Mapping the complete glycoproteome of virion-derived HIV-1 gp120 provides insights into broadly neutralizing antibody binding

The surface envelope glycoprotein (SU) of Human immunodeficiency virus type 1 (HIV-1), gp120SU plays an essential role in virus binding to target CD4+ T-cells and is a major vaccine target. Gp120 has remarkably high levels of N-linked glycosylation and there is considerable evidence that this “glycan shield” can help protect the virus from antibody-mediated neutralization. In recent years, however, it has become clear that gp120 glycosylation can also be included in the targets of recognition by some of the most potent broadly neutralizing antibodies. Knowing the site-specific glycosylation of gp120 can facilitate the rational design of glycopeptide antigens for HIV vaccine development. While most prior studies have focused on glycan analysis of recombinant forms of gp120, here we report the first systematic glycosylation site analysis of gp120 derived from virions produced by infected T lymphoid cells and show that a single site is exclusively substituted with complex glycans. These results should help guide the design of vaccine immunogens

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

Infliximab for the treatment of intravenous immunoglobulin resistant Kawasaki disease complicated by coronary artery aneurysms: a case report

This case report describes an 8 year old boy with IVIG resistant Kawasaki disease complicated by severe bilateral coronary artery aneurysms successfully treated with infliximab, a monoclonal antibody against tumour necrosis factor alpha

State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

Respiratory Evolution Facilitated the Origin of Pterosaur Flight and Aerial Gigantism

Pterosaurs, enigmatic extinct Mesozoic reptiles, were the first vertebrates to achieve true flapping flight. Various lines of evidence provide strong support for highly efficient wing design, control, and flight capabilities. However, little is known of the pulmonary system that powered flight in pterosaurs. We investigated the structure and function of the pterosaurian breathing apparatus through a broad scale comparative study of respiratory structure and function in living and extinct archosaurs, using computer-assisted tomographic (CT) scanning of pterosaur and bird skeletal remains, cineradiographic (X-ray film) studies of the skeletal breathing pump in extant birds and alligators, and study of skeletal structure in historic fossil specimens. In this report we present various lines of skeletal evidence that indicate that pterosaurs had a highly effective flow-through respiratory system, capable of sustaining powered flight, predating the appearance of an analogous breathing system in birds by approximately seventy million years. Convergent evolution of gigantism in several Cretaceous pterosaur lineages was made possible through body density reduction by expansion of the pulmonary air sac system throughout the trunk and the distal limb girdle skeleton, highlighting the importance of respiratory adaptations in pterosaur evolution, and the dramatic effect of the release of physical constraints on morphological diversification and evolutionary radiation

Feasibility of a randomised trial of a continuing medical education program in shared decision-making on the use of antibiotics for acute respiratory infections in primary care: the DECISION+ pilot trial

Abstract Background The misuse and limited effectiveness of antibiotics for acute respiratory infections (ARIs) are well documented, and current approaches targeting physicians or patients to improve appropriate use have had limited effect. Shared decision-making could be a promising strategy to improve appropriate antibiotic use for ARIs, but very little is known about its implementation processes and outcomes in clinical settings. In this matter, pilot studies have played a key role in health science research over the past years in providing information for the planning, justification, and/or refinement of larger studies. The objective of our study was to assess the feasibility and acceptability of the study design, procedures, and intervention of the DECISION+ program, a continuing medical education program in shared decision-making among family physicians and their patients on the optimal use of antibiotics for treating ARIs in primary care. Methods A pilot clustered randomised trial was conducted. Family medicine groups (FMGs) were randomly assigned, to either the DECISION+ program, which included three 3-hour workshops over a four- to six-month period, or a control group that had a delayed exposure to the program. Results Among 21 FMGs contacted, 5 (24%) agreed to participate in the pilot study. A total of 39 family physicians (18 in the two experimental and 21 in the three control FMGs) and their 544 patients consulting for an ARI were recruited. The proportion of recruited family physicians who participated in all three workshops was 46% (50% for the experimental group and 43% for the control group), and the overall mean level of satisfaction regarding the workshops was 94%. Conclusions This trial, while aiming to demonstrate the feasibility and acceptability of conducting a larger study, has identified important opportunities for improving the design of a definitive trial. This pilot trial is informative for researchers and clinicians interested in designing and/or conducting studies with FMGs regarding training of physicians in shared decision-making. Trial Registration Clinicaltrials.Gov NCT0035431

Impact of optical coherence tomography on diagnostic decision-making by UK community optometrists: a clinical vignette study.

