Notch signaling induces lymphoproliferation, T helper cell activation and Th1/Th2 differentiation in leprosy.

The present study evaluates role of Notch1 signaling in the regulation of T cell immunity in leprosy. Peripheral blood mononuclear cells from leprosy patients and healthy controls were activated with Mycobacterium leprae antigens along with activation of Notch1 signaling pathway and then lymphoproliferation was analyzed by lymphocytes transformation test and the expression of Notch1 and its ligands DLL1, Jagged1 and Jagged 2, T cell activation marker and Th1-Th2 cytokines on Th cells in PBMCs of study subjects were analyzed by flow cytometry. Further, these parameters were also analyzed after inhibition of Notch1 signaling pathway. Higher percentage of Notch1expressing Th cells were noted in TT/BT cases and higher percentage of DLL1 expressing Th cells in TT/BT and BL/LL cases. M. leprae antigens were found to induce the expression of Jagged1 on Th cells. Interestingly activation of Notch1 signaling pathway induced lymphoproliferation in BL/LL cases in response of PGL-1. Activation of Notch1 signaling was also found to induce the expression of T cell activation markers CD25, CD69 and Th1 cytokine IFN-γ in response to M. leprae antigens. Immunomodulation through Notch1 signaling seen in our study could be helpful in augmenting Th1 response in leprosy.

Active case-finding for tuberculosis in India.

Early identification of presumptive tuberculosis (TB) cases through active case-finding (ACF) would be an important complementary strategy to meet the national urgency in accelerating case detection to achieve the goals of 'End TB' strategy. ACF activities have yielded additional cases in different vulnerable groups in India. The yield of cases depends on the screening tool available, the characteristics of the high-risk population being screened, and most importantly, the linkage between effective diagnostic and treatment facilities. The ACF strategy could be both economically and epidemiologically relevant if it could bring down the level of transmission. This needs long-term research focusing on outcomes such as cases averted and reduction in the prevalence of the disease. Available evidence suggests that ACF is likely to be feasible in Indian settings but needs to be scaled up rapidly to create a good impact.

Recurrence of tuberculosis among newly diagnosed sputum positive pulmonary tuberculosis patients treated under the Revised National Tuberculosis Control Programme, India: A multi-centric prospective study.

INTRODUCTION: There is lack of information on the proportion of new smear-positive pulmonary tuberculosis (PTB) patients treated with a 6-month thrice-weekly regimen under Revised National Tuberculosis Control Programme (RNTCP) who develop recurrent TB after successful treatment outcome. OBJECTIVE: To estimate TB recurrence among newly diagnosed PTB patients who have successfully completed treatment and to document endogenous reactivation or re-infection. Risk factors for unfavourable outcomes to treatment and TB recurrence were determined. METHODOLOGY: Adult (aged ≥ 18 yrs) new smear positive PTB patients initiated on treatment under RNTCP were enrolled from sites in Tamil Nadu, Karnataka, Delhi, Maharashtra, Madhya Pradesh and Kerala. Those declared "treatment success" at the end of treatment were followed up with 2 sputum examinations each at 3, 6 and 12 months after treatment completion. MIRU-VNTR genotyping was done to identify endogenous re-activation or exogenous re-infection at TB recurrence. TB recurrence was expressed as rate per 100 person-years (with 95% confidence interval [95%CI]). Regression models were used to identify the risk factors for unfavourable response to treatment and TB recurrence. RESULTS: Of the1577 new smear positive PTB patients enrolled, 1565 were analysed. The overall cure rate was 77% (1207/1565) and treatment success was 77% (1210 /1565). The cure rate varied from 65% to 86%. There were 158 of 1210 patients who had TB recurrence after treatment success. The pooled TB recurrence estimate was 10.9% [95%CI: 0.2-21.6] and TB recurrence rate per 100 person-years was 12.7 [95% CI: 0.4-25]. TB recurrence per 100 person-years varied from 5.4 to 30.5. Endogenous reactivation was observed in 56 (93%) of 60 patients for whom genotyping was done. Male gender was associated with TB recurrence. CONCLUSION: A substantial proportion of new smear positive PTB patients successfully treated with 6 -month thrice-weekly regimen have TB recurrence under program settings.

Genital tuberculosis in females.

