Hematological Parameters in Patients with Pulmonary Tuberculosis and its Presentation among Favorable and Unfavorable Treatment Outcomes.

BACKGROUND: Tuberculosis (TB) management continues to be a challenge globally; weakened immunity plays a significant role in the reactivation of TB. There is limited information on hematological parameters in patients with pulmonary TB and its association with outcome. OBJECTIVES: We present hematological parameters of newly diagnosed sputum-positive pulmonary TB patients enrolled in a randomized, clinical trial that assessed the efficacy and safety of 3 and 4 regimens using moxifloxacin. MATERIALS AND METHODS: Blood hematological parameters at baseline, comparison of the baseline and end of treatment values, including the monocytes by lymphocytes ratio (M/L), neutrophil lymphocyte ratio (N/L), and platelet lymphocyte ratio (P/L) between the patients with favorable and unfavorable TB treatment outcome, and among different age group and sex presented in this paper. RESULTS: Among the total 1059 patients, 782 were males, the mean hemoglobin (HB) ± standard deviation (SD) was 11.5 g/dL ± 2.0, the mean white blood cell (WBC) count ± SD was 9800 ± 3009 and the mean platelet count (in lakhs) ± SD was 4.24 ± 1.42 cells/uL. There was an increase from baseline in the mean hemoglobin, eosinophil, and lymphocyte count and a decrease in mean neutrophil, monocyte counts to the end of treatment. There was a decrease in baseline mean total WBC count posttreatment, both in favorable (10,271 cells/uL ± 3007 SD to 6689 cells/uL ± 1837 SD, [P ≤ 0.001]), and unfavorable TB outcome patients. CONCLUSION: An increase in HB, and a decrease in WBC count, M/L, N/L, and P/L ratio is possible at the end of TB treatment and future studies to correlate blood hematology parameters with TB treatment outcome.

Significance of isolating non-tuberculous mycobacterial organisms in infertile women with tubal disease: an observational study.

OBJECTIVES: To explore whether non-tuberculous mycobacteria (NTM) are associated with tubal disease leading to infertility. DESIGN: Prospective observational study. SETTING: Teaching hospital. POPULATION: Women with tubal factor infertility. METHODS: In all, 173 infertile women with tubal disease were investigated for genital tuberculosis, Chlamydia trachomatis and Neisseria gonorrhoeae using polymerase chain reaction, culture and histopathological examination. On culture, NTM were grown in 23.7% of endometrial samples. The mycolic characteristics of these organisms were analysed. MAIN OUTCOME MEASURE: Whether NTM are associated with tubal disease leading to infertility. RESULTS: The organisms identified in association with tubal disease were Mycobacterium tuberculosis in 30%, gonococci in 1.7%, Chlamydia in 7.5% and NTM in 23.7% of cases. Mycobacterium chelonae was the predominant organism identified by high-performance liquid chromatography. In ten women, for whom there was laparoscopic evidence of tubal disease, the only organism that was grown was NTM, and the tests for other organisms were negative. Tests for possible environment (theatre, instruments) contamination was reported negative. CONCLUSION: While evaluating infertile women for tubal disease, culture studies revealed a high prevalence of NTM in the endometrium. In the absence of M. tuberculosis, gonococci and Chlamydia infection, the presence of NTM suggests the possibility that these organisms may be responsible for tubal damage leading to infertility. TWEETABLE ABSTRACT: On evaluating the causes of tubal disease, NTM were associated with tubal disease.

Contribution of medical colleges to tuberculosis control in India under the Revised National Tuberculosis Control Programme (RNTCP): lessons learnt & challenges ahead.

Medical college faculty, who are academicians are seldom directly involved in the implementation of national public health programmes. More than a decade ago for the first time in the global history of tuberculosis (TB) control, medical colleges of India were involved in the Revised National TB Control Programme (RNTCP) of Government of India (GOI). This report documents the unique and extraordinary course of events that led to the involvement of medical colleges in the RNTCP of GOI. It also reports the contributions made by the medical colleges to TB control in India. For more than a decade, medical colleges have been providing diagnostic services (Designated Microscopy Centres), treatment [Directly Observed Treatment (DOT) Centres] referral for treatment, recording and reporting data, carrying out advocacy for RNTCP and conducting operational research relevant to RNTCP. Medical colleges are contributing to diagnosis and treatment of human immunodeficiency virus (HIV)-TB co-infection and development of laboratory infrastructure for early diagnosis of multidrug-resistant and/or extensively drug-resistant TB (M/XDR-TB) and DOTS-Plus sites for treatment of MDR-TB cases. Overall, at a national level, medical colleges have contributed to 25 per cent of TB suspects referred for diagnosis; 23 per cent of 'new smear-positives' diagnosed; 7 per cent of DOT provision within medical college; and 86 per cent treatment success rate among new smear-positive patients. As the Programme widens its scope, future challenges include sustenance of this contribution and facilitating universal access to quality TB care; greater involvement in operational research relevant to the Programme needs; and better co-ordination mechanisms between district, state, zonal and national level to encourage their involvement.

Effect of vitamin D3 on chemokine expression in pulmonary tuberculosis.

1,25 Dihydroxy vitamin D(3) (vitamin D(3)) is an immunomodulator and its deficiency has been associated with susceptibility to tuberculosis. We have studied the immunoregulatory role of vitamin D(3) on various chemokine expression in pulmonary tuberculosis. Peripheral blood mononuclear cells obtained from 21 pulmonary tuberculosis (PTB) patients and 24 healthy controls (HCs) were cultured for 48 h with culture filtrate antigen (CFA) of Mycobacterium tuberculosis with or without vitamin D(3) at a concentration 1 × 10(-7)M. The relative mRNA expression of monocyte chemoattractant protein-1 (MCP-1, CCL2), macrophage inflammatory protein-1α (MIP-1α, CCL3), macrophage inflammatory protein-1ß (MIP-1ß, CCL4), and regulated upon-activation, normal T cell-expressed and secreted (RANTES, CCL5) and IFN-γ inducible protein-10 (IP-10, CXCL10) chemokines were estimated from 48 h old macrophages using real-time polymerase chain reaction (RT-PCR). The culture supernatants were used to estimate the various chemokines including monokine induced by IFN-γ (MIG, CXCL9) levels using cytometric bead array. In HCs, vitamin D(3) significantly suppressed the MCP-1 mRNA expression of CFA stimulated cells (p=0.0027), while no such effect was observed in PTB patients. Vitamin D(3) showed no significant effect on MIP-1α, MIP-1ß and RANTES in both the study groups. The CFA induced IP-10 mRNA and protein expression was significantly suppressed by vitamin D(3) in both the study groups (p<0.05). A similar suppressive effect of vitamin D(3) was observed with MIG protein in healthy controls (p=0.0029) and a trend towards a suppression was observed in PTB patients. The suppressive effect of vitamin D(3) is more prominent in CXC chemokines rather than CC chemokines. This suggests that vitamin D(3) may down regulate the recruitment and activation of T-cells through CXC chemokines at the site of infection and may act as a potential anti-inflammatory agent.

Efficacy of the 6-month thrice-weekly regimen in the treatment of new sputum smear-positive pulmonary tuberculosis under clinical trial conditions.

BACKGROUND: Under the Revised National Tuberculosis Control Programme of India, patients with new smear-positive pulmonary tuberculosis are treated with a thrice-weekly regimen of antitubercular drugs (2H(3)R(3)Z(3)E(3)/4H(3)R(3) [H isoniazid, R rifampicin, Z pyrazinamide and E ethambutol]) for 6 months. We conducted a retrospective analysis of the efficacy andtolerability of this regimen under clinical trial conditions in HIV-negative patients with newly diagnosed smear-positive pulmonary tuberculosis. METHODS: We retrospectively analysed the data on patients assigned to the control regimen (2H (3)R(3)Z(3)E(3)/4H(3)R(3)) in two clinical trials during 2001-06 at the National Institute for Research in Tuberculosis, Chennai, India. RESULTS: Of the 268 patients treated with this regimen, data for efficacy analysis were available for 249. At the end of treatment, of 249 patients, 238 (96%) had a favourable status. Treatment failure occurred in the remaining 11: 7 in whom the organisms were initially drug-susceptible and 4 with initial drug resistance. Of the 238 patients who had a favourable status at the end of treatment, 14 (6%) had recurrence of tuberculosis during the following 24 months. In the intention-to-treat analysis, 245 (94%) of 262 patients had a favourable status at the end of treatment. Of the 28 patients with initial drug resistance, 24 (86%) had a favourable outcome. Only 4 of these 24 patients were found to have recurrence of tuberculosis in 2 years of follow-up. Among the 221 patients initially infected with drug-susceptible organisms, drug resistance did not develop in any of the 7 patients in whom the treatment failed or the 10 who had recurrence of tuberculosis. Further, 5 of the 7 patients in whom the treatment failed continued to excrete drug-susceptible bacilli at 6 months. Adverse drug reactions were observed in 38 (14%) of the 262 patients. Only 3 (1.1%) needed a modification in the treatment. CONCLUSION: This thrice-weekly 6-month regimen of antitubercular drugs, when administered under full supervision, is associated with a high rate of favourable treatment outcomes in HIV-negative patients with newly diagnosed sputum smearpositive pulmonary tuberculosis. There are few adverse drug reactions in these patients.

Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India.

Toll-like receptors (TLRs) are pattern recognition receptors and play an important role in innate immunity. Changes in TLRs and signaling molecules that result from polymorphisms are often associated with susceptibility to various infectious diseases. In the present study, we investigated whether variants in the TLR-1 1805T/G (Ile602Ser), TLR-2 2258G/A (Arg753Gln), TLR-4 896A/G (Asp299Gly), TLR-4 1196C/T (Thr399Ile), TLR-6 745C/T (Ser249Pro), TIRAP 975C/T (Ser180Leu) genes and TLR-9 promoter region polymorphisms at positions -1237C/T and -1486C/T are associated with susceptibility or resistance to pulmonary tuberculosis (PTB). Genotyping of TLR and TIRAP gene polymorphisms was performed by polymerase chain reaction followed by restriction fragment length polymorphism method in 212 healthy control subjects (HCs) and 206 PTB patients. The allele and genotype frequencies of various TLR genes were not different between the HCs and PTB patients. However, the study is underpowered to detect minor associations. The frequency of T allele of TIRAP 975C/T (Ser180Leu) polymorphism was significantly increased among PTB patients as compared to HCs [p = 0.026; Odds ratio (OR) 1.49, 95% Confidence interval (CI) 1.049-2.22]. A trend towards an increased frequency of TT genotype of TIRAP 975C/T was also observed in PTB patients [p = 0.078, OR 3.10 95% CI (0.96-10.05)]. The present study suggests that T allele of TIRAP 975C/T polymorphism may be associated with susceptibility to pulmonary TB in south Indian population. Further study on the regulatory role of this polymorphism may be helpful to understand the innate immunity in TB.

Cultural epidemiology of TB with reference to gender in Bangladesh, India and Malawi.

SETTING: TB control programmes in Bangladesh, India and Malawi. OBJECTIVE: To identify and compare socio-cultural features of tuberculosis (TB) and the distribution of TB-related experiences, meanings and behaviours with reference to gender across cultures in three high-endemic low-income countries. DESIGN: Approximately 100 patients at three sites were interviewed with in-depth semi-structured Explanatory Model Interview Catalogue (EMIC) interviews inquiring about patterns of distress, perceived causes and help-seeking behaviours in the context of illness narratives. RESULTS: Female patients reported more diverse symptoms and men more frequently focused on financial concerns. Most patients reported psychological and emotional distress. Men emphasised smoking and drinking alcohol as causes of TB, and women in Malawi reported sexual causes associated with HIV/AIDS. In Bangladesh, exaggerated concerns about the risk of spread despite treatment contributed to social isolation of women. Public health services were preferred in Malawi, and private doctors in India and Bangladesh. CONCLUSION: Cross-site analysis of these studies has identified features of TB that influence the burden of disease and are likely to affect timely help seeking and adherence to treatment. Health systems benefit from sex-disaggregated epidemiological data complemented by cultural epidemiological study, which together clarify the role of gender and contribute to the knowledge base for TB control at various levels.

Perceptions of gender and tuberculosis in a south Indian urban community.

BACKGROUND: The Revised National Tuberculosis Control Programme (RNTCP) in India advocating Directly Observed Treatment-Short course (DOTS) detects nearly three times more male than female TB patients. The reasons for this difference are unclear. An understanding of the community's health beliefs, perceptions on the disease and behaviour towards TB patients may throw some light on this issue. MATERIAL AND METHODS: A qualitative study using focus group discussions was conducted among men and women of younger and older age groups from lower income neighbourhoods. The information obtained was grouped into themes which included, understanding of TB, vulnerability, access to health care and social responses. Gender differences in community perceptions on TB seem to be critical in issues related to marriage. RESULTS: The stigma of TB is more visible in women than men when it comes to marriage. Men and children were perceived to get preferential attention by their families during illness. While the younger age group, irrespective of gender, accessed care from private providers, the older group preferred a government facility. Awareness of TB was acceptable but it seemed more associated as a respiratory disease and the common symptom associated with TB was cough. CONCLUSION: This study highlights the need for gender specific intervention strategies to enhance better access of TB services.

1, 25 Dihydroxyvitamin D3 modulated cytokine response in pulmonary tuberculosis.

1, 25 Dihydroxyvitamin D(3) (1, 25(OH)(2) D(3)) has gained significant importance in tuberculosis with regard to its immunoregulatory activities. Our aim was to evaluate the effect of 1, 25(OH)(2) D(3) on cytokine response to Mycobacterium tuberculosis antigens in pulmonary tuberculosis. Peripheral blood mononuclear cells obtained from 60 healthy controls and 52 pulmonary tuberculosis patients were cultured with culture filtrate antigen (CFA) of M. tuberculosis and live M. tuberculosis with and without 1, 25(OH)(2) D(3) (10(-9), 10(-8)and 10(-7)M concentrations). The culture supernatants were used to estimate IL-8, IL-6, TGF-beta, IL-10, IFN-gamma, IL-12p40, IL-2, IL-4 and IL-5 levels by ELISA. 1, 25 Dihydroxyvitamin D(3) significantly suppressed IL-12p40 and IFN-gamma production in response to CFA and live M. tuberculosis with a maximum suppression at 10(-7)M concentration (p<0.0001). In CFA stimulated cultures, addition of 1, 25(OH)(2) D(3) significantly suppressed IL-8, IL-6 and IL-10 whereas the IL-2 levels were significantly increased in controls. It variably influenced the Th2 cytokines, showing an increased trend for IL-4 and suppressed IL-5 levels. We report that 1, 25(OH)(2) D(3) differentially modulates production of cytokines in response to M. tuberculosis antigens by predominantly suppressing IL-12p40 and IFN-gamma production in a dose dependent manner. Our results suggest a role for vitamin D in restricting acquired immune response against tuberculosis by regulating cytokine production.

Interleukin-12B & interleukin-10 gene polymorphisms in pulmonary tuberculosis.

BACKGROUND & OBJECTIVE: Cytokines play an important role in anti-tuberculosis immune response. Skewing of immunity from protective to pathogenic may involve a shift in Th1-Th2 paradigm. Cytokine gene polymorphism is known to be associated with functional differences in cytokine regulation and altered clinical performance in a variety of diseases. The aim of this study was to know whether Interleukin-12B 3' UTR (Taq1) (A/C) and Interleukin-10 (-1082 G/A) gene polymorphisms were associated with susceptibility to pulmonary tuberculosis. METHODS: IL -10 (-1,082 G/A) and IL-12B gene polymorphisms were studied in 132 pulmonary TB (PTB) patients and 143 normal healthy subjects (NHS), using DNA based polymerase chain reaction (PCR) with sequence specific primers and restriction digestion. RESULTS: The allelic as well as genotypic frequencies of Interleukin -10 (-1082) and Interleukin -12B (3'UTR Taq 1) did not differ significantly between the patients and controls. INTERPRETATION & CONCLUSION: Our findings suggested that IL -10 (-1082 G/A) and IL -12B 3'UTR (Taq I) (A/C) gene polymorphisms were not associated either with susceptibility or resistance to pulmonary tuberculosis in the south Indian population.

Influence of HLA-DR2 on perforin-positive cells in pulmonary tuberculosis.

Perforin is one of the key effector molecules of cytotoxic T cells and natural killer cells. The influence of HLA-DRB1 alleles on peripheral blood perforin-positive CD4, CD8, CD16 and CD 56 cells was studied by flow cytometry. HLA-DRB1 typing was done in normal healthy subjects (NHS: n = 156) and patients with pulmonary tuberculosis (PTB: n = 102) by polymerase chain reaction-based sequence-specific oligonucleotide hybridization method. We observed a significantly decreased percentage of total perforin-positive cells (per(+)) (P = 0.0004); CD8(+)/Per(+) (P = 0.0005); CD16(+)/Per(+) (P = 0.05) and CD 56(+)/Per(+) cells (P = 0.001) in HLA-DR2-positive PTB patients compared to non-DR2 patients. Subtyping of HLA-DR2-positive subjects at the allelic level revealed that the percentage of CD8(+)/Per(+) cells did not differ among DRB1*1501 and DRB1*1502 patients while a trend towards a decreased percentage of CD16(+)/Per(+) and CD 56(+)/Per(+) cells was noticed in DRB1*1501 patients compared to DRB1*1502 patients. The present study suggests that HLA-DR2 may be associated with down-regulation of perforin-positive cytotoxic lymphocytes and natural killer cells in pulmonary tuberculosis.

Influence of HLA-DRB1 alleles on Th1 and Th2 cytokine response to Mycobacterium tuberculosis antigens in pulmonary tuberculosis.

The influence of human leukocyte antigens (HLA) on the immune response is well established. We investigated the regulatory role of HLA-DRB1 alleles on cytokine response to live M. tuberculosis and its culture filtrate antigen (CFA) in normal healthy subjects (NHS) and pulmonary tuberculosis (PTB) patients. Th1 (IFN-gamma and IL-12p40), Th2 (IL-4 and IL-5), pro-inflammatory (IL-6 and IL-8) and anti-inflammatory (TGF-beta and IL-10) cytokines were measured by ELISA in 72-h-old peripheral blood mononuclear cell culture supernatants from 58 NHS and 48 PTB patients. HLA-DRB1 genotyping was carried out by polymerase chain reaction and dot-blot hybridization with biotinylated sequence-specific oligonucleotide probes and detection by chemiluminescence. In response to live M. tuberculosis and CFA, significantly increased levels of IL-6, IL-8 and TGF-beta and decreased IFN-gamma, IL-12p40 and IL-10 were seen in PTB patients compared to NHS. We observed a significantly increased IFN-gamma response in HLA-DRB1*03-positive NHS (p=0.03) and decreased IFN-gamma response in HLA-DRB1*15-positive patients (p=0.04) than respective allele-negative individuals. An increased level of IL-12p40 in DRB1*10 (p=0.02) and IL-10 in DRB1*12- (p=0.03) positive NHS and an increased level of IL-6 in DRB1*04- (p=0.02) positive patients were observed. The study suggests that HLA-DRB1 alleles differentially modulate the various cytokine responses to M. tuberculosis antigens, which may influence the cellular and humoral immune responses to M. tuberculosis infection in a susceptible host.

Interferon gamma (IFNgamma) & interleukin-4 (IL-4) gene variants & cytokine levels in pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Cytokine gene polymorphisms may alter Th1/Th2 balance with major implications in tuberculosis. The aim of our study was to find out whether Interferon gamma +874A and IL-4 -590T polymorphisms were associated with susceptibility to pulmonary tuberculosis as well as the level of IFNgamma and IL-4 in south Indian population. METHODS: Interferon gamma +874A and IL-4 -590T promoter polymorphisms were studied in 129 pulmonary tuberculosis (PTB) patients and 127 normal healthy subjects (NHS) and were associated with culture filtrate and live Mycobacterium tuberculosis induced IFNgamma and IL-4 production in peripheral blood mononuclear cells (PBMCs). IL-4 gene variants were also associated with IgG antibody levels against M. tuberculosis culture filtrate antigen. RESULTS: The variant IFNgamma genotypes and IFNgamma levels between genotypes did not differ significantly in patients and controls. Significantly increased frequency of variant IL-4 'CT' genotype in PTB patients (P<0.05) and 'CC' genotype in control group (P<0.01) was observed. IL-4 levels were detectable in very few subjects and the IgG levels did not differ between the three IL-4 genotypes. INTERPRETATION & CONCLUSION: The study suggests a lack of functional association of Interferon gamma +874A polymorphism in tuberculosis in south Indian population. The higher frequency of IL-4 'CT' genotype in PTB suggests a possible association of IL-4 -590T promoter polymorphism with susceptibility to tuberculosis, and the 'CC' genotype may be associated with protection.

Elevated percentage of perforin positive cells in active pulmonary tuberculosis.

BACKGROUND & OBJECTIVES: Perforin is one of the major effector molecules of cytotoxic cells associated with killing of cells harbouring intracellular bacterial infection. The precise role of perforin positive cells in tuberculosis still remains controversial. The present study was done to determine the number of circulating CD4(+) and CD8(+) perforin positive cells to assess the level of cytotoxic response against Mycobacterium tuberculosis in patients with pulmonary tuberculosis. METHODS: Intracellular perforin and surface CD4 and CD8 staining of peripheral blood lymphocytes was done using specific monoclonal antibodies and enumerated using flowcytometry. RESULTS: A significantly decreased total lymphocytes (P<0.01), CD4 (P<0.001) and CD8 (P<0.01) lymphocyte counts in PTB patients was observed compared to normal healthy individuals (NHS). Intracellular perforin staining showed significantly elevated percentages of total (P<0.05) and CD8 (P<0.01) perforin positive cells in PTB patients compared to NHS. However, the absolute counts of total, CD4 and CD8 cells positive for perforin were similar in patients and NHS. INTERPRETATION & CONCLUSION: Our results suggest that during active stage of pulmonary tuberculosis there was an increased percentage of CD8 cells positive for perforin, irrespective of their absolute counts. Further, CD8(+) perforin positive cells may have increased cytolytic activity against M. tuberculosis in active pulmonary tuberculosis.

Rifampicin-induced renal toxicity during retreatment of patients with pulmonary tuberculosis.

Rifampicin is a crucial component of treatment regimens for tuberculosis and has been in use since the early 1970's. It is usually considered safe. Rarely life-threatening complications like acute renal failure or acute thrombocytopaenia may manifest during treatment with rifampicin. In our experience at the Tuberculosis Research Centre of treating more than 8000 pulmonary and extrapulmonary tuberculosis patients with rifampicin-containing regimens over the last 30 years, we are reporting 3 cases of probably rifampicin-induced acute renal failure. Despite extreme therapeutic safety of this drug the clinician must be aware of this rare complication, which if detected early is completely reversible.

Treatment of lymph node tuberculosis--a randomized clinical trial of two 6-month regimens.

OBJECTIVE: The currently recommended treatment for lymph node tuberculosis is 6 months of rifampicin and isoniazid plus pyrazinamide for the first 2 months, given either daily or thrice weekly. The objective of this study was to assess the efficacy of a 6-month twice-weekly regimen and a daily two-drug regimen. METHODS: Patients with biopsy confirmed superficial lymph node tuberculosis were randomly allocated to receive either a daily self-administered 6-month regimen of rifampicin and isoniazid, or a twice-weekly, directly observed, 6-month regimen of rifampicin and isoniazid plus pyrazinamide for the first 2 months, in Madurai, South India, Patients were followed up for 36 months after completing treatment. RESULTS: Of 277 enrolled patients, data was available for analysis in 268. At the end of treatment, 116 of 134 [87%; 95% confidence interval (CI) 81-93%] patients in each treatment group had a favourable clinical response; 14 (11%; 95% CI 6-16%) and 17 (13%; 95% CI 7-19%) patients had a doubtful response, and 4 (3%; 95% CI 0-6%) and 1 (1%; 95% CI 0-2%) patients had an unfavourable response among those treated with the daily and twice-weekly regimen, respectively. During 36 months after completion of treatment, five patients [2 (2%; 95% CI 1-3%) and 3 (2%; 95% CI 1-3%) patients treated with the daily and twice-weekly regimen, respectively] had relapse of lymph node tuberculosis, of 260 assessed. Adverse reactions probably attributable to the treatment regimens occurred in 1% of the patients treated daily and in 11% of those treated twice-weekly (P < 0.001). At the end of 36 months after treatment, 126 of 134 (94%; 95% CI 90-98%) and 129 of 134 (96%; 95% CI 94-98%) of the patients treated with the daily and twice-weekly regimen, respectively, had a successful outcome. CONCLUSION: Both the self-administered daily regimen and the fully observed twice-weekly regimen were highly efficacious for treating patients with lymph node tuberculosis and may be considered as alternative options to the recommended regimens.

Current trends in chemotherapy of tuberculosis.

After treptomycin, which heralded the era of antibacterial chemotherapy for tuberculosis (TB), many important advances have made available treatment regimens that are almost 100 per cent curative. Randomised clinical trials by the Tuberculosis Research Centre, in Chennai and British Medical Research Council in East Africa and in the Far East have helped to establish many of the principles of antituberculosis chemotherapy. With successes have also come fresh challenges. Mycobacterium tuberculosis becomes rapidly resistant to the drugs used against it and in the last decade, the HIV epidemic has had an adverse impact on the global epidemiology of tuberculosis, with many countries in Sub-Saharan Africa experiencing a 2-3 fold increase in their TB burden. While the currently recommended treatment regimens are very effective, they have failed to control the burden of TB in the developing countries due to less than satisfactory implementation of the control programmes. Faced with the dual threat of multidrug resistant TB and the HIV/facilitated increase in TB, the WHO has instituted a Global TB Control Programme based on the directly observed treatment shortcourse (DOTS) strategy. Much of the principles of this strategy have come out of research in India. As part of this strategy, the Government of India is implementing a Revised National Tuberculosis Control Programme (RNTCP). Under the RNTCP standardized treatment regimens are prescribed for different treatment categories. Already more than 80 per cent of the population is covered by this Programme and full coverage is slated for 2005. Meanwhile, fresh research is ongoing to shorten treatment duration, a measure that should greatly aid TB control.

Regulatory role of vitamin D receptor gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on macrophage phagocytosis and lymphoproliferative response to mycobacterium tuberculosis antigen in pulmonary tuberculosis.

The regulatory role of vitamin D receptor (VDR) gene variants of Bsm I, Apa I, Taq I, and Fok I polymorphisms on vitamin D(3)-modulated macrophage phagocytosis with live Mycobacterium tuberculosis and lymphoproliferative response to M. tuberculosis culture filtrate antigen (CFA) was studied in patients with pulmonary tuberculosis (n = 46) and in normal healthy subjects (NHS) (n = 64). Vitamin D(3) at a concentration of 1 x 10(-7) M enhanced the phagocytic potential of normal subjects who had a phagocytic index of less than 20%. This increase was seen in subjects with the genotypes BB (p = 0.017), AA (p = 0.016), tt (p = 0.034), and FF (p = 0.013) and the extended genotype BBAAtt (p = 0.034). Normal subjects with BBAAtt performed better phagocytosis than individuals with bbaaTT genotype (p = 0.034). Vitamin D(3) at 10(-9), 10(-8), and 10(-7) M concentrations suppressed the lymphoproliferative response to CFA antigen in normal subjects. This decreased lymphocyte response was observed in normal individuals with the genotypes BB (p = 0.0009), tt (p = 0.016), and FF (p = 0.008) and the extended genotype BBAAtt (p = 0.02). Addition of vitamin D(3) had no significant effect on macrophage phagocytosis and lymphoproliferative response to CFA in pulmonary TB patients. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) or the downregulated VDR expression by virtue of the disease, which renders them inactive. The genotypes BB, tt, and the extended genotype BBAAtt may be associated with increased expression of VDR which in turn regulate the action of vitamin D(3) and modulate the immune functions to M. tuberculosis in NHS.

Effect of vitamin D3 on phagocytic potential of macrophages with live Mycobacterium tuberculosis and lymphoproliferative response in pulmonary tuberculosis.

Immune responses are elicited through antigen presentation and recognition by macrophages and T-lymphocytes, respectively. The immunomodulatory effect of vitamin D(3) on macrophage phagocytic potential with live Mycobacterium tuberculosis, spontaneous and M. tuberculosis culture filtrate antigen induced lymphocyte responses were studied in pulmonary tuberculosis patients (PTBPs) ( n = 31) and normal healthy subjects (NHSs) ( n = 43). Vitamin D(3) at a concentration of 10(-7) M significantly enhanced the macrophage phagocytosis of live M. tuberculosis in normal subjects with low phagocytic potential (less than 10%) ( p = 0.015). No such increase was observed in PTBPs. Vitamin D(3) significantly decreased the spontaneous lymphoproliferative response ( p = 0.022) and increased the apoptosis of peripheral blood mononuclear cells in PTBPs ( p = 0.024). In normals, vitamin D(3) increased the spontaneous lymphoproliferative response. An inverse correlation between macrophage phagocytosis and spontaneous response was observed in NHSs, whereas a direct correlation was seen between vitamin D(3)-treated cells in normal subjects under in vitro condition. Vitamin D(3) decreased the M. tuberculosis culture filtrate antigen induced lymphocyte response significantly in normal subjects ( p = 0.0003), while it had no influence on the lymphocyte response in PTBPs. The present study suggests that exposure to vitamin D(3) increases the phagocytic potential and spontaneous lymphoproliferative response but brings down the antigen-induced response in normals. In tuberculosis, addition of vitamin D(3) has no significant effect on antigen-induced lymphoproliferative response. This may be due to the unresponsive nature of the cells to the action of vitamin D(3) by virtue of the disease, which renders them inactive.