Plasma Levels of Transforming Growth Factor-β1 Reflect Left Ventricular Remodeling in Aortic Stenosis

Background: TGF-b1 is involved in cardiac remodeling through an auto/paracrine mechanism. The contribution of TGF-b1 from plasmatic source to pressure overload myocardial remodeling has not been analyzed. We investigated, in patients with valvular aortic stenosis (AS), and in mice subjected to transverse aortic arch constriction (TAC), whether plasma TGF-b1 relates with myocardial remodeling, reflected by LV transcriptional adaptations of genes linked to myocardial hypertrophy and fibrosis, and by heart morphology and function. Methodology/Principal Findings: The subjects of the study were: 39 patients operated of AS; 27 healthy volunteers; 12 mice subjected to TAC; and 6 mice sham-operated. Myocardial samples were subjected to quantitative PCR. Plasma TGF-b1 was determined by ELISA. Under pressure overload, TGF-b1 plasma levels were significantly increased both in AS patients and TAC mice. In AS patients, plasma TGF-b1 correlated directly with aortic transvalvular gradients and LV mass surrogate variables, both preoperatively and 1 year after surgery. Plasma TGF-b1 correlated positively with the myocardial expression of genes encoding extracellular matrix (collagens I and III, fibronectin) and sarcomeric (myosin light chain-2, b-myosin heavy chain) remodelling targets of TGF-b1, in TAC mice and in AS patients. Conclusions/Significance: A circulating TGF-b1-mediated mechanism is involved, in both mice and humans, in the excessive deposition of ECM elements and hypertrophic growth of cardiomyocytes under pressure overload. The possible value of plasma TGF-b1 as a marker reflecting preoperative myocardial remodeling status in AS patients deserves further analysis in larger patient cohorts

Knowledge of modifiable risk factors of heart disease among patients with acute myocardial infarction in Karachi, Pakistan: a cross sectional study

BACKGROUND: Knowledge is an important pre-requisite for implementing both primary as well as secondary preventive strategies for cardiovascular disease (CVD). There are no estimates of the level of knowledge of risk factor of heart disease in patients with CVD. We estimated the level of knowledge of modifiable risk factors and determined the factors associated with good level of knowledge among patients presenting with their first acute myocardial infarction (AMI) in a tertiary care hospital in Karachi, Pakistan. METHODS: A hospital based cross-sectional study was conducted at the National Institute of Cardiovascular Disease, a major tertiary care hospital in Karachi Pakistan. Patients admitted with their first AMI were eligible to participate. Standard questionnaire was used to interview 720 subjects. Knowledge of four modifiable risk factors of heart disease: fatty food consumption, smoking, obesity and exercise were assessed. The participants knowing three out of four risk factors were regarded as having a good level of knowledge. A multiple logistic regression model was constructed to identify the determinants of good level of knowledge. RESULTS: The mean age (SD) was 54 (11.66) years. A mere 42% of our study population had a good level of knowledge. In multiple logistic regression analysis, independent predictors of "good" level of knowledge were (odds ratio [95% confidence interval]) more than ten years of schooling were 2.5 [1.30, 4.80] (verses no schooling at all) and nuclear family system (verses extended family system) 2.54 [1.65, 3.89]. In addition, Sindhi ethnicity OR [3.03], higher level of exercise OR [2.76] and non user of tobacco OR [2.53] were also predictors of good level of knowledge. CONCLUSION: Our findings highlight the lack of good level of knowledge of modifiable risk factors for heart disease among subjects admitted with AMI in Pakistan. There is urgent need for aggressive and targeted educational strategies in the Pakistani population

Fatty acid synthase mediates EGFR palmitoylation in EGFR mutated non‐small cell lung cancer

Abstract Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In this report, we describe a novel oncogenic signaling pathway exclusively acting in mutated epidermal growth factor receptor (EGFR) non‐small cell lung cancer (NSCLC) with acquired tyrosine kinase inhibitor (TKI) resistance. Mutated EGFR mediates TKI resistance through regulation of the fatty acid synthase (FASN), which produces 16‐C saturated fatty acid palmitate. Our work shows that the persistent signaling by mutated EGFR in TKI‐resistant tumor cells relies on EGFR palmitoylation and can be targeted by Orlistat, an FDA‐approved anti‐obesity drug. Inhibition of FASN with Orlistat induces EGFR ubiquitination and abrogates EGFR mutant signaling, and reduces tumor growths both in culture systems and in vivo. Together, our data provide compelling evidence on the functional interrelationship between mutated EGFR and FASN and that the fatty acid metabolism pathway is a candidate target for acquired TKI‐resistant EGFR mutant NSCLC patients

High prevalence of lack of knowledge of symptoms of acute myocardial infarction inPakistan and its contribution to delayed presentationto the hospital

