Loss of phosphatase activity in myotubularin-related protein 2 is associated with Charcot-Marie-Tooth disease type 4B1

Mutations in the gene encoding myotubularin-related protein 2 (MTMR2) are responsible for autosomal recessive Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe hereditary motor and sensory neuropathy characterized by focally folded myelin sheaths and demyelination. MTMR2 belongs to the myotubularin family, which is characterized by the presence of a phosphatase domain. Myotubularin (MTM), the archetype member of this family, is mutated in X-linked myotubular myopathy. Although MTMR2 and MTM are closely related, they are likely to have different functions. Recent studies revealed that MTM dephosphorylates specifically phosphatidylinositol 3-phosphate. Here we analyze the biochemical properties of the mouse Mtmr2 protein, which shares 97% amino acid identity with human MTMR2. We show that phosphatidylinositol-3-phosphate is also a substrate for Mtmr2, but, unlike myotubularin, Mtmr2 dephosphorylates phosphatidylinositol 3,5-bisphosphate with high efficiency and peak activity at neutral pH. We demonstrate that the known disease-associated MTMR2 mutations lead to dramatically reduced phosphatase activity, suggesting that the MTMR2 phosphatase activity is crucial for the proper function of peripheral nerves in CMT4B1. Expression analysis of Mtmr2 suggests particularly high levels in neurons. Thus, the demyelinating neuropathy CMT4B1 might be triggered by the malfunction of neural membrane recycling, membrane trafficking, and/or endocytic or exocytotic processes, combined with altered axon-Schwann cell interactions. Furthermore, the different biochemical properties of MTM and MTMR2 offer a potential explanation for the different human diseases caused by mutations in their respective gene

Sentinel surveillance of HIV-1 transmitted drug resistance, acute infection and recent infection.

BackgroundHIV-1 acute infection, recent infection and transmitted drug resistance screening was integrated into voluntary HIV counseling and testing (VCT) services to enhance the existing surveillance program in San Francisco. This study describes newly-diagnosed HIV cases and characterizes correlates associated with infection.Methodology/principal findingsA consecutive sample of persons presenting for HIV VCT at the municipal sexually transmitted infections (STI) clinic from 2004 to 2006 (N = 9,868) were evaluated by standard enzyme-linked immunoassays (EIA). HIV antibody-positive specimens were characterized as recent infections using a less-sensitive EIA. HIV-RNA pooled testing was performed on HIV antibody-negative specimens to identify acute infections. HIV antibody-positive and acute infection specimens were evaluated for drug resistance by sequence analysis. Multivariable logistic regression was performed to evaluate associations. The 380 newly-diagnosed HIV cases included 29 acute infections, 128 recent infections, and 47 drug-resistant cases, with no significant increases or decreases in prevalence over the three years studied. HIV-1 transmitted drug resistance prevalence was 11.0% in 2004, 13.4% in 2005 and 14.9% in 2006 (p = 0.36). Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) was the most common pattern detected, present in 28 cases of resistance (59.6%). Among MSM, recent infection was associated with amphetamine use (AOR = 2.67; p<0.001), unprotected anal intercourse (AOR = 2.27; p<0.001), sex with a known HIV-infected partner (AOR = 1.64; p = 0.02), and history of gonorrhea (AOR = 1.62; p = 0.03).ConclusionsNew HIV diagnoses, recent infections, acute infections and transmitted drug resistance prevalence remained stable between 2004 and 2006. Resistance to NNRTI comprised more than half of the drug-resistant cases, a worrisome finding given its role as the backbone of first-line antiretroviral therapy in San Francisco as well as worldwide. The integration of HIV-1 drug resistance, recent infection, and acute infection testing should be considered for existing HIV/STI surveillance and prevention activities, particularly in an era of enhanced efforts for early diagnosis and treatment

Endocrine Effects of Inhaled Corticosteroids in Children

Inhaled corticosteroids (ICSs) are widely used as first-line treatment for various chronic respiratory illnesses. Advances in devices and formulations have reduced their local adverse effects. However, as delivery of ICSs to the lungs improves, the systemic absorption increases, and an adverse effect profile similar to, although milder than, oral corticosteroids has emerged. The most serious potential adverse effect is adrenal insufficiency, which can be life threatening. Adrenal insufficiency occurs most in patients taking the highest doses of ICSs but is reported with moderate or even low doses as well. Our recommendations include greater vigilance in testing adrenal function than current standard practice. In patients with diabetes mellitus (types 1 and 2), an increase in glucose levels is likely, and diabetes medication adjustment may be needed when initiating or increasing ICSs. The risk of linear growth attenuation and adverse effects on bone mineral density is generally low but should be considered in the face of additional risk factors. On behalf of the Pediatric Endocrine Society Drugs and Therapeutics Committee, we present a review of the endocrine adverse effects of ICSs in children and offer recommendations relating to testing and referral. Limited data in particular realms diminish the strength of certain recommendations, and clinical judgment continues to be paramount

Novel lactoferrin-conjugated gallium complex to treat Pseudomonas aeruginosa wound infection

Pseudomonas aeruginosa is one of the leading causes of opportunistic infections such as chronic wound infection that could lead to multiple organ failure and death. Gallium (Ga3+) ions are known to inhibit P. aeruginosa growth and biofilm formation but require carrier for localized controlled delivery. Lactoferrin (LTf), a two-lobed protein, can deliver Ga3+ at sites of infection. This study aimed to develop a Ga-LTf complex for the treatment of wound infection. The characterisation of the Ga-LTf complex was conducted using differential scanning calorimetry (DSC), Infra-Red (FTIR) and Inductive Coupled Plasma Optical Emission Spectrometry (ICP-OES). The antibacterial activity was assessed by agar disc diffusion, liquid broth and biofilm inhibition assays using the colony forming units (CFUs). The healing capacity and biocompatibility were evaluated using a P.aeruginosa infected wound in a rat model. DSC analyses showed thermal transition consistent with apo-lactoferrin; FTIR confirmed the complexation of gallium to lactoferrin. ICP-OES confirmed the controlled local delivery of Ga3+. Ga-LTf showed a 0.57 log10 CFUs reduction at 24 h compared with untreated control in planktonic liquid broth assay. Ga-LTf showed the highest antibiofilm activity with a 2.24 log10 CFUs reduction at 24 h. Furthermore, Ga-LTf complex is biocompatible without any adverse effect on brain, kidney, liver and spleen of rats tested in this study. Ga-LTf can be potentially promising novel therapeutic agent to treat pathogenic bacterial infections

A multi-national European cross-sectional study of feline calicivirus epidemiology, diversity and vaccine cross-reactivity

Background Feline calicivirus (FCV) is an important pathogen of cats for which vaccination is regularly practised. Long-term use of established vaccine antigens raises the theoretical possibility that field viruses could become resistant. This study aimed to assess the current ability of the FCV-F9 vaccine strain to neutralise a randomly collected contemporary panel of FCV field strains collected prospectively in six European countries. Methods Veterinary practices (64) were randomly selected from six countries (UK, Sweden, Netherlands, Germany, France and Italy). Oropharyngeal swabs were requested from 30 (UK) and 40 (other countries) cats attending each practice. Presence of FCV was determined by virus isolation, and risk factors for FCV shedding assessed by multivariable logistic regression. Phylogenetic analyses were used to describe the FCV population structure. In vitro virus neutralisation assays were performed to evaluate FCV-F9 cross-reactivity using plasma from four vaccinated cats. Results The overall prevalence of FCV was 9.2%. Risk factors positively associated with FCV shedding included multi-cat households, chronic gingivostomatitis, younger age, not being neutered, as well as residing in certain countries. Phylogenetic analysis showed extensive variability and no countrywide clusters. Despite being first isolated in the 1950s, FCV-F9 clustered with contemporary field isolates. Plasma raised to FCV-F9 neutralized 97% of tested isolates (titres 1:4 to 1:5792), with 26.5%, 35.7% and 50% of isolates being neutralized by 5, 10 and 20 antibody units respectively. Conclusions This study represents the largest prospective analysis of FCV diversity and antigenic cross-reactivity at a European level. The scale and random nature of sampling used gives confidence that the FCV isolates used are broadly representative of FCVs that cats are exposed to in these countries. The in vitro neutralisation results suggest that antibodies raised to FCV-F9 remain broadly cross-reactive to contemporary FCV isolates across the European countries sampled

Decreases in Community Viral Load Are Accompanied by Reductions in New HIV Infections in San Francisco

BACKGROUND: At the individual level, higher HIV viral load predicts sexual transmission risk. We evaluated San Francisco's community viral load (CVL) as a population level marker of HIV transmission risk. We hypothesized that the decrease in CVL in San Francisco from 2004-2008, corresponding with increased rates of HIV testing, antiretroviral therapy (ART) coverage and effectiveness, and population-level virologic suppression, would be associated with a reduction in new HIV infections. METHODOLOGY/PRINCIPAL FINDINGS: We used San Francisco's HIV/AIDS surveillance system to examine the trends in CVL. Mean CVL was calculated as the mean of the most recent viral load of all reported HIV-positive individuals in a particular community. Total CVL was defined as the sum of the most recent viral loads of all HIV-positive individuals in a particular community. We used Poisson models with robust standard errors to assess the relationships between the mean and total CVL and the primary outcome: annual numbers of newly diagnosed HIV cases. Both mean and total CVL decreased from 2004-2008 and were accompanied by decreases in new HIV diagnoses from 798 (2004) to 434 (2008). The mean (p = 0.003) and total CVL (p = 0.002) were significantly associated with new HIV cases from 2004-2008. CONCLUSIONS/SIGNIFICANCE: Reductions in CVL are associated with decreased HIV infections. Results suggest that wide-scale ART could reduce HIV transmission at the population level. Because CVL is temporally upstream of new HIV infections, jurisdictions should consider adding CVL to routine HIV surveillance to track the epidemic, allocate resources, and to evaluate the effectiveness of HIV prevention and treatment efforts

A screening tool to prioritize public health risk associated with accidental or deliberate release of chemicals into the atmosphere

The Chemical Events Working Group of the Global Health Security Initiative has developed a flexible screening tool for chemicals that present a risk when accidentally or deliberately released into the atmosphere. The tool is generic, semi-quantitative, independent of site, situation and scenario, encompasses all chemical hazards (toxicity, flammability and reactivity), and can be easily and quickly implemented by non-subject matter experts using freely available, authoritative information. Public health practitioners and planners can use the screening tool to assist them in directing their activities in each of the five stages of the disaster management cycle

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio