A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide

Why business angels reject investment opportunities: Is it personal?

A major focus of research on business angels has examined their decision-making processes and investment criteria. As business angels reject most of the opportunities that they receive, this article explores the reasons informing such decisions. In view of angel heterogeneity, investment opportunities might be expected to be rejected for differing reasons. Two sources of data are used to examine this issue. Face-to-face interviews with 30 business angels in Scotland and Northern Ireland provided information on typical ‘deal killers’. This was complemented by an Internet survey of United Kingdom that attracted responses from 238 UK business angels. The findings confirm that the main reason for rejection relates to the entrepreneur/management team. However, angel characteristics do not explain the number of reasons given for opportunity rejection nor do they predict the reasons for rejecting investment opportunities. This could be related to the increasing trend for business angels to join organised groups which, in turn, leads to the development of a shared repertoire of investment approaches. We suggest the concept of ‘communities-of-practice’ as an explanation for this finding

Preliminary Limits on the WIMP-Nucleon Cross Section from the Cryogenic Dark Matter Search (CDMS)

We are conducting an experiment to search for WIMPs, or weakly-interacting massive particles, in the galactic halo using terrestrial detectors. This generic class of hypothetical particles, whose properties are similar to those predicted by extensions of the standard model of particle physics, could comprise the cold component of non-baryonic dark matter. We describe our experiment, which is based on cooled germanium and silicon detectors in a shielded low-background cryostat. The detectors achieve a high degree of background rejection through the simultaneous measurement of the energy in phonons and ionization. Using exposures on the order of one kilogram-day from initial runs of our experiment, we have achieved (preliminary) upper limits on the WIMP-nucleon cross section that are comparable to much longer runs of other experiments.Comment: 5 LaTex pages, 5 eps figs, epsf.sty, espcrc2dsa2.sty. Proceedings of TAUP97, Gran Sasso, Italy, 7-11 Sep 1997, Nucl. Phys. Suppl., A. Bottino, A. di Credico and P. Monacelli (eds.). See also http://cfpa.berkeley.ed

Alcohol affects neuronal substrates of response inhibition but not of perceptual processing of stimuli signalling a stop response

Alcohol impairs inhibitory control, including the ability to terminate an initiated action. While there is increasing knowledge about neural mechanisms involved in response inhibition, the level at which alcohol impairs such mechanisms remains poorly understood. Thirty-nine healthy social drinkers received either 0.4g/kg or 0.8g/kg of alcohol, or placebo, and performed two variants of a Visual Stop-signal task during acquisition of functional magnetic resonance imaging (fMRI) data. The two task variants differed only in their instructions: in the classic variant (VSST), participants inhibited their response to a “Go-stimulus” when it was followed by a “Stop-stimulus”. In the control variant (VSST_C), participants responded to the “Go-stimulus” even if it was followed by a “Stop-stimulus”. Comparison of successful Stop-trials (Sstop)>Go, and unsuccessful Stop-trials (Ustop)>Sstop between the three beverage groups enabled the identification of alcohol effects on functional neural circuits supporting inhibitory behaviour and error processing. Alcohol impaired inhibitory control as measured by the Stop-signal reaction time, but did not affect other aspects of VSST performance, nor performance on the VSST_C. The low alcohol dose evoked changes in neural activity within prefrontal, temporal, occipital and motor cortices. The high alcohol dose evoked changes in activity in areas affected by the low dose but importantly induced changes in activity within subcortical centres including the globus pallidus and thalamus. Alcohol did not affect neural correlates of perceptual processing of infrequent cues, as revealed by conjunction analyses of VSST and VSST_C tasks. Alcohol ingestion compromises the inhibitory control of action by modulating cortical regions supporting attentional, sensorimotor and action-planning processes. At higher doses the impact of alcohol also extends to affect subcortical nodes of fronto-basal ganglia- thalamo-cortical motor circuits. In contrast, alcohol appears to have little impact on the early visual processing of infrequent perceptual cues. These observations clarify clinically-important effects of alcohol on behaviour

Glucocorticoids—All-Rounders Tackling the Versatile Players of the Immune System

Glucocorticoids regulate fundamental processes of the human body and control cellular functions such as cell metabolism, growth, differentiation, and apoptosis. Moreover, endogenous glucocorticoids link the endocrine and immune system and ensure the correct function of inflammatory events during tissue repair, regeneration, and pathogen elimination via genomic and rapid non-genomic pathways. Due to their strong immunosuppressive, anti-inflammatory and anti-allergic effects on immune cells, tissues and organs, glucocorticoids significantly improve the quality of life of many patients suffering from diseases caused by a dysregulated immune system. Despite the multitude and seriousness of glucocorticoid-related adverse events including diabetes mellitus, osteoporosis and infections, these agents remain indispensable, representing the most powerful, and cost-effective drugs in the treatment of a wide range of rheumatic diseases. These include rheumatoid arthritis, vasculitis, and connective tissue diseases, as well as many other pathological conditions of the immune system. Depending on the therapeutically affected cell type, glucocorticoid actions strongly vary among different diseases. While immune responses always represent complex reactions involving different cells and cellular processes, specific immune cell populations with key responsibilities driving the pathological mechanisms can be identified for certain autoimmune diseases. In this review, we will focus on the mechanisms of action of glucocorticoids on various leukocyte populations, exemplarily portraying different autoimmune diseases as heterogeneous targets of glucocorticoid actions: (i) Abnormalities in the innate immune response play a crucial role in the initiation and perpetuation of giant cell arteritis (GCA). (ii) Specific types of CD4+ T helper (Th) lymphocytes, namely Th1 and Th17 cells, represent important players in the establishment and course of rheumatoid arthritis (RA), whereas (iii) B cells have emerged as central players in systemic lupus erythematosus (SLE). (iv) Allergic reactions are mainly triggered by several different cytokines released by activated Th2 lymphocytes. Using these examples, we aim to illustrate the versatile modulating effects of glucocorticoids on the immune system. In contrast, in the treatment of lymphoproliferative disorders the pro-apoptotic action of glucocorticoids prevails, but their mechanisms differ depending on the type of cancer. Therefore, we will also give a brief insight into the current knowledge of the mode of glucocorticoid action in oncological treatment focusing on leukemia

A 20-year multicentre outcome analysis of salvage mechanical circulatory support for refractory cardiogenic shock after cardiac surgery

Abstract Background Refractory post-cardiotomy cardiogenic shock (PCCS) is a relatively rare phenomenon that can lead to rapid multi-organ dysfunction syndrome and is almost invariably fatal without advanced mechanical circulatory support (AMCS), namely extra-corporeal membrane oxygenation (ECMO) or ventricular assist devices (VAD). In this multicentre observational study we retrospectively analyzed the outcomes of salvage venoarterial ECMO (VA ECMO) and VAD for refractory PCCS in the 3 adult cardiothoracic surgery centres in Scotland over a 20-year period. Methods The data was obtained through the Edinburgh, Glasgow and Aberdeen cardiac surgery databases. Our inclusion criteria included any adult patient from April 1995 to April 2015 who had received salvage VA ECMO or VAD for PCCS refractory to intra-aortic balloon pump (IABP) and maximal inotropic support following adult cardiac surgery. Results A total of 27 patients met the inclusion criteria. Age range was 34–83 years (median 51 years). There was a large male predominance (n = 23, 85 %). Overall 23 patients (85 %) received VA ECMO of which 14 (61 %) had central ECMO and 9 (39 %) had peripheral ECMO. Four patients (15 %) were treated with short-term VAD (BiVAD = 1, RVAD = 1 and LVAD = 2). The most common procedure-related complication was major haemorrhage (n = 10). Renal failure requiring renal replacement therapy (n = 7), fatal stroke (n = 5), septic shock (n = 2), and a pseudo-aneurysm at the femoral artery cannulation site (n = 1) were also observed. Overall survival to hospital discharge was 40.7 %. All survivors were NYHA class I-II at 12 months’ follow-up. Conclusion AMCS for refractory PCCS carries a survival benefit and achieves acceptable functional recovery despite a significant complication rate

Differences in trait impulsivity indicate diversification of dog breeds into working and show lines

Impulsiveness describes the inability to inhibit behaviour in the presence of salient cues. Trait-level impulsivity exists on a continuum and individual differences can be adaptive in different contexts. While breed related differences in behavioural tendency in the domestic dog (Canis familiaris) are well established, the phenomenon within lines of a breed which have been selected more recently is not well studied, although it may challenge the popular notion of breed-typical behaviour. We describe differences in impulsivity between and within two dog breeds with working and show lines selected for different levels of impulsivity: Border Collies (herding work) and Labrador Retrievers (gun work). Recent show line selection might have lessened differences in impulsivity between breeds. We tested this hypothesis on a dataset of 1161 individuals assessed using a validated psychometric tool (Dog Impulsivity Assessment Scale - DIAS). Collies were more impulsive on average, consistent with the original purpose of breed selection. Regarding line, working Collies differed from working Labradors, but show lines from the two breeds were not significantly different. Altered or relaxed artificial selection for behavioural traits when appearance rather than behaviour become the primary focus for breeders may reduce average differences in impulsivity between breeds in show lines

The Anti-inflammatory Effects of Perioperative Dexamethasone Administration and the Relationship to Pain: A Systematic Review and Meta-analysis

Introduction: Post-surgical inflammation is a common adverse event that can have detrimental effects on the recovery phase for patients. Commonly associated with pain severity, inflammation can make the management of postoperative pain difficult. Of the multiple inflammatory molecules that can be found in an inflammatory response, interleukin 6 (IL-6) and C-reactive protein (CRP) are two of the most commonly assayed biomarkers of inflammation. Dexamethasone (DEX), with its anti-inflammatory properties, is thought to reduce IL-6 and CRP. It thus may reduce pain when administered perioperatively. In this review, we assessed the anti-inflammatory effects of DEX and the relationship of such effects in the management of postoperative pain. Methods: We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials using the following criteria: patients greater than or equal to eighteen years of age undergoing surgery. The intervention of interest is perioperative DEX administration and the control was normal saline or the absence of DEX administration. Primary outcomes included postoperative IL-6 and CRP levels, with a secondary outcome of postoperative pain scores. Utilizing the RevMan program, a meta-analysis was performed using a random effect model. Studies not able to be analyzed quantitatively were assessed through a narrative approach. Results: We identified a total of nine studies with 1048 subjects which fulfilled inclusion criteria. Only three of the nine studies were able to be quantitatively analyzed. Our analysis of these studies favored DEX administration for the reduction of postoperative inflammation with regard to IL-6 (SMD = -1.88; 95% CI -2.28 - 1.48; p \u3c 0.01; Figure 3a), and near significant difference with regard to CRP (SMD = -0.93; 95% CI -1.91 - 0.04; p = 0.06; Figure 3b). DEX administration was also shown to significantly reduce postoperative pain (SMD = -1.34; 95% CI -2.12 - -0.56; p \u3c 0.01; Figure 3c). Qualitative analysis for eight of the nine studies favored the administration of DEX for the reduction of inflammation as well as postoperative pain. The total dosage of DEX administered ranged from 6.6 to 40 mg. Regarding complications after DEX administration, all nine studies reported no significant increase in the incidence of serious adverse effects, including hyperglycemia, surgical site infections, or impaired wound healing. Conclusion: Dexamethasone is a commonly used medication for the management of postoperative nausea and vomiting. Additionally, administration of DEX perioperatively also appears to be efficacious in lowering inflammation and managing postoperative pain from various types of surgical procedures. Complications, including impaired wound healing, hyperglycemia, and surgical site infections, which have been reported in previous studies, have not been observed with significance with the administration of one or two doses of DEX as evidenced by the literature in this review. Further research may justify the utilization of DEX as a means to reduce postoperative inflammation and subsequent pain

Extra-corporeal membrane oxygenation for refractory cardiogenic shock after adult cardiac surgery:a systematic review and meta-analysis

Background - Postcardiotomy cardiogenic shock (PCCS) refractory to inotropic support and intra-aortic balloon pump (IABP) occurs rarely but is almost universally fatal without mechanical circulatory support. In this systematic review and meta-analysis we looked at the evidence behind the use of veno-arterial extra-corporeal membrane oxygenation (VA ECMO) in refractory PCCS from a patient survival rate and determinants of outcome viewpoint. Methods - A systematic review was performed in January 2017 using PubMed (with no defined time period) using the keywords “postcardiotomy”, “cardiogenic shock”, “extracorporeal membrane oxygenation” and “cardiac surgery”. We excluded papers pertaining to ECMO following paediatric cardiac surgery, medical causes of cardiogenic shock, as well as case reports, review articles, expert opinions, and letters to the editor. Once the studies were collated, a meta-analysis was performed on the proportion of survivors in those papers that met the inclusion criteria. Meta-regression was performed for the most commonly reported adverse prognostic indicators (API). Results - We identified 24 studies and a cumulative pool of 1926 patients from 1992 to 2016. We tabulated the demographic data, including the strengths and weaknesses for each of the studies, outcomes of VA ECMO for refractory PCCS, complications, and APIs. All the studies were retrospective cohort studies. Meta-analysis of the moderately heterogeneous data (95% CI 0.29 to 0.34, p 70 years, 95% CI −0.057 to 0.001, P = 0.058), and long ECMO support (95% CI −0.068 to 0.166, P = 0.412). Postoperative renal failure, high EuroSCORE (>20%), diabetes mellitus, obesity, rising lactate whilst on ECMO, gastrointestinal complications had also been reported. Conclusion - Haemodynamic support with VA ECMO provides a survival benefit with reasonable intermediate and long-term outcomes. Many studies had reported advanced age, renal failure and prolonged VA ECMO support as the most likely APIs for VA ECMO in PCCS. EuroSCORE can be utilized to anticipate the need for prophylactic perioperative VA ECMO in the high-risk category. APIs can be used to aid decision-making regarding both the institution and weaning of ECMO for refractory PCCS