VEGF-A and Semaphorin3A: Modulators of vascular sympathetic innervation

AbstractSympathetic nerve activity regulates blood pressure by altering peripheral vascular resistance. Variations in vascular sympathetic innervation suggest that vascular-derived cues promote selective innervation of particular vessels during development. As axons extend towards peripheral targets, they migrate along arterial networks following gradients of guidance cues. Collective ratios of these gradients may determine whether axons grow towards and innervate vessels or continue past non-innervated vessels towards peripheral targets. Utilizing directed neurite outgrowth in a three-dimensional (3D) co-culture, we observed increased axon growth from superior cervical ganglion explants (SCG) towards innervated compared to non-innervated vessels, mediated in part by vascular endothelial growth factor (VEGF-A) and Semaphorin3A (Sema3A) which both signal via neuropilin-1 (Nrp1). Exogenous VEGF-A, delivered by high-expressing VEGF-A–LacZ vessels or by rhVEGF-A/alginate spheres, increased sympathetic neurite outgrowth while exogenous rhSema3A/Fc decreased neurite outgrowth. VEGF-A expression is similar between the innervated and non-innervated vessels examined. Sema3A expression is higher in non-innervated vessels. Spatial gradients of Sema3A and VEGF-A may promote differential Nrp1 binding. Vessels expressing high levels of Sema3A favor Nrp1-PlexinA1 signaling, producing chemorepulsive cues limiting sympathetic neurite outgrowth and vascular innervation; while low Sema3A expressing vessels favor Nrp1-VEGFR2 signaling providing chemoattractive cues for sympathetic neurite outgrowth and vascular innervation

Sarcomere length and capillary curvature of rat hindlimb muscles in

length and capillary curvature of rat hindlimb muscles in vivo. J. Appl. Physiol. 78(6): 2047-2051,1995.-Mammalian skeletal muscle fibers have been reported to develop maximum force at a sarcomere length (L,) of -2.5 pm. However, the functional range of muscle length (L,) and L, encountered by skeletal muscle in vivo is not well defined. Changes in L, markedly influence capillary geometry, but this effect has been shown only in fixed preparations. The purpose of this study was to evaluate the influence of limb position on L,, L,, and capillary geometry in living undisturbed hindlimb muscles. We tested the hypothesis that maximal excursion of the foot would have similar effects on L, and capillary geometry of antagonistic soleus (Sol) and extensor digitorum long-us (EDL) muscles in vivo. Female Sprague-Dawley rats (IZ = 9; 243 ? 3 g) were anesthetized (pentobarbital sodium; 35 mg/kg). The right Sol and EDL muscles were exposed and irrigated with physiological saline solution (34°C; pH 7.4). Sarcomeres and capillaries were observed with video microscopy (total magnification X 1,900; spatial resolution <l pm); sarcomeres were labeled with a fluorescent dye [4-(4-diethylaminostyryl)-N-methylpyridinium iodide]. As foot angle increased from 30" (maximal dorsiflexion) to 170" (maximal plantarflexion), L, and L, increased for EDL muscles (27.51 + 0 42 to 30 97 t_ 0.25 mm and 2.33 t 0.01 to 3.09 t 0.05 -. . pm, respectively; P < 0.05) and decreased for Sol muscles (26.09 +-0.38 to 20.27 t 0.34 mm and 3.17 t 0.03 to 2.22 t 0.04 pm, respectively; P < 0.05). Muscle fiber lengths changed in parallel with L, and L, for each muscle, and the ranges of L, and L, were greater (P < 0.05) for Sol muscles compared with EDL muscles. Capillary curvature index (CCI; %capillary segments with axial deviation 25 pm along a 50-,um distance) increased with shortening in both muscles and was greater (P < 0.05) at each corresponding length in Sol muscle compared with EDL muscle. This in vivo difference in CC1 between muscles is consistent with higher capillary volume density in the Sol muscle compared with the EDL muscle. muscle mechanics; microcirculation; soleus; extensor digitorum long-us; muscle blood flow; video microscopy; fluorescence microscopy SARCOMERE LENGTH (L,) and its relation to tension development have been studied by using isolated skeletal muscle fibers (1, 12) and in fiber bundles that have been fixed at controlled muscle lengths (24). Surprisingly, there is a paucity of information regarding how L, may change with limb position in living muscle. In skeletal muscles that have been fixed in various states of shortening or extension, capillary curvature has been found to increase as L, decreases (19, 20, 22). However, neither L, nor capillary geometry have been studied in living muscle throughout the anatomically defined range of motion. The purpose of this study was to evaluate the range of muscle length (L,) and L, in vivo and to investigate the relationship between L, and capillary curvature of intact locomotor muscles of anesthetized rats. The antagonistic soleus (Sol) and extensor digitorum longus (EDL) muscles were used, as the structural and functional properties of these muscles are well defined (2, 3

One Year Out: An Assessment of DADT Repeal’s Impact on Military Readiness

Prior to the repeal of “don’t ask, don’t tell” (DADT) on September 20, 2011, many observers predicted that allowing lesbian, gay and bisexual (LGB) troops to serve openly would harm the military. This study is the first scholarly effort to assess the accuracy of such predictions about the impact of DADT repeal on military readiness. Our conclusions are based on a consideration of all of the evidence that was available to us at the time our research was conducted, the half- year period starting six months after repeal and concluding at the one-year mark. We sought to maximize the likelihood of identifying evidence of damage caused by repeal by pursuing ten separate research strategies, each of which was designed to uncover data indicating that repeal has undermined the military. Our research strategies included outreach to 553 generals and admirals who predicted that repeal would undermine the military, to all major activists and expert opponents of DADT repeal and to 18 watchdog organizations, including opponents and advocates of repeal, who are known for their ability to monitor Pentagon operations. In addition, we conducted in-depth interviews with 18 scholars and practitioners and 62 active-duty heterosexual, lesbian, gay and bisexual troops from every service branch, as well as on-site field observations of four military units. We analyzed relevant media articles published during the research period, administered two surveys and conducted secondary source analysis of surveys independently administered by outside organizations. Our vigorous effort to collect data from opponents of DADT repeal, including anti-repeal generals and admirals, activists, academic experts, service members and watchdog organizations, should sustain confidence in the validity and impartiality of our findings. Our study team includes distinguished scholars from the US Military Academy, US Air Force Academy, US Naval Academy and US Marine Corps War College, as well as scholars with internationally recognized expertise on the issue of gays in the military. Several members advised the Pentagon’s 2010 DADT working group, and one member led the team that drafted the Defense Department’s plan for implementing DADT repeal

Frequent coexistence of anti-topoisomerase I and anti-U1RNP autoantibodies in African American patients associated with mild skin involvement: a retrospective clinical study

Introduction: The presence of anti-topoisomerase I (topo I) antibodies is a classic scleroderma (SSc) marker presumably associated with a unique clinical subset. Here the clinical association of anti-topo I was reevaluated in unselected patients seen in a rheumatology clinic setting.Methods: Sera from the initial visit in a cohort of unselected rheumatology clinic patients (n = 1,966, including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) were screened by radioimmunoprecipitation. Anti-topo I-positive sera were also tested with immunofluorescence and RNA immunoprecipitation.Results: Twenty-five (15 Caucasian, eight African American, two Latin) anti-topo I positive patients were identified, and all except one met the ACR SSc criteria. Coexistence of other SSc autoantibodies was not observed, except for anti-U1RNP in six cases. When anti-topo I alone versus anti-topo I + U1RNP groups were compared, African American (21% vs. 67%), overlap with SLE (0 vs. 50%; P = 0.009) or PM/DM (0 vs. 33%; P = 0.05) or elevated creatine phosphokinase (CPK) (P = 0.07) were more common in the latter group. In comparison of anti-topo I-positive Caucasians versus African Americans, the latter more frequently had anti-U1RNP (13% vs. 50%), mild/no skin changes (14% vs. 63%; P = 0.03) and overlap with SLE (0 vs. 38%; P = 0.03) and PM/DM (0 vs. 25%; P = 0.05).Conclusions: Anti-topo I detected by immunoprecipitation in unselected rheumatology patients is highly specific for SSc. Anti-topo I coexisting with anti-U1RNP in African American patients is associated with a subset of SLE overlapping with SSc and PM/DM but without apparent sclerodermatous changes. \ua9 2011 Satoh et al.; licensee BioMed Central Ltd

