Translational neuroscience: the state of the nation (a PhD student perspective)

Many brain disorders are currently untreatable. It has been suggested that taking a ‘translational’ approach to neuroscientific research might change this. We discuss what ‘translational neuroscience’ is and argue for the need to expand the traditional translational model if we are to make further advances in treating brain disorders

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation

Surface functionalization of polylactic acid fibers with alendronate groups does not improve the mechanical properties of fiber-reinforced calcium phosphate cements

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Association of the intraoperative peripheral perfusion index with postoperative morbidity and mortality in acute surgical patients: a retrospective observational multicentre cohort study

BACKGROUND: We hypothesised that in acute high-risk surgical patients, a lower intraoperative peripheral perfusion index (PPI) would indicate a higher risk of postoperative complications and mortality. METHODS: This retrospective observational study included 1338 acute high-risk surgical patients from November 2017 until October 2018 at two University Hospitals in Denmark. Intraoperative PPI was the primary exposure variable and the primary outcome was severe postoperative complications defined as a Clavien–Dindo Class ≥III or death, within 30 days. RESULTS: intraoperative PPI was associated with severe postoperative complications or death: odds ratio (OR) 1.12 (95% confidence interval [CI] 1.05–1.19; P0.5, P=0.003. If PPI was ≤1.5, 30-day mortality was 16% vs 8% in patients with a PPI >1.5 (P<0.001). In contrast, intraoperative mean MAP ≤65 mm Hg was not significantly associated with severe postoperative complications or death (OR 1.21 [95% CI 0.92–1.58; P=0.2]). CONCLUSIONS: Low intraoperative PPI was associated with severe postoperative complications or death in acute high-risk surgical patients. To guide intraoperative haemodynamic management, the PPI should be further investigated

Daily-life stress reactivity and recovery following virtual-reality-based cognitive behavioral therapy in patients with a psychotic disorder

Introduction: Studies have consistently demonstrated increased stress sensitivity in individuals with psychosis. Since stress sensitivity may play a role in the onset and maintenance of psychosis, this could potentially be a promising target for treatment. The current study was the first to investigate whether reactivity to and recovery from daily-life stressors in psychosis change in response to treatment, namely virtual-reality-based cognitive behavioral therapy (VR-CBT). Methods: 116 patients were randomized to either VR-CBT or the waiting list control group (WL). Pre-treatment and post-treatment participants completed a diary ten times a day during six to ten days. Multilevel analyses were used to model the time-lagged effects of daily stressful events on negative affect (NA) and paranoia symptoms to examine reactivity and recovery. Results: There was a significant difference in NA reactivity. VR-CBT showed higher NA at post-treatment compared to pre-treatment than WL (bpre=0.14; bpost=0.19 vs bpre=0.18; bpost=0.14). There was a significant difference in NA recovery and paranoia recovery between the groups at lag 1: VR-CBT showed relatively lower negative affect (bpre=0.07; bpost=-0.06) and paranoia (bpre= 0.08; bpost=-0.10) at post-treatment compared to pre-treatment than WL (bpre=0.08; bpost=0.08; bpre=0.04; bpost=0.03). Conclusion: Negative affect and paranoia recovery improved in response to treatment. Increased NA reactivity may be explained by a decrease in safety behavior in the VR-CBT group. The discrepancy between reactivity and recovery findings may be explained by the inhibitory learning theory that suggests that an original threat reaction may not erase but can be inhibited as a consequence of exposure therapy.</p

Simultaneous identification of Trypanosoma cruzi surface and internal antigens reactive to different immunoglobulin classes (radio-immunoblotting) Identificação simultânea de antígenos internos e de superfície de Trypanosoma cruzi reativos para diferentes classes de imunoglobulinas (radio-immunoblotting)

A radioactive Western-blotting technique was developed by which the reactivity of Immunoglobulins (Igs) from different classes to both membrane radiolabelled and internal parasite antigens is simultaneously identified. The method includes radioiodination of parasites, polypeptide fractionation by SDS-PAGE, Western-blot transfer and autoradiography of the immunoblots developed with anti-Igs conjugates labelled with enzymes. The analysis is then performed by the comparison of common bands on the autoradiograms and the respective substrate stained nitrocellulose blots. This technique was used to analyse T. cruzi trypomastigote surface labelled antigens reactive to IgM, IgA and IgG specific antibodies. A different pattern of reactivity with acute Chagas' disease patients sera was thus obtained.<br>Classes e subclasses de anticorpos apresentam diferentes funções, influenciando a resposta imune humoral de um hospedeiro, frente a um agente infeccioso. Na maioria dos sistemas, o alvo principal é representado pelos antígenos de membrana do parasita. Entretanto, a identificação de antígenos de superfície de parasitas, reativos para classe (e subclasse) de imunoglobulinas que não se ligam a proteína-A implica em imunoprecipitações sucessivas, que levam a perda de antígenos e/ou reações inespecíficas. Visando esse estudo, foi desenvolvida uma técnica denominada "radio-immunoblotting", através da qual a reatividade de imunoglobulinas de diferentes classes para antígenos de membrana (e/ou internos) foi analisada simultaneamente. O método constitui na marcação prévia da superfície dos parasitas por radioiodação, fracionamento dos polipeptídeos por SDS/PA-GE, transferência das frações para nitrocelulose, reação com soros e conjugados anti-Igs - peroxidase e autoradiografia dos mesmos, a análise é feita comparando-se os antígenos comuns evidenciados na autoradiografia e nas tiras de nitrocelulose coradas com o substrato da peroxidase. Essa técnica foi utilizada para analisar antígenos de superfície de formas tripomastigotas de T. cruzi reativas para IgG, IgM e IgA provenientes de soros de pacientes com doença de Chagas na fase aguda. Obtiveram-se distintos padrões de reatividade para as diferentes classes de anticorpos provenientes de um mesmo soro humano

No major role for rare plectin variants in arrhythmogenic right ventricular cardiomyopathy

Aims Likely pathogenic/pathogenic variants in genes encoding desmosomal proteins play an important role in the pathophysiology of arrhythmogenic right ventricular cardiomyopathy (ARVC). However, for a substantial proportion of ARVC patients, the genetic substrate remains unknown. We hypothesized that plectin, a cytolinker protein encoded by the PLEC gene, could play a role in ARVC because it has been proposed to link the desmosomal protein desmoplakin to the cytoskeleton and therefore has a potential function in the desmosomal structure. Methods We screened PLEC in 359 ARVC patients and compared the frequency of rare coding PLEC variants (minor allele frequency [MAF] <0.001) between patients and controls. To assess the frequency of rare variants in the control population, we evaluated the rare coding variants (MAF <0.001) found in the European cohort of the Exome Aggregation Database. We further evaluated plectin localization by immunofluorescence in a subset of patients with and without a PLEC variant. Results Forty ARVC patients carried one or more rare PLEC variants (11%, 40/359). However, rare variants also seem to occur frequently in the control population (18%, 4754/26197 individuals). Nor did we find a difference in the prevalence of rare PLEC variants in ARVC patients with or without a desmosomal likely pathogenic/pathogenic variant (14% versus 8%, respectively). However, immunofluorescence analysis did show decreased plectin junctional localization in myocardial tissue from 5 ARVC patients with PLEC variants. Conclusions Although PLEC has been hypothesized as a promising candidate gene for ARVC, our current study did not show an enrichment of rare PLEC variants in ARVC patients compared to controls and therefore does not support a major role for PLEC in this disorder. Although rare PLEC variants were associated with abnormal localization in cardiac tissue, the confluence of data does not support a role for plectin abnormalities in ARVC development