Prevalence of Chronic airflow limitation in Kashmir, North India: Results from the BOLD study.

BACKGROUND: Data on spirometrically defined chronic airflow limitation (CAL) are scarce in developing countries. OBJECTIVE: To estimate the prevalence of spirometrically defined CAL in Kashmir, North India. METHODS: Using Burden of Obstructive Lung Disease survey methods, we administered questionnaires to randomly selected adults aged 40 years. Post-bronchodilator spirometry was performed to estimate the prevalence of CAL and its relation to potential risk factors. RESULTS: Of 1100 participants initially recruited, 953 (86.9%) responded and 757 completed acceptable spirometry and questionnaires. The prevalence of a forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio less than the lower limit of normal was 17.3% (4.5) in males and 14.8% (2.1) in females. Risk factors for CAL included higher age, cooking with wood and lower educational status. The prevalence of current smoking was 61% in males and 22% in females; most smoked hookahs. CAL was found equally in non-smoking males and females, and was independently associated with the use of the hookah, family history of respiratory disease and poor education. A self-reported doctor's diagnosis of chronic obstructive pulmonary disease was reported in 8.4/1000 (0.9% of females and 0.8% of males). CONCLUSION: Spirometrically confirmed CAL is highly prevalent in Indian Kashmir, and seems to be related to the high prevalence of smoking, predominantly in the form of hookah smoking

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

MGMT promoter hypermethylation and K-RAS, PTEN and TP53 mutations in tamoxifen-exposed and non-exposed endometrial cancer cases

background: Tamoxifen has anti-oestrogenic and anti-tumour activity in the breast, but is oestrogenic and carcinogenic in the endometrium. It can induce experimental tumours by both hormonal and DNA-damaging mechanisms, but its carcinogenic mode of action in human endometrium remains unclear. methods: We investigated whether an epigenetic mechanism, involving promoter hypermethylation of the gene for the DNA repair enzyme MGMT (O6-methylguanine DNA methyltransferase), was associated with K-RAS, TP53 and PTEN mutations in endometrial tumours from women treated with tamoxifen (TAM, n=30) or unexposed to the drug (EC, n=38). results: There were significant (PA, occurred in small numbers in both groups. TP53 mutations were of mainly A>G, C>T and indel modifications in both groups, but more frequent in TAM cases. PTEN mutations dominated in EC tumours and were of the type that has large impact on protein function, such as indel or nonsense mutations. These observations alongside the mutational spectrum in PTEN suggest that the malignancies arise from different backgrounds, hence pointing to an effect of tamoxifen. Both groups displayed MGMT promoter hypermethylation. This coincided with mutations more frequently in the TAM (78%) than in the EC (50%) group, even though there were significantly (P<0.05) fewer mutations and methylations in TAM cases. conclusions: Although the difference in coincidence did not reach significance with the current sample size, the findings suggest that epigenetic processes may play a role in the way tamoxifen induces endometrial cancer

High Resolution Methylome Map of Rat Indicates Role of Intragenic DNA Methylation in Identification of Coding Region

DNA methylation is crucial for gene regulation and maintenance of genomic stability. Rat has been a key model system in understanding mammalian systemic physiology, however detailed rat methylome remains uncharacterized till date. Here, we present the first high resolution methylome of rat liver generated using Methylated DNA immunoprecipitation and high throughput sequencing (MeDIP-Seq) approach. We observed that within the DNA/RNA repeat elements, simple repeats harbor the highest degree of methylation. Promoter hypomethylation and exon hypermethylation were common features in both RefSeq genes and expressed genes (as evaluated by proteomic approach). We also found that although CpG islands were generally hypomethylated, about 6% of them were methylated and a large proportion (37%) of methylated islands fell within the exons. Notably, we obeserved significant differences in methylation of terminal exons (UTRs); methylation being more pronounced in coding/partially coding exons compared to the non-coding exons. Further, events like alternate exon splicing (cassette exon) and intron retentions were marked by DNA methylation and these regions are retained in the final transcript. Thus, we suggest that DNA methylation could play a crucial role in marking coding regions thereby regulating alternative splicing. Apart from generating the first high resolution methylome map of rat liver tissue, the present study provides several critical insights into methylome organization and extends our understanding of interplay between epigenome, gene expression and genome stability

Loss of PTEN Is Not Associated with Poor Survival in Newly Diagnosed Glioblastoma Patients of the Temozolomide Era

Introduction: Pre-temozolomide studies demonstrated that loss of the tumor suppressor gene PTEN held independent prognostic significance in GBM patients. We investigated whether loss of PTEN predicted shorter survival in the temozolomide era. The role of PTEN in the PI3K/Akt pathway is also reviewed. Methods: Patients with histologically proven newly diagnosed GBM were identified from a retrospective database between 2007 and 2010. Cox proportional hazards analysis was used to calculate the independent effects of PTEN expression, age

Coma hipopotasémico: a propósito de un caso

Introduction: coma is the extreme degradation of consciousness. A syndrome characterized by a loss of vegetative functions, as an expression of acute and severe brain dysfunction.Presentation of the case: a 65-year-old male patient who two years ago commenced showing signs of loss of consciousness for two days In inter-crisis periods the studies did not confirm positive results. He was brought to the emergency room in a state of hyporeflexic coma. All parameters were normal except for a very discrete metabolic alkalosis and severe hypokalemia with 1,3 millimoles of potassium. General measures and complementary examinations were performed. Potassium values were replenished. As the potassium values standardized, a process of consciousness recovery was initiated. It was interpreted as a hypokalemic coma.Conclusions: hypopotassemia is a common imbalance, with repercussions in the different systems; this imbalance can result in alterations of the cardiovascular dynamics, progressive muscle weakness and coma. Therefore, in case of symptoms similar to hypokalemia, it is required to work on its diagnosis and treatment.Introducción: El coma es la máxima degradación del estado de conciencia. Síndrome caracterizado por una pérdida de las funciones de la vida de relación y conservación de las de la vida vegetativa, como expresión de una disfunción cerebral aguda y grave.Presentación del caso: paciente masculino de 65 años de edad que hace dos años comenzó con cuadros de pérdida de conciencia por espacio de dos días. En períodos intercrisis los estudios no arrojaron resultados positivos. Es traído a servicio de urgencia en estado de coma hiporrefléctico. Se tomaron medidas generales y se realizaron complementarios. Todo en parámetros de normalidad excepto por una muy discreta alcalosis metabólica y una hipocaliemia severa con 1,3 mili moles de potasio. Se reponen valores de potasio. En la medida que los valores de potasio se recuperaban se iniciaba un proceso de recuperación de la conciencia. Se interpreta como un coma hipopotasémico.Conclusiones: la hipopotasemia es un desbalance común, con repercusiones en los diferentes sistemas, que puede causar desde alteraciones de la dinámica cardiovascular, debilidad muscular progresiva y coma.  De ahí que ante sintomatologías similares a una hipopotasemia se deba trabajar en su diagnóstico y tratamiento.

Global and regional burden of chronic respiratory disease in 2016 arising from non-infectious airborne occupational exposures: a systematic analysis for the Global Burden of Disease Study 2016

OBJECTIVES: This paper presents detailed analysis of the global and regional burden of chronic respiratory disease arising from occupational airborne exposures, as estimated in the Global Burden of Disease 2016 study. METHODS: The burden of chronic obstructive pulmonary disease (COPD) due to occupational exposure to particulate matter, gases and fumes, and secondhand smoke, and the burden of asthma resulting from occupational exposure to asthmagens, was estimated using the population attributable fraction (PAF), calculated using exposure prevalence and relative risks from the literature. PAFs were applied to the number of deaths and disability-adjusted life years (DALYs) for COPD and asthma. Pneumoconioses were estimated directly from cause of death data. Age-standardised rates were based only on persons aged 15 years and above. RESULTS: The estimated PAFs (based on DALYs) were 17% (95% uncertainty interval (UI) 14%-20%) for COPD and 10% (95% UI 9%-11%) for asthma. There were estimated to be 519 000 (95% UI 441,000-609,000) deaths from chronic respiratory disease in 2016 due to occupational airborne risk factors (COPD: 460,100 [95% UI 382,000-551,000]; asthma: 37,600 [95% UI 28,400-47,900]; pneumoconioses: 21,500 [95% UI 17,900-25,400]. The equivalent overall burden estimate was 13.6 million (95% UI 11.9-15.5 million); DALYs (COPD: 10.7 [95% UI 9.0-12.5] million; asthma: 2.3 [95% UI 1.9-2.9] million; pneumoconioses: 0.58 [95% UI 0.46-0.67] million). Rates were highest in males; older persons and mainly in Oceania, Asia and sub-Saharan Africa; and decreased from 1990 to 2016. CONCLUSIONS: Workplace exposures resulting in COPD, asthma and pneumoconiosis continue to be important contributors to the burden of disease in all regions of the world. This should be reducible through improved prevention and control of relevant exposures

Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment