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Patients with dilated cardiomyopathy who have developed mitral valve regurgitation (MR) with reduced left ventricular ejection fraction and are too sick to undergo any surgical repair or replacement are being treated worldwide through catheter-based percutaneous intervention techniques to treat MR like MitraClip system®. There are very few case reports especially from India on anesthetic management during MitraClip device implantation and its specific considerations. We present a case of a 48-year-old male patient, diagnosed as post-myocarditis dilated cardiomyopathy with poor left ventricular ejection fraction (30-35%) and severe MR who underwent mitral clip implantation with fluoroscopy and transesophageal echocardiography guidance under general anesthesia. We hope that our experience will help and guide future such undertakings in our country.
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Backrground: Transcatheter aortic valve replacement (TAVR) has become an accepted modality of treatment in intermediate and high surgical risk patients of symptomatic severe calcific aortic stenosis (AS). We herein report Indian data of 84 intermediate and high-risk patients who underwent TAVR at two Armed Forces cardiac centres. Methods: Most of the patients underwent TAVR in cardiac catheterization lab by percutaneous transfemoral approach, under conscious sedation. Patients were followed up and echocardiographic parameters were assessed after six months of procedure. Results: Total of 84 intermediate and high-risk patients underwent TAVR between Jan 2017 and June 2021. Mean age of population was 71.5 ± 8.4 years; 28.5% of patients had bicuspid aortic valve and Mean STS score was 6.34 ± 2.08. Majority (92.8%) patients underwent the procedure under conscious sedation. Self-expanding valves were used in 72.6% and balloon expandable in 27.4% of patients. Predilatation was done in 64% patients while 13% cases underwent post dilatation. Procedural mortality was 2.3%. Rate of permanent pacemaker implantation was 4.9%. Ischemic stroke occurred in 1.1% of patents. There was no case of severe paravalvular leak. Emergency surgical aortic valve replacement was done in 2.4% patients. Procedural success in this study was 97.6%. All-cause mortality was 9.5% at 6 months. Conclusions: TAVR is an effective treatment modality in intermediate and high-risk Indian patients with severe aortic stenosis. Patients with bicuspid or previous bio prosthetic aortic valves also have a good outcome post TAVR.
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Intracellular accumulation of amyloid-ß protein (Aß) is an early event in Alzheimer's disease (AD). The autophagy-lysosomal pathway is an important pathway for maintaining cellular proteostasis and for the removal of damaged organelles and protein aggregates in all eukaryotes. Despite mounting evidence showing that modulating autophagy promotes clearance of Aß aggregates, the regulatory mechanisms and signalling pathways underlying this process remain poorly understood. In order to gain better insight we used our previously characterised yeast model expressing GFP-Aß42 to identify genes that regulate the removal of Aß42 aggregates by autophagy. We report that GFP-Aß42 is sequestered and is selectively transported to vacuole for degradation and that autophagy is the prominent pathway for clearance of aggregates. Next, to identify genes that selectively promote the removal of Aß42 aggregates, we screened levels of GFP-Aß42 and non-aggregating GFP-Aß42 (19:34) proteins in a panel of 192 autophagy mutants lacking genes involved in regulation and initiation of the pathway, cargo selection and degradation processes. The nutrient and stress signalling genes RRD1, SNF4, GCN4 and SSE1 were identified. Deletion of these genes impaired GFP-Aß42 clearance and their overexpression reduced GFP-Aß42 levels in yeast. Overall, our findings identify a novel role for these nutrient and stress signalling genes in the targeted elimination of Aß42 aggregates, which offer a promising avenue for developing autophagy based therapies to suppress amyloid deposition in AD.
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Péptidos beta-Amiloides/metabolismo , Autofagia , Fragmentos de Péptidos/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Isomerasa de Peptidilprolil/genética , Isomerasa de Peptidilprolil/metabolismo , Proteolisis , Saccharomyces cerevisiae , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Sugar Nucleotidyl Transferases (SNTs) constitute a large family of enzymes that play important metabolic roles. Earlier, for one such SNT, termed N-acetylglucosamine-1-phosphate uridyltransferase- GlmU, we had established that two magnesium ions - Mg2+A and Mg2+B - catalyze the sugar-nucleotidyl transfer reaction. Despite a common structural framework that SNTs share, we recognized key differences around the active-site based on the analysis of available structures. Based on these differences, we had classified SNTs into two major groups, Group - I & II; and further, variation in 'Mg2+A-stabilizing motifs' led us to sub-classify them into five distinct sub-groups. Since group specific conservation of 'Mg2+A-stabilizing motifs' was based only for 45 available structures, here we validate this via an exhaustive analysis of 1,42,025 protein sequences. Previously, we had hypothesized that a metal-ion-catalyzed mechanism would be operative in all SNTs. Here, we validate it biochemically and establish that Mg2+ is a strict requirement for nucleotidyl transfer reactions in every group or sub-group and that a common metal ion dependent mechanism operates in SNTs. Further, mutating Mg2+A coordinating residue in each sub-group led to abolished catalysis, indicating an important role for both of these residues and suggest that SNTs employ variations over 'a conserved catalytic mechanism mediated by Mg2+ ion(s)', to bring about functional diversity. This would constitute a comprehensive study to establish the catalytic mechanism across the family of SNTs.
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Familia de Multigenes , Nucleotidiltransferasas/química , Nucleotidiltransferasas/clasificación , Azúcares/metabolismo , Secuencia de Aminoácidos , Secuencia Conservada , Estabilidad de Enzimas , Glucosamina/análogos & derivados , Glucosamina/química , Glucosamina/metabolismo , Magnesio/metabolismo , Modelos MolecularesRESUMEN
Neurodegenerative diseases result in a range of conditions depending on the type of proteinopathy, genes affected or the location of the degeneration in the brain. Proteinopathies such as senile plaques and neurofibrillary tangles in the brain are prominent features of Alzheimer's disease (AD). Autophagy is a highly regulated mechanism of eliminating dysfunctional organelles and proteins, and plays an important role in removing these pathogenic intracellular protein aggregates, not only in AD, but also in other neurodegenerative diseases. Activating autophagy is gaining interest as a potential therapeutic strategy for chronic diseases featuring protein aggregation and misfolding, including AD. Although autophagy activation is a promising intervention, over-activation of autophagy in neurodegenerative diseases that display impaired lysosomal clearance may accelerate pathology, suggesting that the success of any autophagy-based intervention is dependent on lysosomal clearance being functional. Additionally, the effects of autophagy activation may vary significantly depending on the physiological state of the cell, especially during proteotoxic stress and ageing. Growing evidence seems to favour a strategy of enhancing the efficacy of autophagy by preventing or reversing the impairments of the specific processes that are disrupted. Therefore, it is essential to understand the underlying causes of the autophagy defect in different neurodegenerative diseases to explore possible therapeutic approaches. This review will focus on the role of autophagy during stress and ageing, consequences that are linked to its activation and caveats in modulating this pathway as a treatment.
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Enfermedad de Alzheimer/patología , Autofagia/fisiología , Envejecimiento/patología , Animales , Humanos , Lisosomas/patología , Estrés Fisiológico/fisiologíaRESUMEN
BACKGROUND: Prior research from India demonstrates a need for family planning counseling that engages both women and men, offers complete family planning method mix, and focuses on gender equity and reduces marital sexual violence (MSV) to promote modern contraceptive use. Effectiveness of the three-session (two male-only sessions and one couple session) Counseling Husbands to Achieve Reproductive Health and Marital Equity (CHARM) intervention, which used male health providers to engage and counsel husbands on gender equity and family planning (GE + FP), was demonstrated by increased pill and condom use and a reduction in MSV. However, the intervention had limited reach to women and was therefore unable to expand access to highly effective long acting reversible contraceptives such as the intrauterine device (IUD). We developed a second iteration of the intervention, CHARM2, which retains the three sessions from the original CHARM but adds female provider- delivered counseling to women and offers a broader array of contraceptives including IUDs. This protocol describes the evaluation of CHARM2 in rural Maharashtra. METHODS: A two-arm cluster randomized controlled trial will evaluate CHARM2, a gender synchronized GE + FP intervention. Eligible married couples (n = 1200) will be enrolled across 20 clusters in rural Maharashtra, India. Health providers will be gender-matched to deliver two GE + FP sessions to the married couples in parallel, and then a final session will be delivered to the couple together. We will conduct surveys on demographics as well as GE and FP indicators at baseline, 9-month, and 18-month follow-ups with both men and women, and pregnancy tests at each time point from women. In-depth interviews will be conducted with a subsample of couples (n = 50) and providers (n = 20). We will conduct several implementation and monitoring activities for purposes of assuring fidelity to intervention design and quality of implementation, including recruitment and tracking logs, provider evaluation forms, session observation forms, and participant satisfaction surveys. DISCUSSION: We will complete the recruitment of participants and collection of baseline data by July 2019. Findings from this work will offer important insight for the expansion of the national family planning program and improving quality of care for India and family planning interventions globally. TRIAL REGISTRATION: ClinicalTrial.gov, NCT03514914 .
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Conducta Anticonceptiva/estadística & datos numéricos , Servicios de Planificación Familiar/estadística & datos numéricos , Educación en Salud , Conocimientos, Actitudes y Práctica en Salud , Matrimonio , Educación Sexual , Protocolos Clínicos , Consejo , Intervención Educativa Precoz , Femenino , Humanos , India , Masculino , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Población RuralRESUMEN
Amyloids are fibrous proteins aggregated into toxic forms that are implicated in several chronic disorders. More than 30 diseases show deposition of fibrous amyloid proteins associated with cell loss and degeneration in the affected tissues. Evidence demonstrates that amyloid diseases result from protein aggregation or impaired amyloid clearance, but the connection between amyloid accumulation and tissue degeneration is not clear. Common examples of amyloid diseases are Alzheimer's disease (AD), Parkinson's disease (PD) and tauopathies, which are the most common forms of neurodegenerative diseases, as well as polyglutamine disorders and certain peripheral metabolic diseases. In these diseases, increased accumulation of toxic amyloid proteins is suspected to be one of the main causative factors in the disease pathogenesis. It is therefore important to more clearly understand how these toxic amyloid proteins accumulate as this will aide in the development of more effective preventive and therapeutic strategies. Protein homeostasis, or proteostasis, is maintained by multiple cellular pathways-including protein synthesis, quality control, and clearance-which are collectively responsible for preventing protein misfolding or aggregation. Modulating protein degradation is a very complex but attractive treatment strategy used to remove amyloid and improve cell survival. This review will focus on autophagy, an important clearance pathway of amyloid proteins, and strategies for using it as a potential therapeutic target for amyloid diseases. The physiological role of autophagy in cells, pathways for its modulation, its connection with apoptosis, cell models and caveats in developing autophagy as a treatment and as a biomarker is discussed.
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Proteínas Amiloidogénicas/química , Autofagia/efectos de los fármacos , Amiloide/química , Amiloide/metabolismo , Proteínas Amiloidogénicas/antagonistas & inhibidores , Proteínas Amiloidogénicas/metabolismo , Animales , Apoptosis , Biomarcadores , Susceptibilidad a Enfermedades , Humanos , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/metabolismo , Agregado de Proteínas , Agregación Patológica de Proteínas/tratamiento farmacológico , Transducción de SeñalRESUMEN
Human islet amyloid polypeptide (hIAPP) is a naturally occurring, intrinsically disordered protein whose abnormal aggregation into amyloid fibrils is a pathological feature in type 2 diabetes, and its cross-aggregation with amyloid beta has been linked to an increased risk of Alzheimer's disease. The soluble, oligomeric forms of hIAPP are the most toxic to ß-cells in the pancreas. However, the structure of these oligomeric forms is difficult to characterise because of their intrinsic disorder and their tendency to rapidly aggregate into insoluble fibrils. Experimental studies of hIAPP have generally used non-physiological conditions to prevent aggregation, and they have been unable to describe its soluble monomeric and oligomeric structure at physiological conditions. Molecular dynamics (MD) simulations offer an alternative for the detailed characterisation of the monomeric structure of hIAPP and its aggregation in aqueous solution. This paper reviews the knowledge that has been gained by the use of MD simulations, and its relationship to experimental data for both hIAPP and rat IAPP. In particular, the influence of the choice of force field and water models, the choice of initial structure, and the configurational sampling method used, are discussed in detail. Characterisation of the solution structure of hIAPP and its mechanism of oligomerisation is important to understanding its cellular toxicity and its role in disease states, and may ultimately offer new opportunities for therapeutic interventions.
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Polipéptido Amiloide de los Islotes Pancreáticos/química , Simulación de Dinámica Molecular , Estructura Molecular , Multimerización de Proteína , Amiloide/química , Amiloide/metabolismo , Amiloide/ultraestructura , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Amiloidosis/metabolismo , Animales , Dicroismo Circular , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Espectroscopía de Resonancia Magnética , Agregado de Proteínas , Agregación Patológica de Proteínas , Ratas , Transducción de SeñalRESUMEN
RATIONALE: Little is known about the long-term effects of air pollution exposure and the root causes of asthma. We use exposure to intense air pollution from the 1952 Great Smog of London as a natural experiment to examine both issues. OBJECTIVES: To determine whether exposure to extreme air pollution in utero or soon after birth affects asthma development later in life. METHODS: This was a natural experiment using the unanticipated pollution event by comparing the prevalence of asthma between those exposed to the Great Smog in utero or the first year of life with those conceived well before or after the incident and those residing outside the affected area at the time of the smog. MEASUREMENTS AND MAIN RESULTS: Prevalence of asthma during childhood (ages 0-15) and adulthood (ages >15) is analyzed for 2,916 respondents to the Life History portion of the English Longitudinal Study on Aging born from 1945 to 1955. Exposure to the Great Smog in the first year of life increases the likelihood of childhood asthma by 19.87 percentage points (95% confidence interval [CI], 3.37-36.38). We also find suggestive evidence that early-life exposure led to a 9.53 percentage point increase (95% CI, -4.85 to 23.91) in the likelihood of adult asthma and exposure in utero led to a 7.91 percentage point increase (95% CI, -2.39 to 18.20) in the likelihood of childhood asthma. CONCLUSIONS: These results are the first to link early-life pollution exposure to later development of asthma using a natural experiment, suggesting the legacy of the Great Smog is ongoing.
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Contaminantes Atmosféricos/efectos adversos , Contaminación del Aire/efectos adversos , Asma/epidemiología , Esmog/efectos adversos , Adolescente , Adulto , Causalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Londres/epidemiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Embarazo , Prevalencia , Factores de Riesgo , Adulto JovenRESUMEN
Currently, percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is the most commonly employed modality in the treatment of patients with coronary artery disease. PCI has come of age over the last four decades with enormous forays in the technology and drugs which have greatly enhanced its capability. Angioplasty and bare metal stents were plagued by high failure rates on account of restenosis leading to repeat revascularization procedures. Insights into pathophysiology of instent restenosis (ISR) and neointimal hyperplasia triggered the development of DES. The dreamlike remarkable reduction in ISR with DES was enthusiastically welcomed. Soon thereafter emerged the spectre of very late stent thrombosis (VLST) with DES. VLST was a new entity seen predominantly with DES and pathological insights as to the cause was instrumental in the development and efficacy of new generation DES. This review will highlight the evolution and present day DES for coronary interventions.
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BACKGROUND & OBJECTIVES: Acute myocardial infarction (AMI) is characterized by irreparable and irreversible loss of cardiac myocytes. Despite major advances in the management of AMI, a large number of patients are left with reduced left ventricular ejection fraction (LVEF), which is a major determinant of short and long term morbidity and mortality. A review of 33 randomized control trials has shown varying improvement in left ventricular (LV) function in patients receiving stem cells compared to standard medical therapy. Most trials had small sample size and were underpowered. This phase III prospective, open labelled, randomized multicenteric trial was undertaken to evaluate the efficacy in improving the LVEF over a period of six months, after injecting a predefined dose of 5-10 × 10 [8] autologous mononuclear cells (MNC) by intra-coronary route, in patients, one to three weeks post ST elevation AMI, in addition to the standard medical therapy. METHODS: In this phase III prospective, multicentric trial 250 patients with AMI were included and randomized into stem cell therapy (SCT) and non SCT groups. All patients were followed up for six months. Patients with AMI having left ventricular ejection fraction (LVEF) of 20-50 per cent were included and were randomized to receive intracoronary stem cell infusion after successfully completing percutaneous coronary intervention (PCI). RESULTS: On intention-to-treat analysis the infusion of MNCs had no positive impact on LVEF improvement of ≥ 5 per cent. The improvement in LVEF after six months was 5.17 ± 8.90 per cent in non SCT group and 4.82 ± 10.32 per cent in SCT group. The adverse effects were comparable in both the groups. On post hoc analysis it was noted that the cell dose had a positive impact when infused in the dose of ≥ 5 X 10 [8] (n=71). This benefit was noted upto three weeks post AMI. There were 38 trial deviates in the SCT group which was a limitation of the study. INTERPRETATION & CONCLUSIONS: Infusion of stem cells was found to have no benefit in ST elevation AMI. However, the procedure was safe. A possible benefit was seen when the predefined cell dose was administered which was noted upto three weeks post AMI, but this was not significant and needs confirmation by larger trials.
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Infarto del Miocardio/terapia , Trasplante de Células Madre , Células Madre/citología , Disfunción Ventricular Izquierda/terapia , Anciano , Médula Ósea , Ecocardiografía , Femenino , Humanos , India , Masculino , Persona de Mediana Edad , Infarto del Miocardio/patología , Resultado del Tratamiento , Disfunción Ventricular Izquierda/patologíaRESUMEN
Using two decades of data from 12 low-income countries in West Africa, we show that dust carried by harmattan trade winds increases infant and child mortality. Health investments respond to dust exposure, consistent with compensating behaviours. Despite these efforts, surviving children still exhibit negative health impacts. Our data allow us to investigate differential impacts over time and across countries. We find declining impacts over time, suggesting adaptation. Using national-level measures of macroeconomic conditions and health resources, we find suggestive evidence that both economic development and public health improvements have contributed to this adaptation, with health improvements playing a larger role.
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INTRODUCTION: Transcatheter Aortic Valve Implantation (TAVI) techniques gradually evolved since 2002 and have undergone various refinements. Achieving optimal implantation depth has become crucial for good long term outcome. High implantation decreases the likelihood of conduction disturbances. Conventionally TAVI valve is positioned in a tricusp coplanar (CON) fluoroscopic projection however it does not ensure a optimal implantation. In an attempt to attain higher implantation(3 mm) and decrease rate of permanent pacemaker, cuspal overlap technique (COT) view has been developed. There is scarcity of Indian literature comparing TAVI deployment using coplanar and cuspal overlap techniques. METHODS: We included 111 patients who underwent TAVR with a self-expanding Core Valve Evolut R (Medtronic, Minneapolis, Minnesota), between January 2017 to September 2022 at our centre.Transcatheter Heart Valves (THV) were implanted using the traditional coplanar in 55 patients, while in 56 patients valves were implanted using the COT. RESULTS: Baseline characteristics including electrocardiographic findings were comparable in both groups. In all patients Evolut R or Evolut PRO valves were used. Procedure was done in conscious sedation in 90.9 % of patients in CON and 96.4 % in COT group. Predilatation and postdilatation was used in 38.8 % vs 33.9 % and 27 % vs 32 % in CON and COT groups respectively. 90 day PPI rate was less in COT group (7.3 % CON vs 3.5 % COP). Majority of patients who received permanent pacemaker implantation (PPI) had baseline ECG abnormality (RBBB in 50 %, LBBB in 16 %, Grade 1 AV block 16 %). Mean time of post procedure PPI was 5.6 days in COT group and 7.3 days in CON group. New onset LBBB was also less in COT group (21 % CON vs 12.5 % COT).There were 3.6 % intraprocedural deaths in CON group and 1.8 % in COT group. Depth of deployed valve was 4.8 ± 2.34 mm in COT and 6.6 ± 2.11 mm in CON group. Valve deployment time was more in COT group(10.40 CON vs 14.34 min COT). Average valve recapture rate was 2.58 in COP and 2.11 in CON. Stroke rate was more in COT group(3.6 % CON vs 7.14 % COT). Pericardial effusions were also more in COT group. All cause mortality at 3 months was 10.9 % in CON group and 5.3 % in COT. CONCLUSION: In this study we achieved lower rates of PPI and new onset LBBB using COT technique in Indian patients using self-expandable prostheses. However valve deployment time, stroke rate and pericardial effusion were seen more in COT group. All cause mortality was low in cuspal overlap technique.
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Prótesis Valvulares Cardíacas , Accidente Cerebrovascular , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Resultado del Tratamiento , ElectrocardiografíaRESUMEN
This paper studies the effect of improved early life health care on mortality and long-run academic achievement in school. We use the idea that medical treatments often follow rules of thumb for assigning care to patients, such as the classification of Very Low Birth Weight (VLBW ), which assigns infants special care at a specific birth weight cutoff. Using detailed administrative data on schooling and birth records from Chile and Norway, we establish that children who receive extra medical care at birth have lower mortality rates and higher test scores and grades in school. These gains are in the order of 0.150.22 standard deviations.
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Éxito Académico , Salud del Lactante , Recién Nacido de muy Bajo Peso , Unidades de Cuidado Intensivo Neonatal , Cuidado Intensivo Neonatal , Tensoactivos/uso terapéutico , Peso al Nacer , Salud Infantil , Chile , Edad Gestacional , Humanos , Lactante , Cuidado del Lactante , Mortalidad Infantil , Recién Nacido , Cuidado Intensivo Neonatal/métodos , Noruega , Síndrome de Dificultad Respiratoria del Recién Nacido/tratamiento farmacológicoRESUMEN
BACKGROUND: Radiofrequency catheter ablation is an emerging curative modality of treatment for several types of cardiac arrhythmias. The aim of our study was to evaluate our experience of electrophysiology procedures over a 10-year-period and compare it with the published literature. METHODS AND RESULT: All patients undergoing cardiac electrophysiology and radiofrequency ablation procedures during the period from 01 January 2003 to 30 April 2012 were included in this study. The study analyzed 892 patients of which atrioventricular nodal reentrant tachycardia (AVNRT) was n = 513 (57.5%), accessory pathways n = 230 (25.8%), atrial tachycardia n = 26 (2.9%), atrial flutter n = 15 (1.7%), atrial fibrillation = 9 (1.0%), ventricular tachycardia n = 37 (4.2%) and diagnostic studies n = 62 (6.9%). Three-dimensional electro-anatomic mapping was performed in n = 17 (1.9%). The success rate was 99% with AVNRT, 94% with accessory pathway, 81% with atrial tachycardia, 64% with ventricular tachycardia and 34% with atrial fibrillation. The major and serious complications rate was 0.45%. CONCLUSIONS: The procedural success rate and the complication rate in this real-world study of the Armed Forces were comparable/superior to the reported literature.
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OBJECTIVES: Globalisation and industrialisation can increase economic opportunity for low/middle-income nations, but these processes may also increase industrial accidents and harm workers. This paper examines the long-term, cohort-based health effects of the Bhopal gas disaster (BGD), one of the most serious industrial accidents in history. DESIGN: This retrospective analysis uses geolocated data on health and education from India's National Family Health Survey-4 (NFHS-4) and the 1999 Indian Socio-Economic Survey by the National Sample Survey Organization (NSSO-1999) to examine the health effects of exposure to the BGD among men and women aged 15-49 years living in Madhya Pradesh in 2015-2016 (women n=40 786; men n=7031 (NFHS-4) and n=13 369 (NSSO-1999)), as well as their children (n=1260). A spatial difference-in-differences strategy estimated the relative effect of being in utero near Bhopal relative to other cohorts and to those further from Bhopal separately for each dataset. RESULTS: We document long-term, intergenerational impacts of the BGD, showing that men who were in utero at the time were more likely to have a disability that affected their employment 15 years later, and had higher rates of cancer and lower educational attainment over 30 years later. Changes in the sex ratio among children born in 1985 suggest an effect of the BGD up to 100 km from the accident. CONCLUSIONS: These results indicate social costs stemming from the BGD that extend far beyond the mortality and morbidity experienced in the immediate aftermath. Quantifying these multigenerational impacts is important for policy consideration. Moreover, our results suggest that the BGD affected people across a substantially more widespread area than has previously been demonstrated.
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Éxito Académico , Desastres , Niño , Masculino , Humanos , Femenino , Adulto , Estudios Retrospectivos , Industrias , EscolaridadRESUMEN
We examine the relationship between parental disability and child outcomes in the American Community Survey. We focus on families with veteran parents, for whom parental disability is a direct result of service-related activities and thus is more plausibly exogenous to child outcomes than other forms of parental disability. Using the service connected disability rating (SCDR) as a measure of the severity of veteran disability, we document a gradient in child outcomes with respect to parental disability (even conditional on having a disabled parent). Children with more severely disabled parents are more likely to be late for grade, less likely to be in private school, and more likely to have disabilities themselves. These results lend meaningful insight to broader populations; we find similar associations between parental disability and child outcomes in non-veteran families. We provide evidence consistent with two broad mechanisms: first, parental disability reduces parental labor supply and thus household income (even net of transfers) and second, children-especially older children-allocate time away from work and schooling to provide care for disabled parents.
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Niños con Discapacidad , Niño , Humanos , Adolescente , Padres , FamiliaRESUMEN
BACKGROUND: Type 2 diabetes related human islet amyloid polypeptide (hIAPP) plays a dual role in Alzheimer's disease (AD). hIAPP has neuroprotective effects in AD mouse models whereas, high hIAPP concentrations can promote co-aggregation with amyloid-ß (Aß) to promote neurodegeneration. In fact, both low and high plasma hIAPP concentration has been associated with AD. Therefore, non-aggregating hIAPP analogues have garnered interest as a treatment for AD. The aromatic amino acids F23 and I26 in hIAPP have been identified as the key residues involved in self-aggregation and Aß cross-seeding. OBJECTIVE: Three novel IAPP analogues with single and double alanine mutations (A1â=âF23, A2â=âI26, and A3â=âF23â+âI26) were assessed for their ability to aggregate, modulate Aß oligomer formation, and alter neurotoxicity. METHODS: A range of biophysical methods including Thioflavin-T, gel electrophoresis, photo-crosslinking, circular dichroism combined with cell viability assays were utilized to assess protein aggregation and toxicity. RESULTS: All IAPP analogues showed significantly less self-aggregation than hIAPP. Co-aggregated Aß42-A2 and A3 also showed reduced aggregation compared to Aß42-hIAPP mixtures. Self- and co-oligomerized A1, A2, and A3 exhibited random coil conformations with reduced beta sheet content compared to hIAPP and Aß42-hIAPP aggregates. A1 was toxic at high concentrations compared to A2 and A3. However, co-aggregated Aß42-A1, A2, or A3 showed reduced neurotoxicity compared to Aß42, hIAPP, and Aß42-hIAPP aggregates. CONCLUSION: These findings confirm that hIAPP analogues with non-aromatic residues at positions 23 and 26 have reduced self-aggregation and the ability to neutralize Aß42 toxicity. This warrants further characterization of their protective effects in pre-clinical AD models.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Síndromes de Neurotoxicidad , Enfermedad de Alzheimer/genética , Amiloide , Péptidos beta-Amiloides/metabolismo , Animales , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Ratones , Agregado de ProteínasRESUMEN
COVID-19 caused by a positive-sense single stranded RNA virus named as severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) triggered the global pandemic. This virus has infected about 10.37 Crores and taken lives of 2.24 Crores people of 213 countries to date. To cope-up this emergency clinical trials are undergoing with some existing drugs like remdesivir, flavipiravir, lopinavir-ritonavir, nafamostat, doxycycline, hydroxy-chloroquine, dexamethasone, etc., despite their severe toxicity and health hazards among diabetics, hypertensive, cardiac patients or normal individuals. The lack of safe and approved treatment for COVID-19 has forced the scientific community to find novel and safe compounds with potential efficacy. This study evaluates a few selective herbal compounds like glucoraphanin, vitexin, niazinin, etc., as a potential inhibitor of the spike protein and 3-chymotrypsin-like protease (3CLpro) or main protease (Mpro) of SARS-COV-2 through in-silico virtual studies such as molecular docking, target analysis, toxicity prediction and ADME prediction and supported by a Molecular-Dynamic simulation. Selective phytocompounds were docked successfully in the binding site of spike glycoprotein and 3CLpro (Mpro) of SARS-CoV-2. In-silico approaches also predict this molecule to have good solubility, pharmacodynamic property and target accuracy through MD simulation and ADME studies. These hit molecules niazinin, vitexin, glucoraphanin also obey Lipinski's rule along with their stable binding towards target protein of the virus, which makes them suitable for further biochemical and cell-based assays followed by clinical investigations to highlight their potential use in COVID-19 treatment.Communicated by Ramaswamy H. Sarma.