PURPOSE: In recent years, there has been widespread investment in imaging technologies by community optometrists in the UK, most notably optical coherence tomography (OCT). The aim of the current study was to determine the value of OCT in the diagnosis of posterior segment diseases in a representative sample of community optometrists using a clinical vignette methodology. METHODS: A group of community optometrists (n = 50) initially completed a standardised training package on OCT interpretation followed by a computer-based assessment featuring 52 clinical vignettes, containing images of healthy (n = 8) or glaucomatous (n = 18) discs or healthy (n = 8) or diseased (n = 18) fundi. Each vignette featured either a single fundus/disc photographic image, or a combination of a fundus/disc image with the corresponding OCT scan. An expert panel confirmed that the fundus images presented alone and those in combination with OCT data were of a similar level of difficulty and that the cases were typical of those seen in primary care. For each case, the optometrist selected their diagnosis from a pull-down list and reported their confidence in their decision using a 10-point Likert scale. Pairwise comparisons of the fundus image alone and fundus image/OCT combination were made for both diagnostic performance and confidence. RESULTS: The mean percentage of correct diagnoses using fundus imaging alone was 62% (95% CI 59-64%) and for the combination of fundus image/OCT was 80% (95% CI 77-82%). The mean false negative rate with fundus alone was 27% reducing to 13% with the OCT combination. Median confidence scores for fundus imaging alone was 8.0 (IQR 7.0-8.0) and 8.3 (IQR 8.0-9.0) for the combination. Improvements in performance and confidence were statistically significant (p < 0.001). CONCLUSION: The results from this vignette study suggests that OCT improves optometrists' diagnostic performance compared to fundus observation alone. These initial results suggest that OCT provides valuable additional data that could augment case-finding for glaucoma and retinal disease; however, further research is needed to assess its diagnostic performance in a routine clinical practice setting

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Informant-reported cognitive symptoms that predict amnestic mild cognitive impairment

<p>Abstract</p> <p>Background</p> <p>Differentiating amnestic mild cognitive impairment (aMCI) from normal cognition is difficult in clinical settings. Self-reported and informant-reported memory complaints occur often in both clinical groups, which then necessitates the use of a comprehensive neuropsychological examination to make a differential diagnosis. However, the ability to identify cognitive symptoms that are predictive of aMCI through informant-based information may provide some clinical utility in accurately identifying individuals who are at risk for developing Alzheimer's disease (AD).</p> <p>Methods</p> <p>The current study utilized a case-control design using data from an ongoing validation study of the Alzheimer's Questionnaire (AQ), an informant-based dementia assessment. Data from 51 cognitively normal (CN) individuals participating in a brain donation program and 47 aMCI individuals seen in a neurology practice at the same institute were analyzed to determine which AQ items differentiated aMCI from CN individuals.</p> <p>Results</p> <p>Forward stepwise multiple logistic regression analysis which controlled for age and education showed that 4 AQ items were strong indicators of aMCI which included: repetition of statements and/or questions [OR 13.20 (3.02, 57.66)]; trouble knowing the day, date, month, year, and time [OR 17.97 (2.63, 122.77)]; difficulty managing finances [OR 11.60 (2.10, 63.99)]; and decreased sense of direction [OR 5.84 (1.09, 31.30)].</p> <p>Conclusions</p> <p>Overall, these data indicate that certain informant-reported cognitive symptoms may help clinicians differentiate individuals with aMCI from those with normal cognition. Items pertaining to repetition of statements, orientation, ability to manage finances, and visuospatial disorientation had high discriminatory power.</p

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes