Reduced-intensity conditioning allogeneic transplantation after salvage treatment with DT-PACE in myeloma patients relapsing early after autologous transplant.

OBJECTIVE: In this retrospective single-centre study, we have looked into the transplant outcomes(overall survival OS, progression-free survival PFS, GvHD) and the role of chimerism, DLI and pretransplant characteristics in patients who had a suboptimal response (<12 months) to an autologous stem cell transplant for myeloma and underwent an alemtuzumab T-cell depleted reduced-intensity allograft(RIC). METHODS: Twenty-four patients were salvaged with two cycles of DT-PACE and received a RIC transplant with fludarabine, melphalan and alemtuzumab. All the patients received PBSC grafts, eight patients had a sibling donor, and 16 had a graft from a fully matched unrelated donor. The median follow-up was 65.3 months (6-132 months). RESULTS: The median overall survival was 55.4 months. DLI administration was associated with a trend towards better overall survival (P=.05). Disease status at allo-HCT, PR or VGPR, ISS score and CMV serostatus was not significant predictors of OS and PFS. Full donor whole blood chimerism (≥98%) at 3 months post-transplant was associated with PFS (P=.04) but did not have a significant impact on OS(P=.45). CONCLUSION: Reduced-intensity alemtuzumab-conditioned allograft for myeloma after DT-PACE salvage chemotherapy is an efficient and low toxicity treatment for those who had a suboptimal response postautologous stem cell transplant for myeloma.

Urine drug screen findings among ambulatory oncology patients in a supportive care clinic.

PURPOSE: Professional organizations provide no guidelines regarding assessment and management of opioid abuse risk in cancer. Universal precautions (UP) developed for non-cancer pain, include assessments for aberrant behavior, screening questionnaires, and urine drug screens (UDS). The role of UDS for identifying opioid abuse risk in cancer is uncertain. Our aim is to characterize inappropriate UDS, and identify a potential role for UDS in therapeutic decision-making. METHODS: An observational retrospective chart review of 232 consecutive supportive care clinic patients were seen during the study. Twenty-eight of the two hundred thirty-two did not meet inclusion criteria. One hundred fifty of the two hundred four had active cancer, while 54 had no evidence of active disease. Clinicians ordered UDS based on their clinical judgment of patients' substance misuse risk. Edmonton symptom assessment scores, history of substance abuse, alcohol use, tobacco use, aberrant behavior, and morphine equivalent daily dose (MEDD) were obtained. RESULTS: Pain scores and MEDD were higher (p = 0.021; p < 0.001) in the UDS group vs non-UDS. Forty percent of the patients (n = 82/204) had at least one UDS and 70% (60/82) had an inappropriate result. Thirty-nine percent (32) were inappropriately negative, showing no prescribed opioids. Forty-nine of the eighty-two were positive for non-prescribed opioids, benzodiazepine, or illicit substance. Eleven of the forty-nine had only cannabis metabolites in their urine. There were no significant differences between appropriate and inappropriate UDS groups regarding pain scores, MEDD or referral to psychology, psychiatry, or substance abuse specialists. CONCLUSIONS: UDS on the 82 oncology patients at high risk for substance misuse were frequently positive (46%) for non-prescribed opioids, benzodiazepines or potent illicit drugs such as heroin or cocaine, and 39% had inappropriately negative UDS, raising concerns for diversion.

Measuring the impact of a burns school reintegration programme on the time taken to return to school: A multi-disciplinary team intervention for children returning to school after a significant burn injury.

INTRODUCTION: Returning to school can be a major step for burn-injured children, their family, and staff and pupils at the receiving school. Previous literature has recognised the difficulties children may face after a significant injury and factors that may influence a successful reintegration. AIM: A regional paediatric burns service recognised that some patients were experiencing difficulties in returning to school. A baseline audit confirmed this and suggested factors that hindered or facilitated this process, initiating the development of a school reintegration programme (SRP). Since the programme's development in 2009, it has been audited annually. The aim of this paper was to evaluate the impact of the SRP by presenting data from the 2009 to 2011 audits. METHOD: For the baseline audit, the burn care team gathered information from clinical records (age, gender, total body surface area burned (TBSA), skin grafting and length of stay) and telephone interviews with parents and teachers of the school returners. For the re-audits, the same information was gathered from clinical records and feedback questionnaires. RESULTS: Since its introduction, the mean length of time from discharge to return to school has dropped annually for those that opted into the programme, when compared to the baseline by 62.3% (53 days to 20 days). Thematic analysis highlights positive responses to the programme from all involved. Increased awareness and feeling supported were amongst the main themes to emerge. CONCLUSIONS: Returning to school after a significant burn injury can be challenging for all involved, but we hypothesise that outreach interventions in schools by burns services can have a positive impact on the time it takes children to successfully reintegrate.

Early dysregulation of the memory CD8+ T cell repertoire leads to compromised immune responses to secondary viral infection in the aged.

BACKGROUND: Virus-specific memory CD8+ T cells persist long after infection is resolved and are important for mediating recall responses to secondary infection. Although the number of memory T cells remains relatively constant over time, little is known about the overall stability of the memory T cell pool, particularly with respect to T cell clonal diversity. In this study we developed a novel assay to measure the composition of the memory T cell pool in large cohorts of mice over time following respiratory virus infection. RESULTS: We find that the clonal composition of the virus-specific memory CD8+ T cell pool begins to change within months of the initial infection. These early clonal perturbations eventually result in large clonal expansions that have been associated with ageing. CONCLUSIONS: Maintenance of clonal diversity is important for effective long-term memory responses and dysregulation of the memory response begins early after infection.

Maintenance of peripheral T cell responses during Mycobacterium tuberculosis infection.

Fully functional T cells are necessary for the maintenance of protective immunity during chronic infections. However, activated T cells often undergo apoptosis or exhaustion upon chronic stimulation mediated by Ag or inflammation. T cell attrition can be compensated for by the production of thymus-derived T cells, although the new naive T cells must undergo T cell priming and differentiation under conditions different from those encountered during acute infection. We used a murine model of Mycobacterium tuberculosis infection to address how the activation and differentiation of new thymic emigrants is affected by chronic inflammation, as well as whether the newly developed effector T cells help to maintain peripheral T cell responses. Although new thymic emigrants contributed to the peripheral T cell response early during acute M. tuberculosis infection, the relative contribution of new effector T cells to the peripheral CD4 and CD8 T cell pools declined during chronic infection. The decline in new T cell recruitment was a consequence of quantitative and/or qualitative changes in Ag presentation, because during chronic infection both the priming and expansion of naive T cells were inefficient. Thus, although thymic tolerance is not a major factor that limits protective T cell responses, the chronic environment does not efficiently support naive T cell priming and accumulation during M. tuberculosis infection. These studies support our previous findings that long-term protective T cell responses can be maintained indefinitely in the periphery, but also suggest that the perturbation of homeostasis during chronic inflammatory responses may elicit immune pathology mediated by new T cells.

Effects of atomoxetine with and without behavior therapy on the school and home functioning of children with attention-deficit/hyperactivity disorder.

OBJECTIVE: To evaluate the effects of atomoxetine alone and in combination with behavior therapy on the school functioning of children with attention-deficit/hyperactivity disorder (ADHD). Most atomoxetine studies have not assessed school functioning other than by measuring the change in ADHD symptoms. Combining behavior therapy with atomoxetine may be particularly beneficial for the academic domain as medication has not been found to produce sustained benefits in this realm. However, there is little research examining the effects of combining atomoxetine and behavior therapy. METHOD: In an 8-week open-label trial, 56 children aged 6-12 years with ADHD diagnosed according to DSM-IV-TR were randomly assigned to receive atomoxetine and behavior therapy or atomoxetine alone. Behavior therapy consisted of an 8-week parenting course, a child social skills course, and a teacher-implemented daily report card of classroom behavior. The primary outcome was direct observation of the subject's classroom behavior. Secondary outcomes included change in ADHD symptoms and functioning at home and school. All data were collected between March 2007 and May 2008. RESULTS: Classroom observations showed that atomoxetine decreased rule violations (P < .0001). Moreover, atomoxetine was associated with significant improvements in ADHD and oppositional defiant disorder symptoms at home and school and enhanced functioning in both domains (Impairment Rating Scale: all P < .001). Combined treatment led to greater improvements in parent-rated symptoms of inattention (P < .01), problem behaviors (P < .001), and academic impairment (P < .05). However, teachers did not report significant group differences. CONCLUSIONS: Atomoxetine improved ADHD symptoms and classroom functioning as measured by parents, teachers, and direct observation. The addition of behavior therapy led to further improvements at home but not at school. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00918567.

Differences in the ability to generate type 1 T helper cells need not determine differences in the ability to resist Mycobacterium tuberculosis infection among mouse strains.

BACKGROUND: C57BL/6 (B6) and BALB/c mice are considerably more resistant to infection with Mycobacterium tuberculosis than DBA/2 mice. METHODS: To determine whether the difference in resistance is because DBA/2 mice generate a type 1 T helper (Th1) immune response of lower magnitude, the Th1 response to airborne infection of mice of all 3 strains was measured in terms of the number of interferon (IFN)-gamma-producing CD4 and CD8 T cells generated. RESULTS: Despite the superior resistance of BALB/c mice compared with DBA/2 mice, both strains generated a similarly low number of Th1 cells. On the other hand, B6 mice, despite being approximately equal in resistance compared with BALB/c mice, generated a much larger number of Th1 cells. In DBA/2 mice, a higher level of lung infection was associated with larger numbers of M. tuberculosis bacilli in individual macrophages at sites of infection, indicating lower levels of macrophage mycobacteriostatic function. Despite this, infected macrophages from DBA/2 mice stained positive for nitric oxide synthase type 2 (NOS2) by immunocytochemistry as intensely as did infected macrophages from B6 and BALB/c mice, indicating the acquisition of NOS2-dependent mycobacteriostatic function in all cases. CONCLUSION: The ability to generate a large number of Th1 cells need not determine the ability to resist M. tuberculosis infection.

Genetic and functional characterization of the mouse Trl3 locus in defense against tuberculosis.

The genetic control of susceptibility to tuberculosis in DBA/2J and C57BL/6J mice is complex and influenced by at least four tuberculosis resistance loci (Trl1-Trl4). To further study the Trl3 and Trl4 loci, we have created congenic mouse lines D2.B6-Chr7 and D2.B6-Chr19, in which resistant B6-derived portions of chromosome 7 (Chr.7) and chromosome 19 (Chr.19) overlapping Trl3 and Trl4, respectively, were independently introgressed onto susceptible D2 background. Transfer of B6-derived Trl3 chromosome 7 segment significantly increased resistance of D2 mice, as measured by reduced pulmonary microbial replication at day 70, and increased host survival following aerosol infection. However, transfer of B6-derived chromosome 19 (Trl4) onto D2 mice did not increase resistance by itself and does not improve on the protective effect of chromosome 7. Further study of the protective effect of Trl3 in D2.B6-Chr7 mice indicates that it does not involve modulation of timing or magnitude of Th1 response in the lung, as investigated by measuring the number of Ag-specific, IFN-gamma-producing CD4(+) and CD8(+) T cells. Rather, Trl3 appears to affect the intrinsic ability of activated macrophages to restrict intracellular mycobacterial replication in an NO synthase 2-independent fashion. Microarray experiments involving parental and congenic mouse lines identified a number of genes in the Trl3 interval on chromosome 7 the level of expression of which before infection or in response to Mycobacterium tuberculosis infection is differentially regulated in a parental haplotype-dependent fashion. This gene list represents a valuable entry point for the identification and prioritization of positional candidate genes for the Trl3 effect on chromosome 7.

Disseminated and rapidly fatal tuberculosis in mice bearing a defective allele at IFN regulatory factor 8.

The interferon regulatory factor (IRF) family member IRF-8 participates in IFN-gamma-dependent transcriptional activation of genes containing in their promoter regions IFN-stimulated response element or IFN-gamma activation site elements. To test the role of IRF-8 in host defenses against tuberculosis, BXH-2 mice, which bear a defective IRF-8(R294C) allele, were challenged with low doses of virulent Mycobacterium tuberculosis via the i.v. and aerosol routes. BXH-2 mice were found to be extremely susceptible to M. tuberculosis, as demonstrated by rapid and uncontrolled microbial replication in spleen, liver, and lungs leading to very early death. The BXH-2 defect was expressed very early (10 days postinfection) as uncontrolled intracellular pathogen replication in NOS2-expressing lung macrophages, impaired granuloma formation, rapid dissemination of the infection to distant sites, and rapid necrosis of infected tissues. There was complete absence of IL-12p40 induction, severely reduced IFN-gamma production, and impaired T cell priming in the lungs of infected BXH-2, highlighting the critical role of IRF-8 in this process. Collectively, these results identify IRF-8 as a critical regulator of host defenses against tuberculosis.

'Immunization' against airborne tuberculosis by an earlier primary response to a concurrent intravenous infection.

Tuberculosis in mice is a lung disease. Airborne infection of this host species with Mycobacterium tuberculosis (Mtb) resulted in 20 days of Mtb growth in the lungs before further growth was inhibited and the level of infection stabilized. Inhibition of Mtb growth was associated with the production of interferon-gamma (IFN-gamma)-producing T cells in the lymph nodes and spleen and with the progressive accumulation of these cells in the lungs. Production of IFN-gamma-producing T cells was not discernable until about day 15 of infection, presumably because Mtb did not disseminate from the lungs to the draining lymph nodes and spleen until after an approximate 10-day delay. By contrast, in mice infected via the intravenous (i.v.) route, the spleen became infected almost immediately, resulting in much earlier production of IFN-gamma-producing T cells and earlier control of spleen and lung infection. In mice infected concurrently via both routes, earlier generation of immunity to the i.v. infection resulted in earlier accumulation of IFN-gamma-producing T cells in the lungs and earlier control of lung infection that was initiated via the airborne route. This protection against airborne infection afforded by an earlier primary immune response is equivalent to that expressed by mice vaccinated with bacillus Calmette-Guérin or certain other vaccines.

Fibrotic response as a distinguishing feature of resistance and susceptibility to pulmonary infection with Mycobacterium tuberculosis in mice.

The differential susceptibility of inbred mouse strains DBA/2J (susceptible) and C57BL/6J (resistant) to pulmonary tuberculosis following aerosol infection is under complex genetic control. In this report, transcriptional profiling with RNAs from Mycobacterium tuberculosis-infected lungs was used to investigate the physiological response, cell type, and biochemical pathways underlying differential susceptibility to infection. Statistical analysis of cDNA-based microarrays revealed that 1,097 transcripts showed statistically significant changes in abundance (changes of > or = 1.5-fold) in at least one of four experimental group comparisons (C57BL/6J [day 0] versus DBA/2J [day 0] mice, C57BL/6J [day 90] versus DBA/2J [day 90] mice, C57BL/6J [day 90] versus C57BL/6J [day 0] mice, or DBA/2J [day 90] versus DBA/2J [day 0] mice). A group of genes showing very high degrees of significance (changes of > or = 2.0-fold) displayed enrichment for transcripts associated with tissue remodeling and the fibrotic response. The differential expression of fibrotic response genes (Sparc, Col1a1, Col1a2, Col4a1, and Col4a2) in the infected lungs of the two mouse strains was validated by another microarray platform (Affymetrix oligonucleotide chips) and by reverse transcription-PCR. Furthermore, the differential expression of additional genes known to be associated with fibrosis (Mmp2, Timp1, and Arg1) was also validated by these approaches. Overall, these results identify the differential fibrotic response as a pathological basis for the high susceptibility of DBA/2J mice to pulmonary tuberculosis.

Expression levels of Mycobacterium tuberculosis antigen-encoding genes versus production levels of antigen-specific T cells during stationary level lung infection in mice.

Mycobacterium tuberculosis lung infection in mice was controlled at an approximately stationary level after 20 days of log linear growth. Onset of stationary level infection was associated with the generation by the host of T helper type 1 (Th1) immunity, as evidenced by the accumulation of CD4 Th1 cells specific for the early secretory antigen (ESAT-6) of M. tuberculosis encoded by esat6, and for a mycolyl transferase (Ag85B) encoded by fbpB. CD4 T cells specific for these antigens were maintained at relatively high numbers throughout the course of infection. The number of CD4 T cells generated against ESAT-6 was larger than the number generated against Ag85B, and this was associated with a higher transcription level of esat6. The total number of transcripts of esat6 increased during the first 15 days of infection, after which it decreased and then approximately stabilized at 10(6.5) per lung. The total number of fbpB transcripts increased for 20 days of infection before decreasing and then approximately stabilizing at 10(4.8) per lung. The number of transcripts of esat6 per colony-forming unit of M. tuberculosis fell from 8.6 to 0.8 after day 15, and of fbpB from 0.3 to less than 0.02 after day 10, suggesting that at any given time during stationary level infection the latter gene was expressed by a very small percentage of bacilli. Expressed at an even lower level was an M. tuberculosis replication gene involved in septum formation (ftsZ), indicating that there was no significant turnover of the M. tuberculosis population during stationary level infection.

Superior virulence of Mycobacterium bovis over Mycobacterium tuberculosis (Mtb) for Mtb-resistant and Mtb-susceptible mice is manifest as an ability to cause extrapulmonary disease.

Mice of a Mycobacterium tuberculosis-resistant (BALB/c) and of a M. tuberculosis-susceptible (DBA/2) strain proved considerably more susceptible, and equally so, to infection with Mycobacterium bovis than with M. tuberculosis when infection was initiated via the iv route. Infection with M. tuberculosis was eventually controlled at an approximately stationary level in the lungs, livers, spleens and kidneys of BALB/c mice, and in all of these organs except the lungs in DBA/2 mice. M. tuberculosis-infected DBA/2 mice died with a much shorter median survival time (MST) than M. tuberculosis-infected BALB/c mice. By contrast, infection with M. bovis killed mice of both strains with the same and much shorter MST. Unexpectedly, M. bovis caused progressive infection and pathology in the livers of BALB/c mice, but not in this organ in DBA/2 mice. More importantly, this pathogen caused progressive infection and infection-induced pathology in the kidneys and adrenal glands of both strains of mice. It is proposed that disease of the adrenal glands might serve to explain why M. bovis caused mice of both strains to die with the same much shorter MST.

Properties and protective value of the secondary versus primary T helper type 1 response to airborne Mycobacterium tuberculosis infection in mice.

Mice immunized against Mycobacterium tuberculosis (Mtb) infection by curing them of a primary lung infection were compared with naive mice in terms of the ability to generate a Th1 cell immune response and to control growth of an airborne Mtb challenge infection. Immunized mice generated and expressed Th1 cell immunity several days sooner than naive mice, as demonstrated by an earlier increase in the synthesis in the lungs of mRNA for Th1 cytokines and for inducible nitric oxide synthase, an indicator of macrophage activation. This Th1 cytokine/mRNA synthesis was accompanied by an earlier accumulation of Mtb-specific Th1 cells in the lungs and the presence of CD4 T cells in lesions. An earlier generation of immunity was associated with an earlier inhibition of Mtb growth when infection was at a 1-log lower level. However, inhibition of Mtb growth in immunized, as well as in naive, mice was not followed by resolution of the infection, but by stabilization of the infection at a stationary level. The results indicate that there is no reason to believe that the secondary response to an Mtb infection is quantitatively or qualitatively superior to the primary response.

Rehabilitation needs of an inpatient medical oncology unit.

OBJECTIVE: To identify prospectively functional impairments and rehabilitation needs in an acute care medical oncology unit. DESIGN: Prospective cohort study. SETTING: Inpatient medical oncology unit at a Veterans Affairs hospital. PARTICIPANTS: Fifty-five patients admitted over a 6-month period. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM instrument, functionally based physical examination, Rehabilitation Needs Assessment, and Recreational Needs Assessment. RESULTS: On admission, the mean FIM total score was 105 out of 126, the FIM motor score was 72 out of 91, and the FIM cognitive score was 34 out of 35. The functionally based physical examination did not generally correlate with scores obtained on the FIM. Forty-eight (87%) patients had rehabilitation needs on admission. Forty-six (84%) patients had rehabilitation needs on discharge. Rehabilitation Needs Assessment on admission showed deconditioning in 42 (76%) patients; mobility impairment in 32 (58%) patients; a significant decrease in range of motion in 23 (42%) patients; deficits in activities of daily living in 12 (22%) patients; a need for recreational therapy in 7 (13%) patients; potential for benefit from patient education in 30 (55%) patients; and a need for modalities, edema control, or wound care in fever than 5% of patients. The most commonly requested recreational activity was reading. CONCLUSIONS: Patients admitted to inpatient medical oncology units have many unmet, remediable rehabilitation needs that may not be recognized by nonrehabilitation physicians and other clinical staff. These findings suggest that assessment of medical oncology patients may be enhanced by consultation with rehabilitation medicine specialists.

Increased interleukin-10 expression is not responsible for failure of T helper 1 immunity to resolve airborne Mycobacterium tuberculosis infection in mice.

With a view to determining whether failure of mice to resolve Mycobacterium tuberculosis (Mtb) infection is a consequence of downregulation of T helper 1 (Th1) immunity by interleukin (IL)-10, mice deleted of the gene for IL-10 were compared with wild-type (WT) mice in terms of their ability to make IL-10 mRNA, generate Th1-mediated immunity [as measured by synthesis of mRNA for interferon-gamma (IFN-gamma)], IL-12p40 and inducible nitric oxide synthase (iNOS), and to control lung infection. It was found that the response of WT mice to infection included a substantial and sustained increase in IL-10 mRNA synthesis in the lungs. A Th1 response in the lungs of WT and IL-10-/- mice was evidenced by a large and sustained increase in the synthesis of mRNA for IFN-gamma, IL-12p40 and iNOS, with somewhat higher levels of these mRNA species being made in the lungs of IL-10-/- mice, particularly at an early stage of infection. However, IL-10-/- mice were no more capable than WT mice at combating infection.

Susceptibility to tuberculosis: a locus on mouse chromosome 19 (Trl-4) regulates Mycobacterium tuberculosis replication in the lungs.

The mouse DBA/2 (D2) strain is very susceptible to infection with virulent Mycobacterium tuberculosis, whereas C57BL/6 (B6) is much more resistant. Infection of D2 and B6 mice with M. tuberculosis H37Rv by the respiratory route is biphasic: during the first 3 weeks, there is rapid bacterial growth in the lung of both strains, whereas beyond this point replication stops in B6 but continues in D2, causing rapidly fatal pulmonary disease. To identify the genes regulating growth of M. tuberculosis in the lungs of these two strains, 98 informative (B6 x D2) F2 mice were infected by the respiratory route with M. tuberculosis H37Rv (2 x 102 colony-forming units), and the extent of bacterial replication in the lungs at 90 days was used as a quantitative measure of susceptibility in a whole-genome scan. Quantitative trait locus mapping identified a major locus on chromosome 19 (Tuberculosis resistance locus-4, Trl-4; logarithm of odds 5.6), which regulated pulmonary replication of M. tuberculosis and accounted for 25% of the phenotypic variance. B6 alleles at Trl-4 were inherited in an incompletely dominant fashion and associated with reduced bacterial replication. An additional effect of a locus (Trl-3), previously shown to affect survival to i.v. infection with M. tuberculosis, was also noted. F2 mice homozygous for B6 alleles at both Trl-3 and Trl-4 were as resistant as B6 parents, whereas mice homozygous for D2 alleles were as susceptible as D2 parents. These results suggest a strong genetic interaction between Trl-3 and Trl-4 in regulating pulmonary replication of M. tuberculosis.

Expression of NADPH oxidase-dependent resistance to listeriosis in mice occurs during the first 6 to 12 hours of liver infection.

Wild-type mice inoculated with Listeria monocytogenes intravenously were capable of reducing the bacterial load in their livers by 90% within 6 h. In contrast, mice with deletions of the gene for NADPH oxidase were incapable of expressing this early oxygen-dependent anti-Listeria defense and consequently showed higher levels of liver infection at later times.

Virulent but not avirulent Mycobacterium tuberculosis can evade the growth inhibitory action of a T helper 1-dependent, nitric oxide Synthase 2-independent defense in mice.

Control of infection with virulent Mycobacterium tuberculosis (Mtb) in mice is dependent on the generation of T helper (Th)1-mediated immunity that serves, via secretion of interferon (IFN)-gamma and other cytokines, to upregulate the antimycobacterial function of macrophages of which the synthesis of inducible nitric oxide synthase (NOS)2 is an essential event. As a means to understanding the basis of Mtb virulence, the ability of gene-deleted mice incapable of making NOS2 (NOS2(-/-)), gp91(Phox) subunit of the respiratory burst NADPH-oxidase complex (Phox(-/-)), or either enzyme (NOS2/Phox(-/-)), to control airborne infection with the avirulent R1Rv and H37Ra strains of Mtb was compared with their ability control infection with the virulent H37Rv strain. NOS2(-/-), Phox(-/-), and NOS2/Phox(-/-) mice showed no deficiency in ability to control infection with either strain of avirulent Mtb. By contrast, NOS2(-/-) mice, but not Phox(-/-) mice, were incapable of controlling H37Rv infection and died early from neutrophil-dominated lung pathology. Control of infection with avirulent, as well as virulent Mtb, depended on the synthesis of IFN-gamma, and was associated with a substantial increase in the synthesis in the lungs of mRNA for IFN-gamma and NOS2, and with production of NOS2 by macrophages at sites of infection. The results indicate that virulent, but not avirulent, Mtb can overcome the growth inhibitory action of a Th1-dependent, NOS2-independent mechanism of defense.