Sllmmal~Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon % and lipopolysaccharide or tumor necrosis factor or, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line Dg, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymaticaUy generated H202, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the t-arginine-dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the micobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the r-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.

We present prevalence data for adolescents in a large metropolitan area in the US and the association of DSM-IV diagnoses to functional impairment and selected demographic correlates. We sampled 4175 youths aged 11-17 years from households enrolled in large health maintenance organizations. Data were collected using questionnaires and the Diagnostic Interview Schedule for Children, Version IV (DISC-IV). Impairment was measured using the Child Global Assessment Scale and diagnostic specific impairment in the DISC-IV. 17.1% of the sample met DSM-IV criteria for one or more disorders in the past year; 11% when only DISC impairment was considered and 5.3% only using the CGAS. The most prevalent disorders were anxiety (6.9%), disruptive (6.5%), and substance use (5.3%) disorders. The most prevalent specific disorders were agoraphobia, conduct and marijuana abuse/dependence, then alcohol use and oppositional defiant disorder. Younger youths and females had lower odds for any disorder, as did youths from two parent homes. There was increased odds associated with lower family income. Females had greater odds of mood and anxiety disorders, males of disruptive and substance use disorders. There were greater odds of mood and disruptive disorders for older youths. Prevalences were highly comparable to recent studies using similar methods in diverse non-metropolitan populations. We found associations with age, gender, and to a lesser extent, socioeconomic status reported in previous studies. The inclusion of both diagnosis-specific impairment and global impairment reduced prevalence rates significantly. Our results suggest commonality of prevalences and associated factors in diverse study settings, including urban and rural areas.

The potential involvement of reactive oxygen species in the expression ofgenes involved in immune response was examined in mesangial cells. Tumor necrosis factor (TNF-a) and aggregated (aggr.) IgG increased mRNA levels for the monocyte chemoattactant protein, JE/MCP-1, and the colony-stimulating factor, CSF-1. Scavengers for free radicals such as di-and tetra-methylthiourea (DMTU and TMTU) attenuated the increase in mRNA levels in response to TNF-a and aggr. IgG. Generation of superoxide anion by xanthine oxidase and hypoxanthine increased mRNA levels of these genes, but exogenous H202 did not. Addition of NADPH to activate a membranebound NADPH-oxidase generated superoxide and caused a dose-dependent increase in mRNA levels and further enhanced the stimulation by TNF-a or aggr. IgG. An inhibitor of NADPH-dependent oxidase 4'-hydroxy-3'-methoxy-acetophenone attenuated the rise in mRNA levels in response to TNF-a and aggr. IgG. By nuclear run-on experiments TNF-a, aggr. IgG and NADPH increased the transcription rates for JE/MCP-1 and CSF-1, effects inhibited by TMTU. We conclude that generation of reactive oxygen species, possibly by NADPH-dependent oxidase, are involved in the induction of the JE/MCP-1 and CSF-1 genes by TNF-a and IgG complexes. The concerted expression of leukocyte-directed cytokines represents a general response to tissue injury. (J. Clin.

This paper extends our knowledge of comorbidity of substance use disorders (SUDs) and other psychiatric disorders by examining comorbidity of specific types of SUDs and risk of comorbidity separately for abuse and dependence. The research question is whether there is specificity of risk for comorbidity for different SUDs and whether greater comorbidity is associated with dependence. Data are presented from a probability sample of 4,175 youths aged 11-17 assessed with the NIMH DISC-IV and self-administered questionnaires. SUDs outcomes are alcohol, marijuana and other substances in past year. Mean number of other comorbid disorders ranged from 1.9 for marijuana abuse to 2.2 for other substance abuse and 1.9 for marijuana dependence to 2.8 for other substance dependence. None of the abuse SUDs does not increase risk of anxiety disorders, but dependence does. Both abuse and dependence increased risk of comorbid mood disorders. Similar results were observed for disruptive disorders. Patterns of comorbidity varied by substance, by abuse versus dependence, and by category of other psychiatric disorders. In general, there was greater association of comorbidity with other disorders for dependence vs. abuse. Marijuana is somewhat less associated with other disorders than alcohol or other substances. The strongest association is for comorbid disruptive disorders, regardless of SUD category. Having SUDs and comorbid other psychiatric disorders was associated with substantial functional impairment. Females with SUDs tended to have higher rates of comorbid disorders, as did older youths. There were no differences observed among ethnic groups. When comorbidity of SUDs with other disorders was examined, controlling for other non-SUDs disorders for each specific disorder examined, the greater odds for dependence versus abuse essentially disappeared for all disorders except disruptive disorders, suggesting larger number of comorbid non-SUDs in part account for the observed effects for dependence.

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