p38α MAPK in inflammation‐associated colorectal cancer

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular . Fecha de lectura: 23-09-201

"A study of change of posture on the pulmonary function tests : can it help copd patients ?"

Objectives : To know the pulmonary function tests in sitting, supine and standing postures in North Indian population Is there any change in PFTs due to change in posture Settings: Department of Physiology, G.S.V.M. Medical College, Kanpur and Escorts Heart Centre, Kanpur Participants : 50 male and 30 female healthy, non-smoker volunteers comprising of 50 students of first year MBBS and 30 volunteers at Escorts Heart Centre, Kanpur Measurements : PFTs, FEV1, FVC, FER, PEFR and TV Statistical analysis : Students't' test Results: The FEV1, FVC and PEFR increased significantly from supine to sitting to standing posture in both males and females. The FER significantly increased only when moving from supine to sitting in both males and females. The TV increased significantly by moving from supine to sitting and also from supine to standing postures in both males and females

Pulmonary Function Tests In Young Healthy Subjects Of North India

Study Objectives : The diagnosis of disease done by skiagram can be substantiated by pulmonary function tests. Substantial data of Indians on PFTs is not available. The present study therefore has been planned on young healthy north Indians. Setting : 119 males and 49 female medical students of North India. Measurements : PFT's, T.V. FEV1, FVC, FER and PEFR were measured. P<0.05 was considered as significant. Results : In North Indian males, mean T. V was 437.56 ± 65.83 ml, FEV1 3.26 ±041 L, FVC 3.82 ± 0.48 L, FER 85.09 ± 2.42% and PEFR was 495.42 ± 101.82 L / min. In North Indian females, average T. V was 386.12 ± 37.90 ml, FEV1 2.39 ± 0.38 L, FVC 2.79 ± 0.43 L, FER 85.38 ± 257% and PEFR was 307.12 ± 75.74 L / min. Conclusions: Males in comparison to females had more value of PFTs. All the PFTs showed positive correlation with Height, Weight and Surface area except Tidal Volume and FER

MK2 degradation as a sensor of signal intensity that controls stress-induced cell fate

Cell survival in response to stress is determined by the coordination of various signaling pathways. The kinase p38 alpha is activated by many stresses, but the intensity and duration of the signal depends on the stimuli. How different p38 alpha-activation dynamics may impact cell life/death decisions is unclear. Here, we show that the p38 alpha signaling output in response to stress is modulated by the expression levels of the downstream kinase MK2. We demonstrate that p38 alpha forms a complex with MK2 in nonstimulated mammalian cells. Upon pathway activation, p38 alpha phosphorylates MK2, the complex dissociates, and MK2 is degraded. Interestingly, transient p38 alpha activation allows MK2 reexpression, reassembly of the p38 alpha-MK2 complex, and cell survival. In contrast, sustained p38 alpha activation induced by severe stress interferes with p38 alpha-MK2 interaction, resulting in irreversible MK2 loss and cell death. MK2 degradation is mediated by the E3 ubiquitin ligase MDM2, and we identify four lysine residues in MK2 that are directly ubiquitinated by MDM2. Expression of an MK2 mutant that cannot be ubiquitinated by MDM2 enhances the survival of stressed cells. Our results indicate that MK2 reexpression and binding to p38 alpha is critical for cell viability in response to stress and illustrate how particular p38 alpha-activation patterns induced by different signals shape the stress-induced cell fate

IKKα controls ATG16L1 degradation to prevent ER stress during inflammation

Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

"A study of change of posture on the pulmonary function tests : can it help copd patients ?"

<p class="Bodytext201">Objectives :</p><ol><li>To know the pulmonary function tests in sitting, supine and standing postures in North Indian population</li><li>Is there any change in PFTs due to change in posture</li></ol><p class="Bodytext201">Settings: Department of Physiology, G.S.V.M. Medical College, Kanpur and Escorts Heart Centre, Kanpur</p><p class="Bodytext71">Participants : 50 male and 30 female healthy, non-smoker volunteers comprising of 50 students of first year MBBS and 30 volunteers at Escorts Heart Centre, Kanpur</p><p class="Bodytext71">Measurements : PFTs, FEV1, FVC, FER, PEFR and TV</p><p class="Bodytext201">Statistical analysis : Students't' test</p><p class="Bodytext71">Results: The FEV1, FVC and PEFR increased significantly from supine to sitting to standing posture in both males and females. The FER significantly increased only when moving from supine to sitting in both males and females. The TV increased significantly by moving from supine to sitting and also from supine to standing postures in both males and females.</p