Lack of Activity of Orally Administered Clofazimine against Intracellular Mycobacterium tuberculosis in Whole-Blood Culture

The activity of oral clofazimine against intracellular Mycobacterium tuberculosis was compared to that of ofloxacin in healthy volunteers by the use of whole-blood cultures. Clofazimine was inactive whether it was tested alone or combined with other drugs that are used to treat multidrug-resistant tuberculosis, despite a total dose of 2 g. Kanamycin was the most active drug tested

Survival and Replication of Clinical Mycobacterium tuberculosis Isolates in the Context of Human Innate Immunity

The initial host response to Mycobacterium tuberculosis is driven by innate immunity. For this study, we examined the ability of 18 recent clinical isolates and 5 reference strains to survive and replicate in the context of host innate immunity by using whole blood culture. Six healthy tuberculin-negative volunteers served as subjects. H(37)Ra showed the least capacity to replicate of any of the strains tested, decreasing in viability 1.3 log CFU during 72 h of whole blood culture, whereas H(37)Rv increased 0.32 log. Clinical isolates varied greatly in their ability to replicate in blood cells, ranging from −0.4 to +0.8 log (P < 0.001). Four showed significantly more growth than H(37)Rv, and one showed significantly reduced growth. Host mechanisms for restricting intracellular mycobacterial growth were more effective during the first 24 h of whole blood culture than during the 24- to 72-h period. Certain mycobacterial isolates appeared preferentially able to withstand host defenses during each of these intervals. Although there was relatively more homogeneity among subjects than among strains, one of the six subjects showed a reduced capacity to restrict intracellular mycobacterial growth due to a defect expressed during the first 24 h of culture. Our findings indicate substantial variability in the capacity of clinical tuberculosis isolates to replicate in host cells in the face of innate host immunity

Mendelian randomization with incomplete measurements on the exposure in the Hispanic Community Health Study/Study of Latinos

Summary: Mendelian randomization has been widely used to assess the causal effect of a heritable exposure variable on an outcome of interest, using genetic variants as instrumental variables. In practice, data on the exposure variable can be incomplete due to high cost of measurement and technical limits of detection. In this paper, we propose a valid and efficient method to handle both unmeasured and undetectable values of the exposure variable in one-sample Mendelian randomization analysis with individual-level data. We estimate the causal effect of the exposure variable on the outcome using maximum likelihood estimation and develop an expectation maximization algorithm for the computation of the estimator. Simulation studies show that the proposed method performs well in making inference on the causal effect. We apply our method to the Hispanic Community Health Study/Study of Latinos, a community-based prospective cohort study, and estimate the causal effect of several metabolites on phenotypes of interest

Protective Immunity Against a Lethal Respiratory Yersinia pestis Challenge Induced by V Antigen or the F1 Capsular Antigen Incorporated into Adenovirus Capsid

Boyer and colleagues in the laboratory of Dr. Ronald Crystal at Cornell Medical College constructed adenovirus vaccine vectors containing pathogen-specific antigens fused to the pIX capsid protein. Using a mouse model of Yersinia pestis infection, they demonstrate that this vaccine platform has strong adjuvant properties that can stimulate more protective immune responses than equivalent recombinant protein-based subunit vaccines administered with conventional adjuvant

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02-4.27, P = 2.2 x 10(-8)). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio - 1.16, 95% confidence interval: 1.0-1.35, P = 2.3 x 10(-2)). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = -0.51, P = 2.43 x 10(-5)). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men1603579591National Institute of Dental and Craniofacial Research (NIDCR)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [U01DE017018]; NIDCRUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Dental & Craniofacial Research (NIDCR) [U01DE017018, HHSN268201200008I]; Canadian Excellence Research Chairs (CERC) Program grant [CERC09]; US Cancer Pain Relief Committee (Career Development Award "Neurochemistry and Physiology of Human Pain-Processing Nuclei"); Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; network "Greifswald Approach to Individualized Medicine (GANI_MED)" - Federal Ministry of Education and Research [03IS2061A]; Siemens Healthcare (Erlangen, Germany); Federal State of Mecklenburg-West Pomerania; Academy of FinlandAcademy of Finland [104781, 120315, 129269, 1114194, 24300796]; University Hospital Oulu; University of Oulu [75617]; NHLBI grant through the STAMPEED program [5R01HL087679-02, 1RL1MH083268-01]; NIH/National Institute of Mental Health (NIMH) [5R01MH63706: 02]; ENGAGE project; EUEuropean Union (EU) [277849]; Medical Research CouncilMedical Research Council UK (MRC) [G0500539, G0600705, G1002319]; MRC, Centenary Early Career Award; Academy of Finland EGEAproject [285547]; Biocentrum Helsinki; European Commission (EURO-BLCS)European Commission Joint Research Centre [QLG1-CT-2000-01643]; Sigrid Juselius FoundationSigrid Juselius Foundation; US National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [5R01 MH 63706: 02]; Sao Paulo Research FoundationFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2006/56019-8R, 2009/02520-6]; Canadian Excellence Research Chairs (CERC) Program [CERC09]; NIH/National Institute of Neurological Disorders and Stroke (NINDS)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Neurological Disorders & Stroke (NINDS) [NS045685]; National Heart, Lung, and Blood Institute (NHLBI)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [HHSN268201300001I/N01-HC-65233, HHSN268201300004I/N01-HC-65234, HHSN268201300002I/N01-HC-65235, HHSN268201300003I/N01-HC-65236 Northwestern Univ, HHSN268201300005I/N01-HC-65237]; ENGAGE grant [HEALTH-F4-2007-201413]; Intramural Research Program of the NIH, National Institute of Environmental Health SciencesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Environmental Health Sciences (NIEHS); Biocenter; [K12DE022793]; [H2020-633595

Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males

Abstract Painful temporomandibular disorders (TMDs) are the leading cause of chronic orofacial pain, but its underlying molecular mechanisms remain obscure. Although many environmental factors have been associated with higher risk of developing painful TMD, family and twin studies support a heritable genetic component as well. We performed a genome-wide association study assuming an additive genetic model of TMD in a discovery cohort of 999 cases and 2031 TMD-free controls from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. Using logistic models adjusted for sex, age, enrollment site, and race, we identified 3 distinct loci that were significant in combined or sex-segregated analyses. A single-nucleotide polymorphism on chromosome 3 (rs13078961) was significantly associated with TMD in males only (odds ratio = 2.9, 95% confidence interval: 2.02–4.27, P = 2.2 × 10⁻⁸). This association was nominally replicated in a meta-analysis of 7 independent orofacial pain cohorts including 160,194 participants (odds ratio = 1.16, 95% confidence interval: 1.0–1.35, P = 2.3 × 10⁻²). Functional analysis in human dorsal root ganglia and blood indicated this variant is an expression quantitative trait locus, with the minor allele associated with decreased expression of the nearby muscle RAS oncogene homolog (MRAS) gene (beta = −0.51, P = 2.43 × 10⁻⁵). Male mice, but not female mice, with a null mutation of Mras displayed persistent mechanical allodynia in a model of inflammatory pain. Genetic and behavioral evidence support a novel mechanism by which genetically determined MRAS expression moderates the resiliency to chronic pain. This effect is male-specific and may contribute to the lower rates of painful TMD in men