The morbidity and mortality due to tuberculosis (TB) is high worldwide, and the burden of disease among women is significant, especially in developing countries. Mycobacterium tuberculosis bacilli reach the genital tract primarily by haematogenous spread and dissemination from foci outside the genitalia with lungs as the common primary focus. Genital TB in females is a chronic disease with low-grade symptoms. The fallopian tubes are affected in almost all cases of genital TB, and along with endometrial involvement, it causes infertility in patients. Many women present with atypical symptoms which mimic other gynaecological conditions. A combination of investigations is needed to establish the diagnosis of female genital TB (FGTB). Multidrug anti-TB treatment is the mainstay of management and surgery may be required in advanced cases. Conception rates are low among infertile women with genital TB even after multidrug therapy for TB, and the risk of complications such as ectopic pregnancy and miscarriage is high. More research is needed on the changing trends in the prevalence and on the appropriate methods for diagnosis of FGTB.

Association of viable Mycobacterium leprae with Type 1 reaction in leprosy.

UNLABELLED: The working hypothesis is that, viable Mycobacterium leprae (M. leprae) play a crucial role in the precipitation of Type 1 reaction (T1R) in leprosy. MATERIAL AND METHODS: A total of 165 new multibacillary patients were studied. To demonstrate presence of viable M. leprae in reactional lesion (T1R+), three tests were used concurrently viz. growth in the mouse foot pad (MFP), immunohistochemical detection of M. leprae secretory protein Ag85, and 16s rRNA--using in situ RT-PCR. Mirror biopsies and non reactional lesions served as controls (T1R-). FINDINGS: A significantly higher proportion of lesion biopsy homogenates obtained at onset, from T1R(+) cases have shown unequivocal growth in MFP, proving the presence of viable bacteria, as compared to T1R(-) (P < 0.005). In contrast, few Mirror biopsies were positive in both T1R(+) and T1R(-). With respect to Ag85, while the overall positivity was higher in T1R(+) (74%), however the intensity of staining (Grade 2+) was disproportionately higher in T1R(+) BT-BB lesions 11/20 (55%). In the rebiopsies obtained during a repeat episode of T1R, Ag 85 as well as 16s rRNA, positivity (62% & 100%) was higher in T1R(+). It is inferred therefore 'viable' bacteria are an essential component in T1R and difference in the quality of bacilli, not the quantity or the ratio of dead to viable play a role in the precipitation of T1R. In conclusion, the findings show that 'metabolically active' M. leprae is a component/prerequisite and the secretory protein Ag 85, might be the trigger for precipitation of T1R.

10-12 years follow-up of highly bacillated BL/LL leprosy patients on combined chemotherapy and immunotherapy.

This study reports the follow-up results of 36 highly bacillated untreated BL/LL cases who were serially allocated to three treatment groups. Group I patients received a modified WHO regimen (Rifampicin 600 mg once a month supervised, 50 mg of Clofazimine and 100 mg of Dapsone daily unsupervised) and BCG 0.1 mg per dose 6 monthly; group II patients received the same multi-drug treatment (MDT) and Mw (2 x 10(8) killed bacilli per dose) 6 monthly: group III patients received the same MDT with 0.1 ml of distilled water 6 monthly and acted as a control. Treatment was continued till smear negativity. All these three groups were comparable by their initial clinical score, bacteriological index (BI), viable bacilli as assessed by the mouse foot pad (MFP), bacillary adenosine triphosphate (ATP) content and also histologically at the time of starting treatment. All these parameters were evaluated every 6 months. The vaccines were well tolerated. All the patients in group I became smear negative by 3.5 years, in group II in 3 years whereas those in group III took 5 years. The incidence of reactions was the same in all the groups during the first 2 years, however, patients of group III (MDT + placebo) continued to have reactions up to 3 years. No viable bacilli could be detected in the local and distal sites as estimated by MFP and bacillary ATP after 12 months in both the immunotherapy groups. These could be detected in patients on MDT alone up to 24 months of therapy. Histologically patients in both the immunotherapy groups (groups I and II) showed accelerated granuloma clearance, histological upgrading and non-specific healing without granuloma formation both at the local and distal sites and this was achieved much earlier compared to the MDT + placebo group. Thus, by the addition of immunotherapy the effective treatment period of achieving bacteriological negativity could be reduced by about 40%, time period of reactions reduced by 33% and there were no reactions and/or relapses in the 10-12 years post-treatment follow-up.