Nicotinic acetylcholine receptor variants associated with susceptibility to chronic obstructive pulmonary disease: a meta-analysis

<p>Abstract</p> <p>Background</p> <p>Only 10-15% of smokers develop chronic obstructive pulmonary disease (COPD) which indicates genetic susceptibility to the disease. Recent studies suggested an association between COPD and polymorphisms in <it>CHRNA </it>coding subunits of nicotinic acetylcholine receptor. Herein, we performed a meta-analysis to clarify the impact of <it>CHRNA </it>variants on COPD.</p> <p>Methods</p> <p>We searched Web of Knowledge and Medline from 1990 through June 2011 for COPD gene studies reporting variants on <it>CHRNA</it>. Pooled odds ratios (ORs) were calculated using the major allele or genotype as reference group.</p> <p>Results</p> <p>Among seven reported variants in <it>CHRNA</it>, rs1051730 was finally analyzed with sufficient studies. Totally 3460 COPD and 11437 controls from 7 individual studies were pooled-analyzed. A-allele of rs1051730 was associated with an increased risk of COPD regardless of smoking exposure (pooled OR = 1.26, 95% CI 1.18-1.34, p < 10^-5). At the genotypic level, the ORs gradually increased per A-allele (OR = 1.27 and 1.50 for GA and AA respectively, p < 10^-5). Besides, AA genotype exhibited an association with reduced FEV1% predicted (mean difference 3.51%, 95%CI 0.87-6.16%, p = 0.009) and increased risk of emphysema (OR 1.93, 95%CI 1.29-2.90, p = 0.001).</p> <p>Conclusions</p> <p>Our findings suggest that rs1051730 in <it>CHRNA </it>is a susceptibility variant for COPD, in terms of both airway obstruction and parenchyma destruction.</p

Interfacility Helicopter Ambulance Transport of Neurosurgical Patients: Observations, Utilization, and Outcomes from a Quaternary Level Care Hospital

The clinical benefit of helicopter transport over ground transportation for interfacility transport is unproven. We sought to determine actual practice patterns, utilization, and outcomes of patients undergoing interfacility transport for neurosurgical conditions.We retrospectively examined all interfacility helicopter transfers to a single trauma center during 2008. We restricted our analysis to those transfers leading either to admission to the neurosurgical service or to formal consultation upon arrival. Major exclusion criteria included transport from the scene, death during transport, and transport to any area of the hospital other than the emergency department. The primary outcome was time interval to invasive intervention. Secondary outcomes were estimated ground transportation times from the referring hospital, admitting disposition, and discharge disposition. Of 526 candidate interfacility helicopter transfers to our emergency department in 2008, we identified 167 meeting study criteria. Seventy-five (45%) of these patients underwent neurosurgical intervention. The median time to neurosurgical intervention ranged from 1.0 to 117.8 hours, varying depending on the diagnosis. For 101 (60%) of the patients, estimated driving time from the referring institution was less than one hour. Four patients (2%) expired in the emergency department, and 34 patients (20%) were admitted to a non-ICU setting. Six patients were discharged home within 24 hours. For those admitted, in-hospital mortality was 28%.Many patients undergoing interfacility transfer for neurosurgical evaluation are inappropriately triaged to helicopter transport, as evidenced by actual times to intervention at the accepting institution and estimated ground transportation times from the referring institution. In a time when there is growing interest in health care cost containment, practitioners must exercise discretion in the selection of patients for air ambulance transport--particularly when it may not bear influence on clinical outcome. Neurosurgical evaluation via telemedicine may be one strategy for improving air transport triage

The glycan-binding protein galectin-1 controls survival of epithelial cells along the crypt-villus axis of small intestine

Intestinal epithelial cells serve as mechanical barriers and active components of the mucosal immune system. These cells migrate from the crypt to the tip of the villus, where different stimuli can differentially affect their survival. Here we investigated, using in vitro and in vivo strategies, the role of galectin-1 (Gal-1), an evolutionarily conserved glycan-binding protein, in modulating the survival of human and mouse enterocytes. Both Gal-1 and its specific glyco-receptors were broadly expressed in small bowel enterocytes. Exogenous Gal-1 reduced the viability of enterocytes through apoptotic mechanisms involving activation of both caspase and mitochondrial pathways. Consistent with these findings, apoptotic cells were mainly detected at the tip of the villi, following administration of Gal-1. Moreover, Gal-1-deficient (Lgals1−/−) mice showed longer villi compared with their wild-type counterparts in vivo. In an experimental model of starvation, fasted wild-type mice displayed reduced villi and lower intestinal weight compared with Lgals1−/− mutant mice, an effect reflected by changes in the frequency of enterocyte apoptosis. Of note, human small bowel enterocytes were also prone to this pro-apoptotic effect. Thus, Gal-1 is broadly expressed in mucosal tissue and influences the viability of human and mouse enterocytes, an effect which might influence the migration of these cells from the crypt, the integrity of the villus and the epithelial barrier function

Separation of track- and shower-like energy deposits in ProtoDUNE-SP using a convolutional neural network

