Role of oxidative stress & transient receptor potential in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) affect millions of people worldwide and is known to be one of the leading causes of death. The highly sensitive airways protect themselves from irritants by cough and sneeze which propel endogenous and exogenous substances to minimize airway noxious effects. One noxious effect of these substances is activation of peripheral sensory nerve endings of nociceptor neurons innervating these airways lining thus transmitting dangerous signals from the environment to the central nervous system (CNS). Nociceptor neurons include transient receptor potential (TRP) ion channels, especially the vanilloid and ankyrin subfamilies, TRPV1/A1 which can be activated by noxious chemical challenges in models of airways disease. As oxidative stress may activate airways sensory neurons and contribute to COPD exacerbations we sought to review the role that TRP channel activation by oxidative signals may have on airway responses. it would be prudent to target the TRP channels with antagonists and lower systemic oxidative stress with agents that can modulate TRP expression and boost the endogenous levels of antioxidants for treatment and management of COPD.

Consensus & Evidence-based INOSA Guidelines 2014 (First edition).

Obstructive sleep apnoea (OSA) and obstructive sleep apnoea syndrome (OSAS) are subsets of sleep-disordered breathing. Awareness about OSA and its consequences amongst the general public as well as the majority of primary care physcians across India is poor. This necessiated the development of the INdian initiative on Obstructive Sleep Apnoea (INOSA) guidelines under the auspices of Department of Health Research, Ministry of Health & Family Welfare, Government of India. OSA is the occurrence of an average five or more episodes of obstructive respiratory events per hour of sleep with either sleep related symptoms or comorbidities or >15 such episodes without any sleep related symptoms or comorbidities. OSAS is defined as OSA associated with daytime symptoms, most often excessive sleepiness. Patients undergoing routine health check-up with snoring, daytime sleepiness, obesity, hypertension, motor vehicular accidents and high risk cases should undergo a comprehensive sleep evaluation. Medical examiners evaluating drivers, air pilots, railway drivers and heavy machinery workers should be educated about OSA and should comprehensively evaluate applicants for OSA. Those suspected to have OSA on comprehensive sleep evaluation should be referred for a sleep study. Supervised overnight polysomnography (PSG) is the “gold standard” for evaluation of OSA. Positive airway pressure (PAP) therapy is the mainstay of treatment of OSA. Oral appliances are indicated for use in patients with mild to moderate OSA who prefer oral appliances to PAP, or who do not respond to PAP or who fail treatment attempts with PAP or behavioural measures. Surgical treatment is recommended in patients who have failed or are intolerant to PAP therapy.

Management of Obstructive Sleep Apnea.

Obstructive Sleep Apnea (OSA) is an important public health problem and is associated with considerable morbidity and mortality. Therefore, treatment of this condition is of paramount importance. The treatment of OSA includes general and behavioural measures, mechanical measures including continuous positive airway pressure (CPAP), Bilevel positive airway pressure (BiPAP) and Oral Appliances (OA), pharmacological treatment and surgical procedures. Continuous positive airway pressure (CPAP) treatment reverses the repetitive upper airway obstruction of sleep apnea and associated daytime sleepiness and is the most effective treatment for OSA. However maintaining patient adherence to CPAP therapy is a challenge. Weight loss should be recommended to overweight patients with OSA, as it has been shown that weight reduction has additional health benefits. Treatment of underlying medical conditions such as hypothyroidism or acromegaly has profound effect on apnea/hypopnea index. A subset of patients with OSA may benefit from supplemental oxygen and positional therapy. Presently, there are no effective pharmacotherapeutic agents for treatment of patients with OSA and the role of surgical treatment in OSA is controversial. However, pharmacological treatment of persisting residual sleepiness, despite adequate positive airway pressure therapy delivery and adherence, is indicated and may improve daytime sleepiness.

Co-morbidities associated with obstructive sleep apnea.

There are many co-morbid conditions that are associated with obstructive sleep apnea (OSA). Though a causative relationship between OSA and some of the co-morbidities is well established or strongly associated, many risk factors of OSA (age, male gender and obesity) are also known risk factors especially for cardiovascular diseases. Other important co-morbid conditions associated with OSA are neurocognitive dysfunction and, erectile dysfunction. Recently there are reports that ocular manifestations are associated with OSA. It is expected that more co-morbidities will be reported in OSA as the research in this area progresses.

Sleep disordered breathing: OSA, CSA, Pathophysiology and Diagnosis.

Obstructive sleep apnea syndrome (OSAS) is a prevalent disorder that has been reported to occur in 2 to 4% of middle-aged adults. A similar prevalence of OSAS has been reported from India as well. However, this condition is frequently unrecognized and underdiagnosed. Important pathophysiological changes in patients with obstructive sleep apnea (OSA) is an alteration in human upper airway leading to a reduction in cross-sectional area of the upper airway contributing to the easy collapsibility of upper airway during sleep. Other pathophysiological changes in OSA are oxidative stress, systemic inflammation, sympathetic nerve activation, endothelial dysfunction, procoagulant activity, intrathoracic pressure changes and metabolic dysregulation. The gold standard for diagnosis of OSA is full polysomnography.

Chronic obstructive pulmonary disease.

The global prevalence of physiologically defined chronic obstructive pulmonary disease (COPD) in adults aged >40 yr is approximately 9-10 per cent. Recently, the Indian Study on Epidemiology of Asthma, Respiratory Symptoms and Chronic Bronchitis in Adults had shown that the overall prevalence of chronic bronchitis in adults >35 yr is 3.49 per cent. The development of COPD is multifactorial and the risk factors of COPD include genetic and environmental factors. Pathological changes in COPD are observed in central airways, small airways and alveolar space. The proposed pathogenesis of COPD includes proteinase-antiproteinase hypothesis, immunological mechanisms, oxidant-antioxidant balance, systemic inflammation, apoptosis and ineffective repair. Airflow limitation in COPD is defined as a postbronchodilator FEV1 (forced expiratory volume in 1 sec) to FVC (forced vital capacity) ratio <0.70. COPD is characterized by an accelerated decline in FEV1. Co morbidities associated with COPD are cardiovascular disorders (coronary artery disease and chronic heart failure), hypertension, metabolic diseases (diabetes mellitus, metabolic syndrome and obesity), bone disease (osteoporosis and osteopenia), stroke, lung cancer, cachexia, skeletal muscle weakness, anaemia, depression and cognitive decline. The assessment of COPD is required to determine the severity of the disease, its impact on the health status and the risk of future events (e.g., exacerbations, hospital admissions or death) and this is essential to guide therapy. COPD is treated with inhaled bronchodilators, inhaled corticosteroids, oral theophylline and oral phosphodiesterase-4 inhibitor. Non pharmacological treatment of COPD includes smoking cessation, pulmonary rehabilitation and nutritional support. Lung volume reduction surgery and lung transplantation are advised in selected severe patients. Global strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease guidelines recommend influenza and pneumococcal vaccinations.

Quality of asthma management in an urban community in Delhi, India.

Background & objectives: High prevalence and poor control of asthma make its management a major public health issue worldwide, especially in developing countries. Optimum review of asthma management in the community is essential to improve asthma control. This study was conducted to investigate the quality of asthma management, knowledge about asthma and quality of life of asthma patients referred to a public tertiary care chest hospital in Delhi. Methods: Diagnosis of asthma was confirmed by symptoms and reversible spirometry in 50 referred patients on their first visit. Patients were interviewed using three questionnaires on quality of asthma management before visiting referral hospital, asthma knowledge and asthma quality of life (AQLQ). Correlation amongst quality of treatment, asthma quality of life, and asthma knowledge was also determined. Results: Findings revealed that only 60 per cent of patients were informed about their disease, and 10 per cent had undergone lung function tests previously. Only 44 per cent of patients were prescribed inhalers. None were provided with any educational material. Patients had poor knowledge of aetiology, pathophysiology, medication and how to assess the severity of their asthma. The mean scores in AQLQ indicated a moderate degree of impairment in quality of life. Interpretations & conclusions: This study provides evidence of unsatisfactory asthma management and patient-doctor interaction as patients had limited knowledge of asthma disease, its management and had poor quality of life as measured by a standardized questionnaire. Thus, there is need to implement suitable interventions to improve asthma management according to standard treatment guidelines in the community.

Regression equations for spirometry in children aged 6 to 17 years in Delhi region.

