Determining the neurotransmitter concentration profile at active synapses

Establishing the temporal and concentration profiles of neurotransmitters during synaptic release is an essential step towards understanding the basic properties of inter-neuronal communication in the central nervous system. A variety of ingenious attempts has been made to gain insights into this process, but the general inaccessibility of central synapses, intrinsic limitations of the techniques used, and natural variety of different synaptic environments have hindered a comprehensive description of this fundamental phenomenon. Here, we describe a number of experimental and theoretical findings that has been instrumental for advancing our knowledge of various features of neurotransmitter release, as well as newly developed tools that could overcome some limits of traditional pharmacological approaches and bring new impetus to the description of the complex mechanisms of synaptic transmission

A systematic review of the evidence for single stage and two stage revision of infected knee replacement

BACKGROUND: Periprosthetic infection about the knee is a devastating complication that may affect between 1% and 5% of knee replacement. With over 79 000 knee replacements being implanted each year in the UK, periprosthetic infection (PJI) is set to become an important burden of disease and cost to the healthcare economy. One of the important controversies in treatment of PJI is whether a single stage revision operation is superior to a two-stage procedure. This study sought to systematically evaluate the published evidence to determine which technique had lowest reinfection rates. METHODS: A systematic review of the literature was undertaken using the MEDLINE and EMBASE databases with the aim to identify existing studies that present the outcomes of each surgical technique. Reinfection rate was the primary outcome measure. Studies of specific subsets of patients such as resistant organisms were excluded. RESULTS: 63 studies were identified that met the inclusion criteria. The majority of which (58) were reports of two-stage revision. Reinfection rated varied between 0% and 41% in two-stage studies, and 0% and 11% in single stage studies. No clinical trials were identified and the majority of studies were observational studies. CONCLUSIONS: Evidence for both one-stage and two-stage revision is largely of low quality. The evidence basis for two-stage revision is significantly larger, and further work into direct comparison between the two techniques should be undertaken as a priority

Disparities and risks of sexually transmissible infections among men who have sex with men in China: a meta-analysis and data synthesis.

BACKGROUND: Sexually transmitted infections (STIs), including Hepatitis B and C virus, are emerging public health risks in China, especially among men who have sex with men (MSM). This study aims to assess the magnitude and risks of STIs among Chinese MSM. METHODS: Chinese and English peer-reviewed articles were searched in five electronic databases from January 2000 to February 2013. Pooled prevalence estimates for each STI infection were calculated using meta-analysis. Infection risks of STIs in MSM, HIV-positive MSM and male sex workers (MSW) were obtained. This review followed the PRISMA guidelines and was registered in PROSPERO. RESULTS: Eighty-eight articles (11 in English and 77 in Chinese) investigating 35,203 MSM in 28 provinces were included in this review. The prevalence levels of STIs among MSM were 6.3% (95% CI: 3.5-11.0%) for chlamydia, 1.5% (0.7-2.9%) for genital wart, 1.9% (1.3-2.7%) for gonorrhoea, 8.9% (7.8-10.2%) for hepatitis B (HBV), 1.2% (1.0-1.6%) for hepatitis C (HCV), 66.3% (57.4-74.1%) for human papillomavirus (HPV), 10.6% (6.2-17.6%) for herpes simplex virus (HSV-2) and 4.3% (3.2-5.8%) for Ureaplasma urealyticum. HIV-positive MSM have consistently higher odds of all these infections than the broader MSM population. As a subgroup of MSM, MSW were 2.5 (1.4-4.7), 5.7 (2.7-12.3), and 2.2 (1.4-3.7) times more likely to be infected with chlamydia, gonorrhoea and HCV than the broader MSM population, respectively. CONCLUSION: Prevalence levels of STIs among MSW were significantly higher than the broader MSM population. Co-infection of HIV and STIs were prevalent among Chinese MSM. Integration of HIV and STIs healthcare and surveillance systems is essential in providing effective HIV/STIs preventive measures and treatments. TRIAL REGISTRATION: PROSPERO NO: CRD42013003721