Liquid argon time projection chamber detector technology provides high spatial and calorimetric resolutions on the charged particles traversing liquid argon. As a result, the technology has been used in a number of recent neutrino experiments, and is the technology of choice for the Deep Underground Neutrino Experiment (DUNE). In order to perform high precision measurements of neutrinos in the detector, final state particles need to be effectively identified, and their energy accurately reconstructed. This article proposes an algorithm based on a convolutional neural network to perform the classification of energy deposits and reconstructed particles as track-like or arising from electromagnetic cascades. Results from testing the algorithm on experimental data from ProtoDUNE-SP, a prototype of the DUNE far detector, are presented. The network identifies track- and shower-like particles, as well as Michel electrons, with high efficiency. The performance of the algorithm is consistent between experimental data and simulation

Perifosine – a new option in treatment of acute myeloid leukemia?

Introduction: Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other rationally selected targeted agents. The evidence from clinical trials supporting the use of perifosine in the therapy of leukemias is limited. The optimal dose and schedule have yet to be defined. However, given its favorable toxicity profile and mechanism of action, the therapeutic potential of perifosine should be evaluated in well-designed clinical trials. Areas covered: The role of the phosphatidylinositol-3 kinase (PI3K)/Akt zpathway in normal cells, cancer and leukemias is discussed. The mechanism of action of perifosine and the basic information on the development and chemical properties are summarized. The evidence from in vivo and in vitro studies is presented. The efficacy and side effect profile are summarized. Expert opinion: The safety and tolerability profile of perifosine are satisfactory. The evidence from clinical trials in patients with leukemias is very limited. The preclinical data are encouraging. Perifosine has the potential to play a role in the treatment of leukemias in the future. Its role needs to be confirmed in clinical trials

GABA(B1) knockout mice reveal alterations in prolactin levels, gonadotropic axis, and reproductive function

gamma-Aminobutyric acid (GABA) has been implicated in the control of hypophyseal functions. We evaluated whether the constitutive loss of functional GABA(B) receptors in GABA(B1) knockout (GABA(B1)(-/-)) mice alters hormonal levels, under basal and stimulated conditions, and reproductive function. The serum hormone levels were measured by radioimmunoassay, the estrous cyclicity was evaluated by vaginal lavages, and the mating behavior was determined by the presence of vaginal plugs. A moderate hyperprolactinemic condition was observed, in which prolactin increase and thyroid-stimulating hormone decrease were similar between genotypes. Basal luteinizing hormone (LH), follicle-stimulating hormone, thyroid-stimulating hormone, and growth hormone levels were similar between genotypes in each sex. Analysis of the gonadotropin axis revealed no differences in puberty onset between female genotypes. In con trast, the estrous cyclicity was significantly disrupted in GABA(B1)(-/-) female mice, showing significantly extended periods in estrus and shortened periods in proestrus. Reproduction was significantly compromised in GABA(B1)(-/-) females, with a significantly lower proportion of mice (37.5%) getting pregnant during the first 30 days of mating as compared with wild-type controls (87.5%). Moreover, only 14% of vaginal plug positive GABA(B1)(-/-) females had successful pregnancies as compared with 75% in the controls. In addition, the postovariectomy LH rise was significantly advanced in GABA(B1)(-/-) mice, while the response to estradiol feedback was similar in both genotypes. In conclusion, our endocrine analysis of GABA(B1)(-/-) mice reveals that GABA(B) receptors are involved in the regulation of basal prolactin titers. Moreover, the hypothalamic-hypophyseal-ovarian axis is seriously disturbed, with alterations in cyclicity, postcastration LH increase, and fertility indexes. The molecular mechanism underlying these hormonal disturbances remains to be addressed

IL-4Ralpha-associated antigen processing by B cells promotes immunity in Nippostrongylus brasiliensis infection.

In this study, B cell function in protective T(H)2 immunity against N. brasiliensis infection was investigated. Protection against secondary infection depended on IL-4Ralpha and IL-13; but not IL-4. Protection did not associate with parasite specific antibody responses. Re-infection of B cell-specific IL-4Ralpha(-)/(-) mice resulted in increased worm burdens compared to control mice, despite their equivalent capacity to control primary infection. Impaired protection correlated with reduced lymphocyte IL-13 production and B cell MHC class II and CD86 surface expression. Adoptive transfer of in vivo N. brasiliensis primed IL-4Ralpha expressing B cells into naive BALB/c mice, but not IL-4Ralpha or IL-13 deficient B cells, conferred protection against primary N. brasiliensis infection. This protection required MHC class II compatibility on B cells suggesting cognate interactions by B cells with CD4(+) T cells were important to co-ordinate immunity. Furthermore, the rapid nature of these protective effects by B cells suggested non-BCR mediated mechanisms, such as via Toll Like Receptors, was involved, and this was supported by transfer experiments using antigen pulsed Myd88(-)/(-) B cells. These data suggest TLR dependent antigen processing by IL-4Ralpha-responsive B cells producing IL-13 contribute significantly to CD4(+) T cell-mediated protective immunity against N. brasiliensis infection