <p>This study examined how modulations in FMD by HF and LF diets relate to changes in adipocyte parameters.</p> <p>Design</p> <p>Obese subjects (n = 17) were randomized to a HF diet (60% kcal as fat) or a LF diet (25% kcal as fat) for 6 weeks. Both groups were restricted by 25% of energy needs.</p> <p>Results</p> <p>Body weight decreased (<it>P <</it>0.05) in both groups (HF: -6.6 ± 0.5 kg, LF: -4.7 ± 0.6 kg). Fat mass and waist circumference were reduced (<it>P <</it>0.05) in the LF group only (-4.4 ± 0.3 kg; -3.6 ± 0.8 cm, respectively). FMD improved (<it>P <</it>0.05) in the LF group (7.4 ± 0.8% to 9.8 ± 0.8; 32% increase) and was impaired in the HF group (8.5 ± 0.6% to 6.9 ± 0.7; 19% reduction). Increases in plasma adiponectin (<it>P <</it>0.05, 16 ± 5%), and decreases in resistin (<it>P <</it>0.05, -26 ± 11%), were shown by the LF diet only. Greater decreases in leptin were observed with LF (-48 ± 9%) versus HF (-28 ± 12%) (<it>P <</it>0.05, diet × time). Increased FMD by the LF diet was associated with increased adiponectin, and decreased fat mass, waist circumference, leptin, and resistin.</p> <p>Conclusion</p> <p>Beneficial modulations in vascular health by LF diets may be mediated by improvements in adipocyte parameters.</p

Paying Refugees to Leave

States are increasingly paying refugees to repatriate, hoping to decrease the number of refugees residing within their borders. Drawing on in-depth interviews from East Africa and data from Israeli Labour Statistics, I provide a description of such payment schemes and consider whether they are morally permissible. In doing so, I address two types of cases. In the first type of case, governments pay refugees to repatriate to high-risk countries, never coercing them into returning. I argue that such payments are permissible if refugees’ choices are voluntary and if states allow refugees to return to the host country in the event of an emergency. I then describe cases where states detain refugees, and non-governmental organisations provide their own payments to refugees wishing to repatriate. In such cases, non-governmental organisations are only permitted to provide payments if the funds are sufficient to ensure post-return safety and if providing payments does not reinforce the government’s detention policy

The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's “no presumption of advantage” principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of “meaningful competition” is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports

Atheisms and the purification of faith

Philosophers of religion have distinguished between ‘negative’ and ‘positive’ atheism. This article considers further conceptions of atheism, especially the idea that atheism can facilitate a faith in God purified of idolatrous assumptions. After introducing Bultmann’s contention that a ‘conscious atheist’ can find something transcendent in the world, this contention is interpreted through reflection on Ricoeur’s claim that the atheisms of Nietzsche and Freud serve to mediate a transition to a purified faith – a faith involving heightened receptivity to agapeic love. The troubling question of what differentiates atheism from belief in God is then discussed in the light of Simone Weil’s meditations on God’s secret presence