"Why me, why now?" Using clinical immunology and epidemiology to explain who gets nontuberculous mycobacterial infection

BACKGROUND: The prevalence of nontuberculous mycobacterial (NTM) disease is rising. An understanding of known risk factors for disease sheds light on the immunological and physical barriers to infection, and how and why they may be overcome. This review focuses on human NTM infection, supported by experimental and in vitro data of relevance to the practising clinician who seeks to understand why their patient has NTM infection and how to further investigate. DISCUSSION: First, the underlying immune response to NTM disease is examined. Important insights regarding NTM disease susceptibility come from nature's own knockouts, the primary immune deficiency disorders. We summarise the current knowledge surrounding interferon-gamma (IFNγ)-interleukin-12 (IL-12) axis abnormalities, followed by a review of phagocytic defects, T cell lymphopenia and rarer genetic conditions known to predispose to NTM disease. We discuss how these define key immune pathways involved in the host response to NTM. Iatrogenic immunosuppression is also important, and we evaluate the impact of novel biological therapies, as well as bone marrow transplant and chemotherapy for solid organ malignancy, on the epidemiology and presentation of NTM disease, and discuss the host defence dynamics thus revealed. NTM infection and disease in the context of other chronic illnesses including HIV and malnutrition is reviewed. The role of physical barriers to infection is explored. We describe how their compromise through different mechanisms including cystic fibrosis, bronchiectasis and smoking-related lung disease can result in pulmonary NTM colonisation or infection. We also summarise further associations with host factors including body habitus and age. We use the presented data to develop an over-arching model that describes human host defences against NTM infection, where they may fail, and how this framework can be applied to investigation in routine clinical practice

Endogenous human cytomegalovirus gB is efficiently presented by MHC class II molecules to CD4+ CTL

Human cytomegalovirus (HCMV) infects endothelial, epithelial, and glial cells in vivo. These cells can express MHC class II proteins, but are unlikely to play important roles in priming host immunity. Instead, it seems that class II presentation of endogenous HCMV antigens in these cells allows recognition of virus infection. We characterized class II presentation of HCMV glycoprotein B (gB), a membrane protein that accumulates extensively in endosomes during virus assembly. Human CD4+ T cells specific for gB were both highly abundant in blood and cytolytic in vivo. gB-specific CD4+ T cell clones recognized gB that was expressed in glial, endothelial, and epithelial cells, but not exogenous gB that was fed to these cells. Glial cells efficiently presented extremely low levels of endogenous gB--expressed by adenovirus vectors or after HCMV infection--and stimulated CD4+ T cells better than DCs that were incubated with exogenous gB. Presentation of endogenous gB required sorting of gB to endosomal compartments and processing by acidic proteases. Although presentation of cellular proteins that traffic into endosomes is well known, our observations demonstrate for the first time that a viral protein sorted to endosomes is presented exceptionally well, and can promote CD4+ T cell recognition and killing of biologically important host cells

A Novel Document Generation Process for Topic Detection based on Hierarchical Latent Tree Models

We propose a novel document generation process based on hierarchical latent tree models (HLTMs) learned from data. An HLTM has a layer of observed word variables at the bottom and multiple layers of latent variables on top. For each document, we first sample values for the latent variables layer by layer via logic sampling, then draw relative frequencies for the words conditioned on the values of the latent variables, and finally generate words for the document using the relative word frequencies. The motivation for the work is to take word counts into consideration with HLTMs. In comparison with LDA-based hierarchical document generation processes, the new process achieves drastically better model fit with much fewer parameters. It also yields more meaningful topics and topic hierarchies. It is the new state-of-the-art for the hierarchical topic detection

Diffusive benefits of cylinders in front of a Schroeder diffuser

A numerical investigation is performed into the diffusive effects of cylinders positioned in front of a Schroeder diffuser. A regular line of cylinders is shown to offer notable improvements to diffusion from a periodic Schroeder device, provided lateral cylinder spacing is incommensurable with the Schroeder period width. Further investigation considers angular dependence and low frequency results in greater detail, as well as the effects on narrowband and modulated Schroeder devices. An optimization procedure is subsequently performed to investigate the effects of an irregular cylinder arrangement, which provides further diffusive benefits. (C) 2010 Acoustical Society of America

Phase II evaluation of VDC-1101 in canine cutaneous T-cell lymphoma.

BackgroundCanine cutaneous T-cell lymphoma (CTCL) is an uncommon disease for which efficacious therapies are lacking. The novel anticancer nucleotide prodrug VDC-1101 (formerly known as GS-9219) has shown efficacy in dogs with multicentric lymphoma. One of the observed adverse effects with this drug was a skin change characterized by hair loss, erythema, and pruritus, implying delivery of VDC-1101 to the skin.Hypothesis/objectivesThe primary study objective was to identify the objective response rate (ORR) to VDC-1101 in canine CTCL; secondary objectives included characterization of progression-free survival (PFS) and adverse events (AEs).AnimalsTwelve dogs with chemotherapy-naïve or relapsed, histologically and immunohistochemically confirmed CTCL.MethodsDogs received VDC-1101 as a 30-minute IV infusion once every 21 days. Prednisone (1 mg/kg PO q48h) was administered concurrently.ResultsIn 11 evaluable patients, responses included 1 complete response (CR), 4 partial responses (PR), 2 stable disease (SD), and 4 progressive disease for an ORR of 45% and biologic response rate (CR/PR/SD) of 64%. The median PFS was 37.5 days (26 to >399 days), which includes 1 durable and ongoing CR (>1 year). Gastrointestinal and hematologic AEs were mild; no dogs developed grade 3 or 4 AEs. Three dogs developed dermatopathies and 1 of these dogs was removed from the study as a result of this AE.Conclusions and clinical importanceVDC-1101 has activity against canine CTCL and could provide another treatment option in a disease process with a poor prognosis

Challenges in prevention and control of schistosomiasis in the Sudan

No Abstract

Aerobic Exercise Training Protects Against Endothelial Dysfunction By Increasing Nitric Oxide And Hydrogen Peroxide Production In Ldl Receptor-deficient Mice

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Endothelial dysfunction associated with hypercholesterolemia is an early event in atherosclerosis characterized by redox imbalance associated with high superoxide production and reduced nitric oxide (NO) and hydrogen peroxide (H2O2) production. Aerobic exercise training (AET) has been demonstrated to ameliorate atherosclerotic lesions and oxidative stress in advanced atherosclerosis. However, whether AET protects against the early mechanisms of endothelial dysfunction in familial hypercholesterolemia remains unclear. This study investigated the effects of AET on endothelial dysfunction and vascular redox status in the aortas of LDL receptor knockout mice (LDLr-/-), a genetic model of familial hypercholesterolemia. Methods: Twelve-week-old C57BL/6J (WT) and LDLr-/- mice were divided into sedentary and exercised (AET on a treadmill 1 h/5 x per week) groups for 4 weeks. Changes in lipid profiles, endothelial function, and aortic NO, H2O2 and superoxide production were examined. Results: Total cholesterol and triglycerides were increased in sedentary and exercised LDLr-/- mice. Endothelium-dependent relaxation induced by acetylcholine was impaired in aortas of sedentary LDLr-/- mice but not in the exercised group. Inhibition of NO synthase (NOS) activity or H2O2 decomposition by catalase abolished the differences in the acetylcholine response between the animals. No changes were noted in the relaxation response induced by NO donor sodium nitroprusside or H2O2. Neuronal NOS expression and endothelial NOS phosphorylation (Ser1177), as well as NO and H2O2 production, were reduced in aortas of sedentary LDLr-/- mice and restored by AET. Incubation with apocynin increased acetylcholine-induced relaxation in sedentary, but not exercised LDLr-/- mice, suggesting a minor participation of NADPH oxidase in the endothelium-dependent relaxation after AET. Consistent with these findings, Nox2 expression and superoxide production were reduced in the aortas of exercised compared to sedentary LDLr-/- mice. Furthermore, the aortas of sedentary LDLr-/- mice showed reduced expression of superoxide dismutase (SOD) isoforms and minor participation of Cu/Zn-dependent SODs in acetylcholine-induced, endothelium-dependent relaxation, abnormalities that were partially attenuated in exercised LDLr-/- mice. Conclusion: The data gathered by this study suggest AET as a potential non-pharmacological therapy in the prevention of very early endothelial dysfunction and redox imbalance in familial hypercholesterolemia via increases in NO bioavailability and H2O2 production.14Sao Paulo Research Foundation-FAPESP [10/50323-2]University of Campinas fund (FAEPX-PAPDIC Program) [25810]Coordination for the Improvement of Higher Education Personnel-CAPESBrazilian National Council for Scientific and Technological Development-CNPqFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Gaussian Processes for hearing threshold estimation using Auditory Brainstem Responses

The Auditory Brainstem Response (ABR) plays an important role in diagnosing and managing hearing loss, but can be challenging and time-consuming to measure. Test times are especially long when multiple ABR measurements are needed, e.g., when estimating hearing threshold at a range of frequencies. While many detection methods have been developed to reduce ABR test times, the majority were designed to detect the ABR at a single stimulus level and do not consider correlations in ABR waveforms across levels. These correlations hold valuable information, and can be exploited for more efficient hearing threshold estimation. This was achieved in the current work using a Gaussian Process (GP), i.e., a Bayesian approach method for non-linear regression. The function to estimate with the GP was the ABR's amplitude across stimulus levels, from which hearing threshold was ultimately inferred. Active learning rules were also designed to automatically adjust the stimulus level and efficiently locate hearing threshold. Simulation results show test time reductions of up to $\sim$50% for the GP compared to a sequentially applied Hotelling's T2 test, which does not consider correlations across ABR waveforms. A case study was also included to briefly assess the GP approach in ABR data from an adult volunteer

Envelope frequency following responses are stronger for high-pass than low-pass filtered vowels

Background: To assess hearing in response to speech, the envelope frequency following response (FFR) can be observed at the fundamental frequency of a vowel stimulus, and its harmonics. FFRs are complex non-linear phenomena, which require better understanding for allowing robust inferences on the assessment of hearing and hearing aid fitting. Objectives: To evaluate the effect of stimulus bandwidth on FFR detection rates using filtered vowel stimuli with equal sound levels. Design: FFRs were collected whilst presenting repeated vowels (in consonant-vowel-consonant format) filtered into different bandwidths. Eighty stimuli per word were presented at 70 dB SPL LAeq through insert earphones with an inter-stimulus interval of 1s. Responses were detected using frequency-domain Hotelling’s T2 (HT2) tests for individual multiples of the fundamental frequency (F0) and for combinations of F0 multiples. Study Sample: Eleven native English-speaking subjects with normal hearing thresholds. Results: Average detection rates are highest (69%) with stimuli high-pass filtered >1000 Hz, and significantly lower for low-pass filtered stimuli (40%). Conclusion: High-pass filtered vowels elicit stronger FFRs than low-pass filtered vowels at the same dB SPL LAeq. For testing hearing using band-limited speech, filtering effects (due to hearing loss, hearing aid setting or stimulus choice) on responses must be considered