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The tuberculin skin test is limited by its inability to distinguish between infection with Mycobacterium tuberculosis and non-tuberculous mycobacteria (NTM). Newer interferon-gamma release assays using ESAT-6 and CFP-10 antigens should have a higher specificity for tuberculosis but have not been widely tested in adults with pulmonary disease due to NTM. In this study, we tested the T-SPOT.TB Test(R) in patients with pulmonary disease due to Mycobacterium avium complex (MAC), the most common disease-causing NTM. Fourteen patients with prior culture-confirmed pulmonary disease due to MAC, 10 patients with prior culture-confirmed tuberculosis and 4 healthy controls were interviewed and tested with the T-SPOT.TB Test. 13 patients with MAC disease and 4 healthy subjects (negative controls) had non-reactive T-SPOT.TB results and 10 patients with prior tuberculosis (positive controls) had reactive results. One patient with MAC disease had a minimally reactive result on initial testing and a non-reactive result on re-testing. The T-SPOT.TB Test had a specificity of 94% for distinguishing between patients with prior MAC disease and prior tuberculosis disease, and will be useful in low tuberculosis prevalence settings where most mycobacterial infections are due to MAC. Reactions to the T-SPOT.TB Test may persist months to years after treatment of tuberculosis. [ABSTRACT FROM AUTHOR]

d-Serine is a coagonist of the N -methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.

Objectives: In a cross-sectional study of human immunodeficiency virus (HIV)-infected adults, the authors showed lower distortion product otoacoustic emissions (DPOAEs) in HIV+ individuals compared with controls as well as findings consistent with a central auditory processing deficit in HIV+ adults on antiretroviral therapy. The authors hypothesized that HIV+ children would also have a higher prevalence of abnormal central and peripheral hearing test results compared with HIV- controls., Design: Pure-tone thresholds, DPOAEs, and tympanometry were performed on 244 subjects (131 HIV+ and 113 HIV- subjects). Thirty-five of the HIV+, and 3 of the HIV- subjects had a history of tuberculosis treatment. Gap detection results were available for 18 HIV- and 44 HIV+ children. Auditory brainstem response results were available for 72 HIV- and 72 HIV+ children. Data from ears with abnormal tympanograms were excluded., Results: HIV+ subjects were significantly more likely to have abnormal tympanograms, histories of ear drainage, tuberculosis, or dizziness. All audiometric results were compared between groups using a two-way ANOVA with HIV status and ear drainage history as grouping variables. Mean audiometric thresholds, gap detection thresholds, and auditory brainstem response latencies did not differ between groups, although the HIV+ group had a higher proportion of individuals with a hearing loss >25 dB HL in the better ear. The HIV+ group had reduced DPOAE levels (p < 0.05) at multiple frequencies compared with HIV- subjects. No relationships were found between treatment regimens or delay in starting treatment and audiological parameters., Conclusions: As expected, children with HIV+ were more likely to have a history of ear drainage, and to have abnormal tympanograms. Similar to the adult findings, the HIV+ group did not show significantly reduced audiometric thresholds, but did have significantly lower DPOAE magnitudes. These data suggest that (1) HIV+ children often have middle ear damage which complicates understanding the direct effects of HIV on the hearing system, and (2) even when corrected for confounders DPOAEs were lower in the HIV+ group. Previous studies suggest ototoxicity from antiretroviral drugs is an unlikely cause of the reduced DPOAE magnitudes. Other possibilities include effects on efferent pathways connecting to outer hair cells or a direct effect of HIV on the cochlea.

Objectives: Abnormal hearing tests have been noted in human immunodeficiency virus (HIV)-infected patients in several studies, but the nature of the hearing deficit has not been clearly defined. The authors performed a cross-sectional study of both HIV+ and HIV- individuals in Tanzania by using an audiological test battery. The authors hypothesized that HIV+ adults would have a higher prevalence of abnormal central and peripheral hearing test results compared with HIV- controls. In addition, they anticipated that the prevalence of abnormal hearing assessments would increase with antiretroviral therapy (ART) use and treatment for tuberculosis (TB)., Design: Pure-tone thresholds, distortion product otoacoustic emissions (DPOAEs), tympanometry, and a gap-detection test were performed using a laptop-based hearing testing system on 751 subjects (100 HIV- in the United States, plus 651 in Dar es Salaam, Tanzania, including 449 HIV+ [130 ART- and 319 ART+], and 202 HIV-, subjects. No U.S. subjects had a history of TB treatment. In Tanzania, 204 of the HIV+ and 23 of the HIV- subjects had a history of TB treatment. Subjects completed a video and audio questionnaire about their hearing, as well as a health history questionnaire., Results: HIV+ subjects had reduced DPOAE levels compared with HIV- subjects, but their hearing thresholds, tympanometry results, and gap-detection thresholds were similar. Within the HIV+ group, those on ART reported significantly greater difficulties understanding speech in noise, and were significantly more likely to report that they had difficulty understanding speech than the ART- group. The ART+ group had a significantly higher mean gap-detection threshold compared with the ART- group. No effects of TB treatment were seen., Conclusions: The fact that the ART+/ART- groups did not differ in measures of peripheral hearing ability (DPOAEs, thresholds), or middle ear measures (tympanometry), but that the ART+ group had significantly more trouble understanding speech and had higher gap-detection thresholds indicates a central processing deficit. These data suggest that: (1) hearing deficits in HIV+ individuals could be a CNS side effect of HIV infection, (2) certain ART regimens might produce CNS side effects that manifest themselves as hearing difficulties, and/or (3) some ART regimens may treat CNS HIV inadequately, perhaps due to insufficient CNS drug levels, which is reflected as a central hearing deficit. Monitoring of central hearing parameters could be used to track central effects of either HIV or ART.

