Tumors escape immunosurveillance by overexpressing the proteasome activator PSME3

The success of CD8+ T cell-based cancer immunotherapy emphasizes the importance of understanding the mechanisms of generation of MHC-I peptide ligands and the possible pathways of tumor cell escape from immunosurveillance. Recently, we showed that peptides generated in the nucleus during a pioneer round of mRNA translation (pioneer translation products, or PTPs) are an important source of tumor specific peptides which correlates with the aberrant splicing and transcription events associated with oncogenesis. Here we show that up-regulation of PSME3 proteasome activator in cancer cells results in increased destruction of PTP-derived peptides in the nucleus thus enabling cancer cell to subvert immunosurveillance. These findings unveil a previously unexpected role for PSME3 in antigen processing and identify PSME3 as a druggable target to improve the efficacy of cancer immunotherapy

The infectiousness of tuberculosis patients coinfected with HIV

The current understanding of airborne tuberculosis (TB) transmission is based on classic 1950s studies in which guinea pigs were exposed to air from a tuberculosis ward. Recently we recreated this model in Lima, Peru, and in this paper we report the use of molecular fingerprinting to investigate patient infectiousness in the current era of HIV infection and multidrug-resistant (MDR) TB

Risk factors for upper-extremity musculoskeletal disorders in the working population.

OBJECTIVE: To assess the relative importance of personal and occupational risk factors for upper-extremity musculoskeletal disorders in the working population. METHODS: A total of 3,710 workers (58% men) participating in a surveillance program of musculoskeletal disorders in a French region in 2002-2005 were included. Upper-extremity musculoskeletal disorders were diagnosed by 83 trained occupational physicians performing a standardized physical examination. Personal factors and work exposure were assessed by a self-administered questionnaire. Statistical associations between musculoskeletal disorders, personal, and occupational factors were analyzed using logistic regression modeling. RESULTS: A total of 472 workers experienced at least 1 upper-extremity musculoskeletal disorder. The risk of upper-extremity musculoskeletal disorders increased with age for both sexes (P < 0.001, odds ratio [OR] < or =4.9 in men and < or =5.0 in women), and in cases of prior history of upper-extremity musculoskeletal disorders (OR 3.1 and 5.0, respectively, P < 0.001). In men, upper-extremity musculoskeletal disorders were associated with obesity (OR 2.2, P = 0.014), high level of physical demand (OR 2.0, P < 0.001), high repetitiveness of the task (OR 1.5, P = 0.027), postures with the arms at or above shoulder level (OR 1.7, P = 0.009) or with full elbow flexion (OR 1.6, P = 0.006), and high psychological demand (OR 1.5, P = 0.005). In women, upper-extremity musculoskeletal disorders were associated with diabetes mellitus (OR 4.9, P = 0.001), postures with extreme wrist bending (OR 2.0, P < 0.001), use of vibrating hand tools (OR 2.2, P = 0.025), and low level of decision authority (OR 1.4, P = 0.042). CONCLUSION: Personal and work-related physical and psychosocial factors were strongly associated with clinically diagnosed upper-extremity musculoskeletal disorders

Prevalence of mental disorders in French prisons for men

BACKGROUND: Psychiatric surveys conducted in prison populations find high prevalence rates, but diagnoses may be difficult in this particular context. None of these surveys have been conducted in France. METHODS: 800 incarcerated male were sampled at random. Each prisoner was interviewed by a group of 2 clinicians, at least one of them being a senior psychiatrist. One of the clinicians used a structured clinical interview which generated DSM IV diagnosis (MINI plus); the second completed the procedure with an open clinical interview. RESULTS: Prevalence rates for a diagnosis given independently by both clinicians and for a consensual diagnosis were respectively: 3.8% (6.2%) for schizophrenia, 17.9% (24%) for major depressive disorder, 12.0% (17.7%) for generalized anxiety and 10.8% (14.6%) for drug dependence. CONCLUSION: Psychiatric diagnosis can be difficult to interpret in prison, especially using traditional standardized interviews. The approach proposed here, with good reliability and closer to a day-to-day clinical practice, yields high prevalence rates

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative

Causes of stigma and discrimination associated with tuberculosis in Nepal: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Tuberculosis (TB) is a major cause of death. The condition is highly stigmatised, with considerable discrimination towards sufferers. Although there have been several studies assessing the extent of such discrimination, there is little published research explicitly investigating the causes of the stigma and discrimination associated with TB. The objectives of our research were therefore to take the first steps towards determining the causes of discrimination associated with TB.</p> <p>Methods</p> <p>Data collection was performed in Kathmandu, Nepal. Thirty four in-depth interviews were performed with TB patients, family members of patients, and members of the community.</p> <p>Results</p> <p>Causes of self-discrimination identified included fear of transmitting TB, and avoiding gossip and potential discrimination. Causes of discrimination by members of the general public included: fear of a perceived risk of infection; perceived links between TB and other causes of discrimination, particularly poverty and low caste; perceived links between TB and disreputable behaviour; and perceptions that TB was a divine punishment. Furthermore, some patients felt they were discriminated against by health workers</p> <p>Conclusion</p> <p>A comprehensive package of interventions, tailored to the local context, will be needed to address the multiple causes of discrimination identified: basic population-wide health education is unlikely to be effective.</p

Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis

Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen

Variants of OTOF and PJVK Genes in Chinese Patients with Auditory Neuropathy Spectrum Disorder

BACKGROUND: Mutations in OTOF and PJVK genes cause DFNB9 and DFNB59 types of hearing loss, respectively. The patients carrying pathogenic mutations in either of these genes may show the typical phenotype of auditory neuropathy spectrum disorder (ANSD). The aim of the present study was to identify OTOF and PJVK mutations in sporadic ANSD patients. METHODS AND FINDINGS: A total of 76 unrelated Chinese non-syndromic ANSD patients were sequenced on the gene OTOF and PJVK exon by exon. Variants were valued in 105 controls with normal hearing to verify the carrying rate. We identified one pathogenic mutation (c.1194T>A) and three novel, possibly pathogenic, variants (c.3570+2T>C, c.4023+1 G>A, and c.1102G>A) in the OTOF gene, and one novel, possibly pathogenic, variant (c.548G>A) in PJVK. Moreover, we found three novel missense mutations within the exons of OTOF. CONCLUSIONS: As we identified 4 and 1 possible pathogenic variants of the OTOF gene and the PJVK gene, respectively, we believe that screening in these genes are important in sporadic ANSD patients. The pathogenicity of these novel mutations needs further study because of their single heterozygous nature. Knowledge on the mutation spectra of these genes in Chinese would be beneficial in understanding the genetic character of this worldwide disease