Validating module network learning algorithms using simulated data

In recent years, several authors have used probabilistic graphical models to learn expression modules and their regulatory programs from gene expression data. Here, we demonstrate the use of the synthetic data generator SynTReN for the purpose of testing and comparing module network learning algorithms. We introduce a software package for learning module networks, called LeMoNe, which incorporates a novel strategy for learning regulatory programs. Novelties include the use of a bottom-up Bayesian hierarchical clustering to construct the regulatory programs, and the use of a conditional entropy measure to assign regulators to the regulation program nodes. Using SynTReN data, we test the performance of LeMoNe in a completely controlled situation and assess the effect of the methodological changes we made with respect to an existing software package, namely Genomica. Additionally, we assess the effect of various parameters, such as the size of the data set and the amount of noise, on the inference performance. Overall, application of Genomica and LeMoNe to simulated data sets gave comparable results. However, LeMoNe offers some advantages, one of them being that the learning process is considerably faster for larger data sets. Additionally, we show that the location of the regulators in the LeMoNe regulation programs and their conditional entropy may be used to prioritize regulators for functional validation, and that the combination of the bottom-up clustering strategy with the conditional entropy-based assignment of regulators improves the handling of missing or hidden regulators.Comment: 13 pages, 6 figures + 2 pages, 2 figures supplementary informatio

Description of the Efficacy and Safety of Three New Biologics in the Treatment of Rheumatoid Arthritis

English articles on abatacept, golimumab, and tocilizumab in rheumatoid arthritis published between 2002 and 2009 were reviewed systematically. All randomized clinical trials, open-label extensions, meta-analyses, and reviews were examined. There were thirteen articles on abatacept, four on golimumab, and seven on tocilizumab. All three drugs were effective in methotrexate-naïve, methotrexate-incomplete responders, and tumor-necrosis-factor-failure rheumatoid arthritis patients. Of the three, only abatacept has been tested in a head-to-head trial with infliximab, in which it was found to be equivalent to infliximab. Golimumab resulted in a more modest improvement than the others in methotrexate-naïve patients, although no direct comparisons among the three drugs were possible or appropriate. Descriptive analysis of adverse events showed that patients receiving abatacept, golimumab, and tocilizumab were subject to more adverse events than controls overall, as expected. In the abatacept studies, a few cases of tuberculosis, more cardiovascular events and gastrointestinal bleedings and more basal cell carcinoma were seen. Golimumab was associated with more skin rashes and pneumonia, while tocilizumab was associated with increased lipids, more liver-function abnormalities, and neutropenia. These new medications are useful additions to the rheumatologic armamentarium and represent greater convenience (golimumab) or different mechanisms of action (abatacept and tocilizumab) than tumor-necrosis-factor inhibitors for treating rheumatoid arthritis. As expected, some adverse events occur when using these drugs and patients need to be watched carefully

Systematic review of interventions to encourage careers in academic medicine

Aims: Academic medicine is a career route that historically struggles to recruit and retain suitable doctors. The aim of this paper is to review the evidence for interventions to encourage careers in academic medicine by way of a descriptive systematic review. Methods: Key databases were searched in February 2017. Studies that evaluated interventions to encourage careers in academic medicine and that used a pre–post analysis or included a comparison group were included. Interventions reporting only learner satisfaction were excluded. The review was specific to medical students and graduates. Results: Twenty-four studies were identified for inclusion within the review. The included studies identified interventions across five domains: postgraduate funding, postgraduate training, mentoring, undergraduate interventions, and institutional change. The papers varied in terms of strength of conclusion and method of analysis with broad, structured, well-funded programs having the most palpable results. Conclusions: The five domains identified offer a framework that can be used by institutions who wish to develop similar programs. It also offers a body of research on which an evidence base can be built

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes

NADPH Oxidase Limits Innate Immune Responses in the Lungs in Mice

Background: Chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e.g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood. Methodology/Principal Findings: We found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47phox-/- mice and gp91phox-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kB activation, and elevated downstream pro-inflammatory cytokines (TNF-α, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kB activation. Conclusions/Significance: These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD