Prospective Monitoring Reveals Dynamic Levels of T Cell Immunity to Mycobacterium Tuberculosis in HIV Infected Individuals

Monitoring of latent Mycobacterium tuberculosis infection may prevent disease. We tested an ESAT-6 and CFP-10-specific IFN-γ Elispot assay (RD1-Elispot) on 163 HIV-infected individuals living in a TB-endemic setting. An RD1-Elispot was performed every 3 months for a period of 3–21 months. 62% of RD1-Elispot negative individuals were positive by cultured Elispot. Fluctuations in T cell response were observed with rates of change ranging from −150 to +153 spot-forming cells (SFC)/200,000 PBMC in a 3-month period. To validate these responses we used an RD1-specific real time quantitative PCR assay for monokine-induced by IFN-γ (MIG) and IFN-γ inducible protein-10 (IP10) (MIG: r = 0.6527, p = 0.0114; IP-10: r = 0.6967, p = 0.0056; IP-10+MIG: r = 0.7055, p = 0.0048). During follow-up 30 individuals were placed on ARVs and 4 progressed to active TB. Fluctuations in SFC did not correlate with CD4 count, viral load, treatment initiation, or progression to active TB. The RD1-Elispot appears to have limited value in this setting

Increased Virulence of an Epidemic Strain of Mycobacterium massiliense in Mice

Chronic pulmonary disease and skin/soft tissue infections due to non-tuberculous mycobacteria (NTM) of the Mycobacterium chelonae-abscessus-massiliense group is an emerging health problem worldwide. Moreover, the cure rate for the infections this group causes is low despite aggressive treatment. Post-surgical outbreaks that reached epidemic proportions in Brazil recently were caused by M. massiliense isolates resistant to high-level disinfection with glutaraldehyde (GTA). Understanding the differences in the virulence and host immune responses induced by NTM differing in their sensitivity to disinfectants, and therefore their relative threat of causing outbreaks in hospitals, is an important issue.We compared the replication and survival inside macrophages of a GTA-susceptible reference Mycobacterium massiliense clinical isolate CIP 108297 and an epidemic strain from Brazil, CRM-0019, and characterized the immune responses of IFNγ knockout mice exposed to a high dose aerosol with these two isolates. CRM-0019 replicated more efficiently than CIP 108297 inside mouse bone marrow macrophages. Moreover, the animals infected with CRM-0019 showed a progressive lung infection characterized by a delayed influx of CD4+ and CD8+ T cells, culminating in extensive lung consolidation and demonstrated increased numbers of pulmonary CD4+ Foxp3+ regulatory T cells compared to those infected with the reference strain. Immunosuppressive activity of regulatory T cells may contribute to the progression and worsening of NTM disease by preventing the induction of specific protective immune responses.These results provide the first direct evidence of the increased virulence in macrophages and mice and pathogenicity in vivo of the Brazilian epidemic isolate and the first observation that NTM infections can be associated with variable levels of regulatory T cells which may impact on their virulence and ability to persist in the host

Decoding Unattended Fearful Faces with Whole-Brain Correlations: An Approach to Identify Condition-Dependent Large-Scale Functional Connectivity

Processing of unattended threat-related stimuli, such as fearful faces, has been previously examined using group functional magnetic resonance (fMRI) approaches. However, the identification of features of brain activity containing sufficient information to decode, or “brain-read”, unattended (implicit) fear perception remains an active research goal. Here we test the hypothesis that patterns of large-scale functional connectivity (FC) decode the emotional expression of implicitly perceived faces within single individuals using training data from separate subjects. fMRI and a blocked design were used to acquire BOLD signals during implicit (task-unrelated) presentation of fearful and neutral faces. A pattern classifier (linear kernel Support Vector Machine, or SVM) with linear filter feature selection used pair-wise FC as features to predict the emotional expression of implicitly presented faces. We plotted classification accuracy vs. number of top N selected features and observed that significantly higher than chance accuracies (between 90–100%) were achieved with 15–40 features. During fearful face presentation, the most informative and positively modulated FC was between angular gyrus and hippocampus, while the greatest overall contributing region was the thalamus, with positively modulated connections to bilateral middle temporal gyrus and insula. Other FCs that predicted fear included superior-occipital and parietal regions, cerebellum and prefrontal cortex. By comparison, patterns of spatial activity (as opposed to interactivity) were relatively uninformative in decoding implicit fear. These findings indicate that whole-brain patterns of interactivity are a sensitive and informative signature of unattended fearful emotion processing. At the same time, we demonstrate and propose a sensitive and exploratory approach for the identification of large-scale, condition-dependent FC. In contrast to model-based, group approaches, the current approach does not discount the multivariate, joint responses of multiple functional connections and is not hampered by signal loss and the need for multiple comparisons correction

An evaluation of factors associated with taking and responding positive to the tuberculin skin test in individuals with HIV/AIDS

<p>Abstract</p> <p>Background</p> <p>The tuberculin skin test (TST) is still the standard test for detecting latent infection by <it>M tuberculosis </it>(LTBI). Given that the Brazilian Health Ministry recommends that the treatment of latent tuberculosis (LTBI) should be guided by the TST results, the present study sets out to describe the coverage of administering the TST in people living with HIV at two referral health centers in the city of Recife, where TST is offered to all patients. In addition, factors associated with the non-application of the test and with positive TST results were also analyzed.</p> <p>Methods</p> <p>A cross-sectional study was carried out with HIV patients, aged 18 years or over, attending outpatient clinics at the Correia Picanço Hospital/SES/PE and the Oswaldo Cruz/UPE University Hospital, who had been recommended to take the TST, in the period between November 2007 and February 2010. Univariate and multivariate logistic regression analyses were carried out to establish associations between the dependent variable - taking the TST (yes/no), at a first stage analysis, and the independent variables, followed by a second stage analysis considering a positive TST as the dependent variable. The odds ratio was calculated as the measure of association and the confidence interval (CI) at 95% as the measure of accuracy of the estimate.</p> <p>Results</p> <p>Of the 2,290 patients recruited, 1087 (47.5%) took the TST. Of the 1,087 patients who took the tuberculin skin test, the prevalence of TST ≥ 5 mm was 21.6% among patients with CD4 ≥ 200 and 9.49% among those with CD4 < 200 (p = 0.002). The patients most likely not to take the test were: men, people aged under 39 years, people with low educational levels and crack users. The risk for not taking the TST was statiscally different for health service. Patients who presented better immunity (CD4 ≥ 200) were more than two and a half times more likely to test positive that those with higher levels of immunodeficiency (CD4 < 200).</p> <p>Conclusions</p> <p>Considering that the TST is recommended by the Brazilian health authorities, coverage for taking the test was very low. The most serious implication of this is that LTBI treatment was not carried out for the unidentified TST-positive patients, who may consequently go on to develop TB and eventually die.</p

Development and validation of the motivations for selection of medical study (MSMS) questionnaire in India

Background and Objective Understanding medical students' motivation to select medical studies is particularly salient to inform practice and policymaking in countries-such as India-where shortage of medical personnel poses crucial and chronical challenges to healthcare systems. This study aims to develop and validate a questionnaire to assess the motivation of medical students to select medical studies. Methods A Motivation for Selection of Medical Study (MSMS) questionnaire was developed using extensive literature review followed by Delphi technique. The scale consisted of 12 items, 5 measuring intrinsic dimensions of motivations and 7 measuring extrinsic dimensions. Exploratory factor analysis (EFA), confirmatory factor analysis (CFA), validity, reliability and data quality checks were conducted on a sample of 636 medical students from six medical colleges of three North Indian states. Results The MSMS questionnaire consisted of 3 factors (subscales) and 8 items. The three principal factors that emerged after EFA were the scientific factor (e.g. research opportunities and the ability to use new cutting edge technologies), the societal factor (e.g. job security) and the humanitarian factor (e.g. desire to help others). The CFA conducted showed goodnessof-fit indices supporting the 3-factor model. Conclusion The three extracted factors cut across the traditional dichotomy between intrinsic and extrinsic motivation and uncover a novel three-faceted motivation construct based on scientific factors, societal expectations and humanitarian needs. This validated instrument can be used to evaluate the motivational factors of medical students to choose medical study in India and similar settings and constitutes a powerful tool for policymakers to design measures able to increase selection of medical curricula

Molecular evidence of synaptic pathology in the CA1 region in schizophrenia

Alterations of postsynaptic density (PSD)95-complex proteins in schizophrenia ostensibly induce deficits in synaptic plasticity, the molecular process underlying cognitive functions. Although some PSD95-complex proteins have been previously examined in the hippocampus in schizophrenia, the status of other equally important molecules is unclear. This is especially true in the cornu ammonis (CA)1 hippocampal subfield, a region that is critically involved in the pathophysiology of the illness. We thus performed a quantitative immunoblot experiment to examine PSD95 and several of its associated proteins in the CA1 region, using post mortem brain samples derived from schizophrenia subjects with age-, sex-, and post mortem interval-matched controls (n=20/group). Our results indicate a substantial reduction in PSD95 protein expression (−61.8%). Further analysis showed additional alterations to the scaffold protein Homer1 (Homer1a: +42.9%, Homer1b/c: −24.6%), with a twofold reduction in the ratio of Homer1b/c:Homer1a isoforms (P=0.011). Metabotropic glutamate receptor 1 (mGluR1) protein levels were significantly reduced (−32.7%), and Preso, a protein that supports interactions between Homer1 or PSD95 with mGluR1, was elevated (+83.3%). Significant reduction in synaptophysin (−27.8%) was also detected, which is a validated marker of synaptic density. These findings support the presence of extensive molecular abnormalities to PSD95 and several of its associated proteins in the CA1 region in schizophrenia, offering a small but significant step toward understanding how proteins in the PSD are altered in the schizophrenia brain, and their relevance to overall hippocampal and cognitive dysfunction in the illness