Tracheostomy in the COVID-19 era: global and multidisciplinary guidance

Global health care is experiencing an unprecedented surge in the number of critically ill patients who require mechanical ventilation due to the COVID-19 pandemic. The requirement for relatively long periods of ventilation in those who survive means that many are considered for tracheostomy to free patients from ventilatory support and maximise scarce resources. COVID-19 provides unique challenges for tracheostomy care: health-care workers need to safely undertake tracheostomy procedures and manage patients afterwards, minimising risks of nosocomial transmission and compromises in the quality of care. Conflicting recommendations exist about case selection, the timing and performance of tracheostomy, and the subsequent management of patients. In response, we convened an international working group of individuals with relevant expertise in tracheostomy. We did a literature and internet search for reports of research pertaining to tracheostomy during the COVID-19 pandemic, supplemented by sources comprising statements and guidance on tracheostomy care. By synthesising early experiences from countries that have managed a surge in patient numbers, emerging virological data, and international, multidisciplinary expert opinion, we aim to provide consensus guidelines and recommendations on the conduct and management of tracheostomy during the COVID-19 pandemic

The ChromaTest, a digital color contrast sensitivity analyzer, for diabetic maculopathy: a pilot study

BACKGROUND: To assess the ability of the Chromatest in investigating diabetic maculopathy. METHOD: Patients with Type 2 diabetes and no concurrent ocular pathology or previous laser photocoagulation were recruited. Visual acuities were assessed followed by colour contrast sensitivity testing of each eye using Chromatest. Dilated fundoscopy with slit lamp biomicroscopy with 78 D lens was then performed to confirm the stage of diabetic retinopathy according to the Early Treatment Diabetic Retinopathy Study. RESULTS: 150 eyes in 150 patients were recruited into this study. 35 eyes with no previous laser photocoagulation were shown to have clinically significant macular oedema (CSMO) and 115 eyes with untreated non-proliferative diabetic retinopathy (NPDR) on fundus biomicroscopy. Statistical significant difference was found between CSMO and NPDR eyes for protan colour contrast threshold (p = 0.01). Statistical significance was found between CSMO and NPDR eyes for tritan colour contrast threshold (p = 0.0002). Sensitivity and specificity for screening of CSMO using pass-fail criterion for age matched TCCT results achieved 71% (95% confidence interval: 53-85%) and 70% (95% confidence interval: 60-78%), respectively. However, threshold levels were derived using the same data set for both training and testing the effectiveness since this was the first study of NPDR using the Chromatest CONCLUSION: The ChromaTest is a simple, cheap, easy to use, and quick test for colour contrast sensitivity. This study did not achieve results to justify use of the Chromatest for screening, but it reinforced the changes seen in tritan colour vision in diabetic retinopathy

Double Blind Study Investigating the Effect of Different Voice Prostheses on Ease of Swallowing and Residue Post Laryngectomy.

Voice prostheses have been examined for their effect on voice production but there is little datum on their effect on swallow function. This study investigated the difference between six commonly available voice prostheses in terms of swallowing. Laryngectomy patients had up to six voice prostheses placed in a random order over two visits. Swallowing was evaluated for each prosthesis using FEES (Fibreoptic Endoscopic Evaluation of Swallowing). After each prosthesis trial, patients self-evaluated their experience of swallowing. Three independent experts indicated which prosthesis they considered best for swallowing for each patient and judged residue on the voice prosthesis and in the upper esophagus. Raters were blinded to participant details, voice prosthesis type and scores of other raters. On patient self-evaluation, scores were equally distributed across all prostheses for swallowing. Experts most frequently chose the Blom Singer Low pressure and Blom Singer Classic Indwelling voice prostheses as best for swallowing but consensus was poor for most patients. Experts found that the Blom Singer Classic Indwelling and the Provox Vega had least residue on the voice prosthesis on thin liquid (p ≤ 0.001) and soft (p = 0.001), respectively. Experts also found that the Blom Singer Low Pressure had least residue in the upper esophagus on soft consistency (p ≤ 0.001). While self-evaluation by patients did not identify a consistently preferred prosthesis for swallow, many patients expressed personal preferences, suggesting benefits to involving patients in the choice of prosthesis. Some voice prostheses may be associated with lower levels of residue on the prosthesis and upper esophagus with certain consistencies