Objectives: To identify the sources of disseminated Mycobacterium avium complex (MAC) infection in AIDS., Methods: HIV positive subjects with CD4 counts <100/mm(3) in Atlanta, Boston, New Hampshire and Finland were entered in a prospective cohort study. Subjects were interviewed about potential MAC exposures, had phlebotomy performed for determination of antibody to mycobacterial lipoarabinomannin and for culture. Patient-directed water samples were collected from places of residence, work and recreation. Patients were followed for the development of disseminated MAC. Univariate and multivariate risk factors for MAC were analyzed., Results: Disseminated MAC was identified in 31 (9%) subjects. Significant risks in univariate analysis included prior Pneumocystis carinii pneumonia (PCP) (hazard ratio 1.821), consumption of spring water (4.909), consumption of raw seafood (34.3), gastrointestinal endoscopy (2.894), and showering outside the home (0.388). PCP, showering and endoscopy remained significant in a Cox proportional hazards model. There was no association between M. avium colonization of home water and risk of MAC. In patients with CD4<25, median OD antibody levels to lipoarabinomannin at baseline were 0.054 among patients who did not develop MAC and 0.021 among patients who did develop MAC (P=0.077)., Conclusions: MAC infection results from diverse and likely undetectable environmental and nosocomial exposures. Mycobacterial infection before HIV infection may confer protection against disseminated MAC in advanced AIDS., (Copyright 2002 The British Infection Society.)

Background: Among adults with advanced HIV infection in developing countries, bacteremia due to Mycobacterium tuberculosis (MTB) is common and bacteremia due to M. bovis (bacille Calmette-Guérin; BCG) is rare. Comparable data are not available for children with HIV., Objective: To compare the prevalence of bacteremia due to M. tuberculosis or M. bovis BCG in hospitalized children and adults with HIV infection in a developing country with a high prevalence of tuberculosis and HIV and > 95% BCG immunization coverage., Design: Descriptive cross-sectional study., Methods: Prospectively hospitalized patients in Lusaka, Zambia who were suspected to have HIV infection underwent phlebotomy for HIV ELISA, HIV viral load, and lysis-centrifugation blood culture for mycobacteria. Histories were obtained and patients were examined for BCG scars. Mycobacterial isolates were identified using DNA probes for MTB complex (MTBC), multiplex PCR and IS6110 typing., Results: The median age of 387 HIV-positive children was 15 months; 98% were BCG immunized. The median age of 344 HIV-positive adults was 32 years; 44% were BCG immunized. Blood cultures were positive for mycobacteria in six children (2%) and 38 adults(11%) (P < 0.001). The six pediatric isolates included five MTBC (40% clustered) and one BCG. The 38 adult isolates included 36 MTBC (16% clustered) and two M. avium complex., Conclusion: Bacteremia due to MTB is less common among children than adults with advanced HIV infection in Zambia. Bacteremia due to M. bovis BCG is rare even among children with recent BCG immunization and symptomatic HIV infection.

Five doses of inactivated Mycobacterium vaccae vaccine were administered intradermally to 22 human immunodeficiency virus (HIV)-infected patients (11 bacille Calmette-Guérin [BCG]-positive and 11 BCG-negative) in Zambia whose CD4 lymphocyte counts were >/=200 cells/mm(3). HIV viral load and lymphocyte proliferation responses were compared for vaccine recipients and 22 HIV-infected control patients (11 BCG-positive and 11 BCG-negative). Immunization was safe and well tolerated in all patients, and induration at the vaccine site decreased from dose 1 to dose 5. A transient decrease in HIV viral load was observed in BCG-positive vaccine recipients after dose 3 but not after subsequent doses. Median lymphocyte stimulation indices to M. vaccae were 6.0 in vaccine recipients and 2.3 in control patients (P<.001). Stimulation indices were >/=3.0 in 19 vaccine recipients (86%) and 7 control patients (32%; P=.001). A 5-dose series of vaccination with inactivated M. vaccae is safe in HIV-infected patients and induces lymphocyte proliferation responses to the vaccine antigen. M. vaccae vaccine is a candidate for the prevention of tuberculosis in HIV infection.

This study assessed the safety of inactivated Mycobacterium vaccae as a candidate vaccine to prevent disseminated mycobacterial disease in children with HIV infection. 35 children ages 1-8 with CD4 counts > or =300/mm3 in New Hampshire, Boston and Chicago were randomised in a 2:1 schedule to receive a 3-dose series of intradermal M. vaccae vaccine (MV) or hepatitis B vaccine (HBV) at 2-month intervals. Immunisation was safe and well tolerated; 2-day median vaccine site in duration was 5 mm in MV recipients and 0 mm in HBV recipients (p < 0.001). There were no significantly different changes in viral load or CD4 count between the two vaccine groups. No PPD skin test conversions occurred after immunisation. MV is safe and well tolerated and deserves further evaluation as a vaccine to prevent mycobacterial disease in HIV-infected children.

Setting: University hospital in Lusaka, Zambia., Objective: To determine the effects of childhood bacille Calmette-Guerin (BCG) immunization and human immunodeficiency virus (HIV) infection on dual skin test reactions to purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS) in a developing country., Design: Descriptive cross-sectional study., Results: Dual skin testing was performed on 112 adults, 58 HIV-positive and 54 HIV-negative. Forty-seven (42%) of 112 had PPD reactions > or =10 mm and 52 (46%) had MAS reactions > or =10 mm. PPD reactions > or =10 mm were present in 30 (63%) of 48 BCG-positive subjects compared to 17 (27%) of 64 BCG-negative subjects (P<0.001). Nineteen (33%) of 58 PPD or MAS skin test positive subjects were PPD dominant, 15 (26%) were MAS dominant, and 24 (41%) were non-dominant. MAS dominant and non-dominant reactions were significantly reduced in HIV-positive subjects, and non-dominant reactions were increased in BCG-positive subjects., Conclusions: Childhood BCG immunization is associated with PPD reactions > or =10 mm among adults. Reduced PPD reaction rates in HIV-positive adults appear to be due to a loss of BCG-induced PPD reactivity. Prior infection with M. avium complex is detectable in a significant proportion of adults in a developing country.

Heat-killed Mycobacterium vaccae vaccine was administered in a three-dose intradermal schedule to 10 healthy adult volunteers at 0, 2, and 10 months. Local and systemic side effects were monitored and vaccine site reactions were measured and photographed at visits 2 days, 14 days, and 2 months after each dose. Reactions to skin tests with purified protein derivative (PPD) and Mycobacterium avium sensitin (MAS) and titers of antibody to arabinose lipoarabinomannin were determined at baseline and after each dose of vaccine. Lymphocyte proliferation responses to MAS were determined after the final dose of vaccine. Immunization was safe and well tolerated, with maximal induration (range, 6-25 mm) at 2 days. PPD skin test conversions did not occur. Seven subjects completed the three-dose schedule; preexisting immunologic responses to mycobacteria were boosted in three, and a new response was elicited in one. M. vaccae vaccine is safe and induces measurable immunologic responses to mycobacterial antigens in some healthy adults.

Disseminated infection with organisms of the Mycobacterium avium complex (MAC) is a common complication of AIDS in the United States and other developing countries, but it is rare or absent in sub-Saharan Africa. To assess the comparative likelihood of exposure to MAC in these geographic areas, we used a standard protocol to culture 91 water samples from environmental sites and piped water supply systems in the United States, Finland, Zaire, and Kenya. MAC was isolated from all geographic areas and from 22 of 91 (24%) samples. Isolation rates were 13 of 47 (28%) for environmental samples and 9 of 44 (20%) for water supply samples. Overall isolation rates were 18 of 52 (35%) samples in the United States and Finland, whereas they were 4 of 39 (10%) samples in Zaire and Kenya (P = 0.015). MAC isolation rates from water supply systems were 8 of 25 (32%) samples in the United States and Finland and 1 of 19 (5%) samples in Zaire and Kenya (P = 0.056). MAC was isolated from hospital water in the United States and Finland but not in hospital water in Zaire and Kenya. Serovar determinations showed that six of eight isolates from the United States were serovar 4 or 8. One MAC isolate from Zaire was identified as an "X" mycobacterium. These data suggest that exposure to MAC in water is likely in diverse areas of the world, but that the likelihood of human exposure to the organism in water may be slightly less in sub-Saharan Africa than in developed countries in the Northern Hemisphere.