A study to assess the relationship between vitamin D3 levels and the risk of acute exacerbation in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is one of the top three causes of mortality worldwide. Vitamin D deficiency in COPD has been associated with poor lung function and decreased muscle power, which further increases the risk of exacerbations. The role of vitamin D in preventing acute exacerbations of COPD has conflicting results in the literature. Hence, we planned this study to assess the relationship between vitamin D3 levels and the risk of acute exacerbations among COPD patients in a tertiary care center in north India. This was a prospective randomized control trial that was performed on 100 consecutive stable COPD patients attending the Department of Respiratory Medicine at Maharishi Markandeshwar Medical College and Hospital, Solan, India. The patients with subnormal vitamin D3 levels (i.e., less than 30 ng/mL) were divided into the intervention and control groups. Baseline demographic profiles, lung function, COPD assessment test (CAT) score, modified Medical Research Council grade and chest radiology were performed and repeated after 12 months in all these patients. All these parameters were recorded and compared with the baseline values obtained at the beginning of the study. Out of 100 subjects, 96 had vitamin D deficiency, of which 48 were assigned to the intervention group and 48 to the control group. Among the 100 subjects, 74 (74%) were males and 26 (26%) were females, with a mean age of 66.9±9.4 years. The mean vitamin D level was 14.71±6.69 in these 96 patients. The vitamin D level improved after 3 months of supplementation to the mean level of 45.56±16.18 in the intervention group. Vitamin D supplementation was positively correlated with a decrease in the rate of acute exacerbations in the intervention group in terms of reduction in mean CAT score (4.17 in intervention and 1.43 in non-interventional group, p<0.001), number of acute exacerbations (1.7 in intervention and -1.05 in non-interventional group, p<0.001), and number of emergency visits (p=0.0121) during the 9-month period after attainment of a normal vitamin D level. Vitamin D supplementation plays a key role in COPD patients with D3 hypovitaminosis in decreasing COPD acute exacerbations, improving the CAT score, and reducing the number of emergency visits.

Association between IL6 gene polymorphism and the risk of chronic obstructive pulmonary disease in the north Indian population.

Interleukin-6 (IL6) is encoded by the IL6 gene in human and acts as pro-inflammatory cytokine and an anti-inflammatory cytokine. Recent studies established that IL6 substantially contribute in the diagnosed of systemic inflammation for the patients suffering from lung diseases such as chronic obstructive pulmonary disease (COPD). Thereof, this work aimed to investigate the protagonist of IL6 (-174 G/C) genotypes as an essential risk factor for COPD in north Indian population. In the study, a total of 200 clinically diagnosed patients with COPD were selected against 200 patients. Statistical analysis reveleaed that there was no significant association between the IL6 -174 G/C genetic polymorphism and the risk of COPD (P>0.05).

An Accord of Nuclear Receptor Expression in M. tuberculosis Infected Macrophages and Dendritic Cells.

Mycobacterium tuberculosis instigates interactions with host factors to promote its survival within the host inimical conditions. Among such factors, nuclear receptors (NRs) seem to be promising candidates owing to their role in bacterial pathogenesis. However, only few members of NR superfamily have been implicated in M. tuberculosis infection and there is a dearth of comprehensive knowledge about expression or function of the entire superfamily. In this study, we performed detailed expression analysis and identified key NRs getting differentially regulated in murine macrophages and dendritic cells (DC) upon infection with H37Rv. The murine macrophages and DCs infected with H37Rv entailed overlapping changes in the expression of certain NRs which reflect upon the possibility that both cells might utilize similar transcriptional programs upon M. tuberculosis infection. We identified Nr4a3 and Rora, which have not been implicated in M. tuberculosis pathogenesis, undergo similar changes in expression in macrophages and DCs upon H37Rv infection. Interestingly, a similar pattern in their expression was also observed in infected human monocyte derived macrophages and the findings corroborated well with PBMCs obtained from TB patients. This all-inclusive analysis provides the basis for a precise approach in identifying NRs that can be targeted therapeutically in intracellular bacterial infections.

A human xenobiotic nuclear receptor contributes to nonresponsiveness of Mycobacterium tuberculosis to the antituberculosis drug rifampicin.

Mycobacterium tuberculosis is the causative agent of tuberculosis (TB). It acquires phenotypic drug resistance inside macrophages, and this resistance mainly arises from host-induced stress. However, whether cellular drug-efflux mechanisms in macrophages contribute to nonresponsiveness of M. tuberculosis to anti-TB drugs is unclear. Here, we report that xenobiotic nuclear receptors mediate TB drug nonresponsiveness by modulating drug-efflux transporters in macrophages. This was evident from expression analysis of drug-efflux transporters in macrophages isolated from TB patients. Among patients harboring rifampicin-susceptible M. tuberculosis, we observed increased intracellular survival of M. tuberculosis upon rifampicin treatment of macrophages isolated from patients not responding to anti-TB drugs compared with macrophages from patients who did respond. Of note, M. tuberculosis infection and rifampicin exposure synergistically modulated macrophage drug-efflux transporters in vitro We also found that the xenobiotic nuclear receptor pregnane X receptor (PXR) modulates macrophage drug-efflux transporter expression and activity, which compromised the anti-TB efficacy of rifampicin. We further validated this finding in a TB mouse model in which use of the PXR antagonist ketoconazole rescued rifampicin anti-TB activity. We conclude that PXR activation in macrophages compromises the efficacy of the anti-TB drug rifampicin. Alternative therapeutic strategies, such as use of the rifampicin derivatives rifapentine and rifabutin, which do not activate PXR, or of a PXR antagonist, may be effective for tackling drug nonresponsiveness of M. tuberculosis that arises from drug-efflux systems of the host.

Lactobacillus coryniformis Causing Pulmonary Infection in a Patient with Metastatic Small Cell Carcinoma: Case Report and Review of Literature on Lactobacillus Pleuro-Pulmonary Infections.

Lactobacilli are normal commensals of the gastrointestinal and female genital tract. Due to its low virulence these bacteria are known to cause opportunistic infections. They cause mostly bacteraemia with or without endocarditis and rarely cause pleuro-pulmonary infection. We report a case of Lactobacillus coryniformis pleuro-pulmonary infection and review 14 previously reported cases of lactobacilli causing pleuro-pulmonary infections. Our patient had small cell carcinoma with metastasis. All the 14 cases had pre-existing risk factors like immunosuppresion, cancer or chronic disease. There was no consensus on choice of antimicrobial agents to be used. Different species of lactobacilli were involved. Available susceptibility data showed that lactobacilli species were more susceptible to ampicillin, erythromycin, gentamycin, and clindamycin and decreased to ceftriaxone, ciprofloxacin and trimethoprim-sulphamethoxazole. Isolation of Lactobacillus species from a case of pleuro-pneumonia infection could be a marker of poor long-term prognosis. The diagnosis of these infections requires both microbiologist and clinical correlation to rule out contamination.

Human Xenobiotic Nuclear Receptor PXR Augments Mycobacterium tuberculosis Survival.

Mycobacterium tuberculosis can evade host defense processes, thereby ensuring its survival and pathogenesis. In this study, we investigated the role of nuclear receptor, pregnane X receptor (PXR), in M. tuberculosis infection in human monocyte-derived macrophages. In this study, we demonstrate that PXR augments M. tuberculosis survival inside the host macrophages by promoting the foamy macrophage formation and abrogating phagolysosomal fusion, inflammation, and apoptosis. Additionally, M. tuberculosis cell wall lipids, particularly mycolic acids, crosstalk with human PXR (hPXR) by interacting with its promiscuous ligand binding domain. To confirm our in vitro findings and to avoid the reported species barrier in PXR function, we adopted an in vivo mouse model expressing hPXR, wherein expression of hPXR in mice promotes M. tuberculosis survival. Therefore, pharmacological intervention and designing antagonists to hPXR may prove to be a promising adjunct therapy for tuberculosis.

Interstitial Lung Disease with Chilaiditi Syndrome.

Chilaiditi sign is the peculiar radiographic presentation of interposition of colon between diaphragm and liver. When associated with symptomatology, it is called as chilaiditi's syndrome. Though rare, respiratory symptoms may be present. In such cases, it becomes difficult to determine if the symptomatology is due to the syndrome only, or there is some underlying lung involvement, until this is specifically considered in the differential diagnosis. We present a male patient, where thorough investigations revealed Interstitial Lung Disease (ILD), along with Chilaiditi sign on chest radiograph. Respiratory symptomatology responded partially to the management of underlying ILD. It is left for discussion, whether the Chilaiditi syndrome was also contributing to the overall clinical presentation or the respiratory complaints were solely due to ILD and Chilaiditi sign was an incidental finding.

Gender disparities in retreatment patients of tuberculosis: A north Indian study.

BACKGROUND: 'Retreatment' for tuberculosis (TB) has long been a neglected area in global TB control India. However India disproportionately accounts for nearly half of retreatment TB cases notified globally. Sex differences vary in different age groups and in different parts of the world. The present study focuses on whether gender-based differences are present in notification rates, clinical presentation, and treatment outcomes of different subcategories of patients registered under category II of Revised National TB Control Programme (RNTCP) Chandigarh. MATERIALS AND METHODS: A longitudinal study was designed and the patients registered under RNTCP category II from June 2010 to December 2011. Out of total 607 patients registered during this period under category II of RNTCP in Chandigarh, 545 consented to participate in the study. These were followed-up to September 2012 till the completion of treatment. All 545 recruited cases were stratified into males and females and the results analyzed. The Z test for proportion (for comparing differences in proportions) and Student's t-test (for comparing mean) were performed for statistical analysis. RESULTS: From the cohort of 545 patients, 348 (63.9%) were males and 197 (36.1%) were female patients with overall male to female ratio 1.8:1. The proportion of male patients notified was significantly higher than females (Z = 5.93, P < 0.001). The proportion of extrapulmonary cases was higher in the females (28.4%) as compared with males (17%) (P < 0.001). Males outnumbered females in all the unfavorable outcomes death, default, and failure. The default in males was significant as compared to the females (Z = 5.21, P < 0.001). CONCLUSIONS: The findings of this study suggest a sex difference in the notification rate of retreatment cases of TB. Reasons for a better outcome and low notification rate for TB in females are more due to epidemiological factors than a differential access of the health care. Integrated research is required to outline the relative roles played by epidemiology.

Reasons for interruption of anti-tubercular treatment among the retreatment patients in category II of RNTCP in Chandigarh, north India.

INTRODUCTION: More re-treatment TB patients are notified in India than any other country in the world, and default among this group is a serious public health problem. Adherence to the long course of TB treatment is a complex, dynamic phenomenon with a wide range of factors impacting on treatment taking behaviour. The main aim of the study was to study the basic clinical and demographic profile of the defaulters and the reasons for discontinuation of treatment among these retreatment patients in category II of RNTCP. METHODS: A longitudinal study was designed and the patients registered under RNTCP category II from June 2010 to December 2011 at various centres in Chandigarh formed the study cohort. Out of total 607 patients registered during this period under category II of RNTCP in Chandigarh, 545 consented to participate in the study. These were followed up to September 2012 till the completion of treatment. 32 patients among the registered 545 defaulted from the treatment during the period. These patients were traced in the community and information regarding reasons for interruption and barriers to treatment was obtained from them using a pre-structured pre-tested questionnaire. Data were analysed using SPSS 18 statistical software package. RESULTS: 32(5.9%) patients defaulted from the treatment under RNTCP category II. 29(90.6%) were pulmonary patients while 3(9.4%) were extra-pulmonary patients. 46.9% of the defaulters were in the age group of 20-35 years, followed by 31.3% in the age group of 36-50 years. 21.9% went to traditional healers for cure while 12.5% tried herbal medicine during the treatment. 25% (eight) patients did not have faith on the DOTS treatment. Most common side effects of treatment complained by the patients were GI upset (62.5%), fatigue (59.4%), drowsiness (34.4%) and itching (31.3%). 46.8% believed that ATT induced side-effects were the main reason for treatment interruption. Maximum treatment interruption was seen at the end of the third month (31.3%). CONCLUSIONS: Maximum interruptions were found to occur by end of third month of ATI. AT" induced side-effects were the main reason for treatment interruption. Efforts need to be made to improve the pre-treatment counselling, increase proportion of patients treated by community-based DOTS providers, repeated health education to the patients emphasizing the need to continue treatment.

Quality of life impairment in patients of obstructive sleep apnea and its relation with the severity of disease.

BACKGROUND: Several studies have demonstrated considerable impairment of quality of life (QOL) in obstructive sleep apnea (OSA) patients, but its relation with severity of OSA is yet unclear. STUDY OBJECTIVES: To investigate the effects of OSA on the QOL and its association with the disease severity. DESIGN AND SETTING: Observational, prospective case-control study. MATERIALS AND METHODS: QOL of 69 OSA patients and 41 healthy controls were assessed using the Calgary sleep apnea quality of life index (SAQLI) on the morning following the polysomnography (PSG) study. STATISTICS: All statistical analyses were performed using the SPSS 17.0 (SPSS Inc., Chicago). Differences between sleep-related symptoms and SAQLI subscales scores were assessed with the Chi-square test and the Student t-test. Due to non-normal distribution, differences between SAQLI scores of controls and OSA patients were evaluated using a non-parametric Mann-Whitney test. Spearman correlation and backward multiple regression analysis were used to analyze the association between SAQLI scores and sleep indices and anthropometric variables and PSG variables. RESULTS: Study included 69 cases (57 male and 12 females) with a mean age, weight, height, neck circumference, and body mass index 48.45 ± 10.12 years, 83.03 ± 16.48 kg, 159.75 ± 28.29 cm, 44.01 ± 3.23 cm and 30.77 ± 6.71 kg/m(2). Mean apnea-hypopnea index was 26.39 ± 16.62. The median score of four SAQLI domains daily function, social interaction, emotional, symptoms and total mean SAQLI score were 3.64 (3.46-3.90), 3.77 (3.51-3.88), 3.64 (3.53-3.83), 4.80 (4.68-5.11), 4.09 (3.88-4.09),and 1.36 (1.29-1.71), 1.38 (1.24-1.62), 1.45 (1.23-1.62), 2.00 (1.78-2.26), 1.55 (1.46-1.73) for patients and controls respectively. All the individual domain scores and the mean SAQLI scores of patients were significantly higher than the controls. CONCLUSION: OSA causes significant impairment of QOL, but the severity of impairment is not directly proportional to the severity of OSA.

Mycobacterium tuberculosis modulates macrophage lipid-sensing nuclear receptors PPARγ and TR4 for survival.

Mycobacterium tuberculosis-macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis-macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.

Factors associated with hospital admission in patients with acute exacerbation of chronic obstructive pulmonary disease.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) impair quality of life (QOL), accelerate the decline in lung function and often require hospitalisation, and thus, leading to increased healthcare burden. By identifying factors that may be associated with AE-COPD and managing them rationally, not only the hospital admissions could be avoided but progression of the disease may also be slowed. Objective. The aim of the present study was to determine the factors associated with hospital admissions among adults with AE-COPD. METHODS: Seventy-three patients admitted with AE-COPD were administered a structured questionnaire during their hospital stay. Data on body mass index (BMI), smoking, symptoms, co-morbidities course of the disease, spirometry management and outcomes during the hospitalisation were obtained. Factors associated with hospital admissions were analysed. RESULTS: The hospitalisation due to AE-COPD was significantly associated with the reduced forced expiratory volume in one second (FEV1), and peak expiratory flow rates, increasing sputum purulence, number of hospitalisations during previous year for COPD and presence of co-morbidities. CONCLUSIONS: The study shows that both disease and healthcare-related factors are predictors for hospitalisation. Identification of risk factors and appropriate management may reduce hospitalisation due to AE-COPD.

Tuberculous lymphadenitis.

Lymphadenitis is the most common extrapulmonary manifestation of tuberculosis. It remains both diagnostic and therapeutic challenge because it mimics other pathologic processes and yields inconsistent physical and laboratory findings. Diagnosis is difficult often requiring biopsy. A thorough history and physical examination, staining for acid-fast bacilli, fine-needle aspiration and PCR are helpful in obtaining an early diagnosis. It is also important to differentiate tuberculous from nontuberculous mycobacterial cervical lymphadenitis because their treatment protocols vary. Treatment monitoring is more complex due to peculiar behavior of TB lymph nodes. Situation has become worse due to sharp increase in the incidence of atypical mycobacteria, poorly controlled HIV epidemic and rise of drug-resistant TB lymphadenitis. Tuberculous adenitis is best treated as a systemic disease with antituberculosis medication. Surgical therapy along with antituberculosis medication can be beneficial in selected patients.

No association of DNA ligase-I polymorphism with the risk of lung cancer in north-Indian population.

DNA ligases play an essential role in repair, replication, and recombination of DNA, and catalyzes the formation of a phosphodiester bond at a nick junction on single- and double-strand breaks. We have conducted a hospital-based case-control study to examine the role of polymorphism of DNA repair gene ligase I (LIGI) in the context of lung cancer risk for north Indian population. One hundred, fifty-one primary lung cancer cases and an equal number of matching hospital controls were collected. The LIGI polymorphism was determined by using the PCR-RFLP method. The association between polymorphisms in the LIGI gene with the risk of lung cancer was estimated by computing odds ratios (ORs) and a 95% confidence interval (CI) using a Multivariate Logistic Regression Analysis. The risk for lung cancer was not associated for individuals featuring LIGI (AC) (OR -0.8, 95% CI = 0.44-1.40) and (AA) (OR -0.8, 95% CI = 0.41-1.80) genotypes. The DNA repair gene (LIGI) may not be playing an important role in modulating the risk of lung cancer in the north Indian population.