Evidence for Impaired CARD15 Signalling in Crohn's Disease without Disease Linked Variants

BACKGROUND:Sensing of muramyl dipeptide (MDP) is impaired in Crohn's disease (CD) patients with disease-linked variants of the CARD15 (caspase activation and recruitment domain 15) gene. Animal studies suggest that normal CARD15 signalling prevents inflammatory bowel disease, and may be important for disease development in CD. However, only a small fraction of CD patients carry the disease linked CARD15 variants. The aim of this study was thus to investigate if changes could be found in CARD15 signalling in patients without disease associated CARD15 variants. METHODOLOGY/PRINCIPAL FINDINGS:By mapping the response to MDP in peripheral monocytes obtained from CD patients in remission not receiving immunosuppresives, an impaired response to MDP was found in patients without disease linked CARD15 variants compared to control monocytes. This impairment was accompanied by a decreased activation of IkappaB kinase alpha/beta (IKKalpha/beta), the initial step in the nuclear factor kappaB (NFkappaB) pathway, whereas activation of mitogen-activated protein (MAP)-kinases was unaffected. MDP additionally stimulates the inflammasome which is of importance for processing of cytokines. The inflammasome was constitutively activated in CD, but unresponsive to MDP both in CD and control monocytes. CONCLUSIONS/SIGNIFICANCE:These results suggest that inhibited MDP-dependent pathways in CD patients not carrying the disease-associated CARD15 variants might be of importance for the pathogenesis of CD. The results reveal a dysfunctional immune response in CD patients, not able to sense relevant stimuli on the one hand, and on the other hand possessing constitutively active cytokine processing

Identification of a Novel Binding Partner of Phospholipase Cβ1: Translin-Associated Factor X

Mammalian phospholipase Cβ1 (PLCβ1) is activated by the ubiquitous Gαq family of G proteins on the surface of the inner leaflet of plasma membrane where it catalyzes the hydrolysis of phosphatidylinositol 4,5 bisphosphate. In general, PLCβ1 is mainly localized on the cytosolic plasma membrane surface, although a substantial fraction is also found in the cytosol and, under some conditions, in the nucleus. The factors that localize PLCβ1in these other compartments are unknown. Here, we identified a novel binding partner, translin-associated factor X (TRAX). TRAX is a cytosolic protein that can transit into the nucleus. In purified form, PLCβ1 binds strongly to TRAX with an affinity that is only ten-fold weaker than its affinity for its functional partner, Gαq. In solution, TRAX has little effect on the membrane association or the catalytic activity of PLCβ1. However, TRAX directly competes with Gαq for PLCβ1 binding, and excess TRAX reverses Gαq activation of PLCβ1. In C6 glia cells, endogenous PLCβ1 and TRAX colocalize in the cytosol and the nucleus, but not on the plasma membrane where TRAX is absent. In Neuro2A cells expressing enhanced yellow and cyano fluorescent proteins (i.e., eYFP- PLCβ1 and eCFP-TRAX), Förster resonance energy transfer (FRET) is observed mostly in the cytosol and a small amount is seen in the nucleus. FRET does not occur at the plasma membrane where TRAX is not found. Our studies show that TRAX, localized in the cytosol and nucleus, competes with plasma-membrane bound Gαq for PLCβ1 binding thus stabilizing PLCβ1 in other cellular compartments