Background. Most of the studies carried out in India to develop regression equations for spirometry in children are now several years-to-decades old and had used equipment and measurement protocols that have since changed. Prediction equations using the current standardisation protocols for spirometry are not available. The lung health of the population may have changed too. Objective. To develop regression equations for spirometry for children aged 6 to 17 years of north Indian origin in Delhi region. Methods. School children of north Indian origin, as determined by mother tongue and parentage, aged 6 to 17 years were screened by a health questionnaire and physical examination and those found “normal” underwent spirometry according to the standardised procedure recommended by the American Thoracic Society/ European Respiratory Society (ATS/ERS) task force in 2005. Pearson’s correlation analysis was carried out to identify the predictor variables for spirometric parameters. Prediction equations were developed using the multiple linear regression procedure. The independent variables were entered in sequence of height, age and weight. R2, adjusted R2 and R2 change, standard errors of the estimate (SEE), and estimates of regression coefficients were obtained and the goodness of fit was examined. Results. Data was obtained in 365 boys and 305 girls. Forced vital capacity (FVC), forced expiratory volume in one second(FEV1), peak expiratory flow rate (PEFR), forced expiratory flow rate at 50% and 75% exhalation of vial capacity (F50 and F75) and mean forced expiratory flow rate over the middle 50% of the vital capacity (F25-75) showed moderate to strong correlations with age, height and weight in both boys and girls. In both genders, the equations explained very high variability of FVC, FEV1 and PEFR as shown by the R2 values. The explained variability for flow rates was lesser, with that for F75 being the least. Conclusions. Regression equations for spirometry variables for children of north Indian origin in Delhi region have been developed. These represent the first such effort from India after the publication of the ATS/ERS task force 2005 guidelines on standardisation of spirometry.

Role of a pattern-based approach in interpretation of transbronchoscopic lung biopsy and its clinical implications.

Background. Transbronchial lung biopsy (TBLB) is commonly performed for confirming the tissue diagnosis of diffuse parenchymal lung diseases (DPLDs). There is an urgent need to establish guidelines for interpretation of TBLB in order to improve its diagnostic utility. Methods. We retrospectively studied 916 consecutive patients (494 males; mean age 49 years) who underwent TBLB over a 5-year period (July 2005 to July 2010) at Vallabhbhai Patel Chest Institute. Results. In 615 (67.1%) procedures, material obtained during TBLB was adequate for histopathology interpretation. Pathological features evaluated in each case were: alveolar architecture, inflammatory infiltrate, interstitial fibrosis, atypical cells, pigment deposition, honey-comb change and fibroblast foci. The cases were categorised on the basis of histopathology into six patterns: (1) adequate biopsy without a specific diagnostic abnormality (n=137, 22.3%); (2) acute pneumonitis (n=29, 4.7%); (3) neoplasia (n=109, 17.7%); (4) chronic interstitial inflammation with or without fibrosis (n=138, 22.4%); (5) granulomatous inflammation, (n=186, 30.2%); and (6) other specific causes (n=16, 2.6%). Definitive diagnosis could be made after correlation of TBLB histopathology with clinical and radiological features in 55.3% cases. Conclusions. TBLB appears to be an important diagnostic tool for the diagnosis of DPLDs. The use of a pattern-based approach to TBLB adds to its diagnostic yield and can be helpful in cases where open lung biopsy is not available.

Anti-oxidant treatment in obstructive sleep apnoea syndrome.

Purpose. To investigate whether oral intake of N-acetylcysteine (NAC) is a treatment option in patients with obstructive sleep apnoea syndrome (OSAS). Methods. Twenty patients with OSAS were enrolled in the study. After polysomnography (PSG), they were randomly assigned to receive a placebo (n=10) and NAC (n=10). A repeat PSG was done after the treatment period of 30 days. Fasting venous samples were collected for various biochemical analysis. Results. In the patients of NAC group, compared to their baseline values, slow wave sleep as sleep percent time (27.9±2.7 vs 42.3±4.2; p<0.01) and sleep efficiency (90.8±1.3 vs 94.4±1.5; p<0.05) improved considerably. The apnoea-hypopnoea index (61.2±8.5 vs 43.1±8.6; p<0.05), apnoea related arousals (22.2±7.6 vs 11.6±4.7; p<0.05), longest apnoeic episode duration (seconds) (54.9±7.1 vs 37.8±5.6; p<0.01), oxygen desaturation events per hour (51.8±7.7 vs 37±7.8; p<0.01) and epworth sleepiness score (16.6±0.8 vs 9.2±0.9; p<0.001) decreased significantly. The relative snore time (%) (10.2±2.9 vs 4.9±1.9; p<0.01), number of snore episodes (63.8±23.9 vs 28.2±9.9; p<0.05) and duration of longest snore episode (min) (2.5±0.7 vs 0.6±0.1; p<0.05) also decreased significantly. Such responses were not evident in the placebo group. N-acetylcysteine produced significant decrease in lipid peroxidation and increase in total reduced glutathione. Conclusions. Oral NAC administration appears to have a therapeutic potential in the treatment of OSAS. It is proposed that long-term treatment with NAC in patients with OSAS may reduce their dependency on continuous positive airway pressure therapy.

Role of nitric oxide in the diuresis and natriuresis occurring in patients with obstructive sleep apnoea syndrome.

Objective. To determine whether nitric oxide (NO) has any role in the diuresis and natriuresis observed in patients with obstructive sleep apnoea syndrome (OSAS). Methods. We measured 12-hour urine volume in the day and in the night in patients with OSAS (n=20) and determined the concentrations of urinary sodium and nitrate. The frequency of urination in the night was also noted. The measurements were done again after two nights of continuous positive airway pressure (CPAP) therapy and after putting the patients on oral anti-oxidant treatment (vitamin C–100mg BD and vitamin E–400IU BD) for 45 days. Ten healthy normal subjects underwent the same protocol except the CPAP therapy. Results. In patients with OSAS, the night urine volume and sodium concentration were similar and the nitrate levels were higher compared to those in the day. After CPAP therapy, while the urine volume and sodium concentration decreased, the nitrate level became similar to that in the day. Such effects were not observed after anti-oxidant treatment. The frequency of urination was decreased in both the instances. The effects observed after CPAP therapy were similar to those observed in control subjects with or without anti-oxidant treatment. Conclusion. Renal NO promotes diuresis and natriuresis in patients with OSAS.

Assessment of protective role of polyherbal preparation, Livina, against anti-tubercular drug induced liver dysfunction.

The present study evaluated the possible protective role of Livina (a polyherbal preparation) against anti-tubercular therapy (ATT)-induced liver dysfunction in patients of pulmonary tuberculosis. Patients were given intensive phase treatment with 4-drugs (rifampicin, INH, pyrazinamide and ethambutol) used for anti-tubercular therapy for 2 months, followed by a 4-month continuous phase treatment with 2 drugs (rifampicin and INH) under clinical advice and supervision. Both qualitative and quantitative measures of liver function were assessed, at different time intervals, before and after ATT. Analysis of data showed that the incidence of qualitative manifestations of liver dysfunction were greater in the placebo treated group as compared to the test drug group. None of the patients of either group showed clinical jaundice. Most signific changes ant were observed in the SGOT and SGPT levels in the placebo group, wherein the levels of both enzymes were higher at 4 and 8 weeks post–ATT, as compared to the respective baseline (0 week) values. When Livina (2 capsules twice daily) was given with ATT drugs, incidence of qualitative manifestation of liver dysfunction was insignificant and SGOT and SGPT levels were also significantly lower than the placebo+ATT drugs treated group. These results indicate that the test drug (Livina) was efficacious, against ATT-induced hepatic dysfunction in patients of pulmonary tuberculosis.

Breath carbon monoxide concentration in Cigarette and Bidi smokers in India.

Objective. To measure and compare the breath carbon monoxide (CO) levels in cigarette and bidi smokers in India. Methods. Breath CO was measured in 389 smokers (241 cigarette smokers,148 bidi smokers) using portable breath CO analyser (Bedfont-England, Smokelyzer). Tobacco contents and length of single stick of different brands of cigarette and bidi were also measured. Results. Their mean age was 38.7±13.4 years. The average duration of smoking was 18.2±13.0 years. Average breath CO levels were 15.6±7.0 ppm in smokers and 4.07±1.16 ppm in non-smokers. Average breath CO level was significantly higher in bidi smokers (18.9±7.7 ppm) compared to cigarette smokers (13.6±5.8 ppm) when total consumption of cigarette/bidi was more than five pack-years (p=0.002). Average tobacco weight of bidi (216.8mg) was significantly less than cigarette (696mg). Conclusions. Bidi is equally or more harmful than cigarette smoking. One bidi may be considered to one cigarette for calculating “pack-years” of smoking.

Oxidative stress and obstructive sleep apnoea syndrome.

Rationale. Even though oxidative stress has been proposed as an underlying mechanism for the symptoms in patients with obstructive sleep apnoea syndrome (OSAS), little information is available on the effects of anti-oxidant treatment on their improvement. Objectives. To observe the effects of anti-oxidant treatment on polysomnographic parameters and oxidative stress markers in OSAS patients. Methods. Polysomnography (PSG) was performed on 20 male patients. They were administered continuous positive airway pressure (CPAP) therapy for two nights followed by oral intake of vitamin C (100 IU BD) and vitamin E (400 IU BD) for 45 days and a repeat PSG was done. Ten healthy normal subjects underwent the same protocol excepting the CPAP therapy. Results. In OSAS patients, plasma lipid peroxidation increased significantly and whole blood reduced glutathione decreased significantly. The CPAP therapy as well as anti-oxidant treatment reduced the lipid peroxidation and restored the reduced glutathione concentrations. After anti-oxidant intake, OSAS patients slept better with decrease in Epworth sleepiness score and the number of apnoeic episodes. They spent more time in stages 3 and 4 of sleep. The optimum pressure of CPAP device was significantly lowered also. Conclusions. Oxidative stress contributes to sleep behaviour in OSAS patients, and anti-oxidant intake improves the quality of sleep in them.

Influenza A (H1N1) 2009: a pandemic alarm.

At this critical juncture when the world has not yet recovered from the threat of avian infl uenza, the virus has returned in the disguise of swine infl uenza, a lesser known illness common in pigs. It has reached pandemic proportions in a short time span with health personnel still devising ways to identify the novel H1N1 virus and develop vaccines against it. The H1N1 virus has caused a considerable number of deaths within the short duration since its emergence. Presently, there are no effective methods to contain this newly emerged virus. Therefore, a proper and clear insight is urgently required to prevent an outbreak in the future and make preparations that may be planned well in advance. This review is an attempt to discuss the historical perspective of the swine fl u virus, its epidemiology and route of transmission to better understand the various control measures that may be taken to fi ght the danger of a global pandemic.

Infl uenza a virus induced apoptosis: Inhibition of DNA laddering & caspase-3 activity by zinc supplementation in cultured HeLa cells.

Background & objectives: The pathogenesis of infl uenza virus infection involves virus replication in epithelial cells of the respiratory tract and the consequent degeneration of infected cells. Infl uenza virus induces cellular degeneration following infection of cultured cells in vitro, and the cytopathic effect (CPE) occurs principally through apoptotic cell death. This study was undertaken to fi nd out the effect of zinc on infl uenza virus induced apoptosis in cultured HeLa cells. Methods: The sub-confl uent monolayer HeLa cells were used to study the effect of zinc on infl uenza virus induced apoptosis. The apoptotic markers viz., caspase-3 activity, phagocytic index, morphological changes, and DNA fragmentation were assayed. Results: When HeLa cells were infected with a cell adapted pathogenic strain of infl uenza A (A/Udorn/ 317/72H3N2) virus, DNA fragmentation was observed in virus infected cells by 24 h post infection and caspase-3 activity was maximum at 4 h post infection after which it reached to plateau. Treatment of cells with 0.1 5mM concentration of zinc till 8 h post infection inhibited DNA fragmentation and also caspase 3 activity was decreased signifi cantly up to 2 h post infection. Interpretation & conclusions: When the infected HeLa cells were incubated with adherent macrophages, effi cient phagocytosis occurred and the release of virus into the culture medium was inhibited. These results suggested that inhibitory effect on infl uenza virus induced apoptotic death of cultured cells can be determined at an early stage of the infection by treatment of zinc.

Immunohistochemical staining on fine needle aspiration biopsy-cell block specimens in the differential diagnosis of lung cancers.

BACKGROUND: Fine needle aspiration biopsy [FNAB] is used extensively in the clinical work-up of radiologically detected lung lesions. However, categorisation of lung cancer by computed tomography guided FNAB alone is limited by overlapping morphological features. AIM: To examine further the utility of immunohistochemical panel of antibodies to thyroid transcription factor [TTF-1], synaptophysin, chromogranin A [CgA], cytokeratin-pan, cytokeratin-7 [CK-7], cytokeratin-20 [CK-20], leucocyte common antigen [LCA], and carcinoembryonic antigen [CEA] in cytologic cell block samples in the differential diagnosis of lung cancer. METHODS: Twenty-nine FNABs of newly diagnosed cases of lung cancer were studied. Immunohistochemistry was done on paraffin embedded cell block sections using Dako monoclonal antibodies. RESULTS: Morphological diagnosis of non-small cell carcinoma (NSCLC) was made in 22/29 [76%] and small cell carcinoma in 7/29 (24%) cases. Five of the seven (71.4%) cases of small cell carcinoma were CgA+/TTF-1+, 14.3% [1/7] were CgA+/ synaptophysin+/TTF-1-negative. In one case, LCA positivity lead to the diagnosis of non-Hodgkins lymphoma. The NSCLC was categorised further into well differentiated 11/22 [50%], moderately differentiated 7/22 [31.8%] and poorly differentiated 4/22 [18.2%] cases. Cytokeratin-pan positivity in squamous cell carcinomas [n=15] was seen to be related to cellular differentiation. All the three cases of adenocarcinoma were CK-7+/CK-20 negative. In one case with large cell carcinoma, CgA-positivity lead to recategorisation as large cell neuroendocrine carcinoma. CONCLUSIONS: Our results suggest that the proposed panel of immunohistochemical markers might help further classification of lung carcinomas even in small FNAB material and permit more consistent patient enrollment for trials with targeted treatments.