<p>Abstract</p> <p>Background</p> <p>We conducted an observational study to determine the delay in presentation to hospital, and its associates among patients experiencing first Acute Myocardial Infarction (AMI) in Karachi, Pakistan.</p> <p>Methods</p> <p>A hospital based cross-sectional study was conducted at National Institute of Cardiovascular Disease (NICVD) in Karachi. A structured questionnaire was used to collect data. The primary outcome was delay in presentation, defined as a time interval of six or more hours from the onset of symptoms to presentation to hospital. Logistic regression analysis was performed to determine the factors associated with prehospital delay.</p> <p>Results</p> <p>A total of 720 subjects were interviewed; 22% were females. The mean age (SD) of the subjects was 54 (± 12) years. The mean (SE) and median (IQR) time to presentation was 12.3 (1.7) hours and 3.04 (6.0) hours respectively. About 34% of the subjects presented late. Lack of knowledge of any of the symptoms of heart attack (odds ratio (95% CI)) (1.82 (1.10, 2.99)), and mild chest pain (10.05 (6.50, 15.54)) were independently associated with prehospital delay.</p> <p>Conclusion</p> <p>Over one-third of patients with AMI in Pakistan present late to the hospital. Lack of knowledge of symptoms of heart attack, and low severity of chest pain were the main predictors of prehospital delay. Strategies to reduce delayed presentation in this population must focus on education about symptoms of heart attack.</p

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Global burden of 87 risk factors in 204 countries and territories, 1990�2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: Rigorous analysis of levels and trends in exposure to leading risk factors and quantification of their effect on human health are important to identify where public health is making progress and in which cases current efforts are inadequate. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a standardised and comprehensive assessment of the magnitude of risk factor exposure, relative risk, and attributable burden of disease. Methods: GBD 2019 estimated attributable mortality, years of life lost (YLLs), years of life lived with disability (YLDs), and disability-adjusted life-years (DALYs) for 87 risk factors and combinations of risk factors, at the global level, regionally, and for 204 countries and territories. GBD uses a hierarchical list of risk factors so that specific risk factors (eg, sodium intake), and related aggregates (eg, diet quality), are both evaluated. This method has six analytical steps. (1) We included 560 risk�outcome pairs that met criteria for convincing or probable evidence on the basis of research studies. 12 risk�outcome pairs included in GBD 2017 no longer met inclusion criteria and 47 risk�outcome pairs for risks already included in GBD 2017 were added based on new evidence. (2) Relative risks were estimated as a function of exposure based on published systematic reviews, 81 systematic reviews done for GBD 2019, and meta-regression. (3) Levels of exposure in each age-sex-location-year included in the study were estimated based on all available data sources using spatiotemporal Gaussian process regression, DisMod-MR 2.1, a Bayesian meta-regression method, or alternative methods. (4) We determined, from published trials or cohort studies, the level of exposure associated with minimum risk, called the theoretical minimum risk exposure level. (5) Attributable deaths, YLLs, YLDs, and DALYs were computed by multiplying population attributable fractions (PAFs) by the relevant outcome quantity for each age-sex-location-year. (6) PAFs and attributable burden for combinations of risk factors were estimated taking into account mediation of different risk factors through other risk factors. Across all six analytical steps, 30 652 distinct data sources were used in the analysis. Uncertainty in each step of the analysis was propagated into the final estimates of attributable burden. Exposure levels for dichotomous, polytomous, and continuous risk factors were summarised with use of the summary exposure value to facilitate comparisons over time, across location, and across risks. Because the entire time series from 1990 to 2019 has been re-estimated with use of consistent data and methods, these results supersede previously published GBD estimates of attributable burden. Findings: The largest declines in risk exposure from 2010 to 2019 were among a set of risks that are strongly linked to social and economic development, including household air pollution; unsafe water, sanitation, and handwashing; and child growth failure. Global declines also occurred for tobacco smoking and lead exposure. The largest increases in risk exposure were for ambient particulate matter pollution, drug use, high fasting plasma glucose, and high body-mass index. In 2019, the leading Level 2 risk factor globally for attributable deaths was high systolic blood pressure, which accounted for 10·8 million (95 uncertainty interval UI 9·51�12·1) deaths (19·2% 16·9�21·3 of all deaths in 2019), followed by tobacco (smoked, second-hand, and chewing), which accounted for 8·71 million (8·12�9·31) deaths (15·4% 14·6�16·2 of all deaths in 2019). The leading Level 2 risk factor for attributable DALYs globally in 2019 was child and maternal malnutrition, which largely affects health in the youngest age groups and accounted for 295 million (253�350) DALYs (11·6% 10·3�13·1 of all global DALYs that year). The risk factor burden varied considerably in 2019 between age groups and locations. Among children aged 0�9 years, the three leading detailed risk factors for attributable DALYs were all related to malnutrition. Iron deficiency was the leading risk factor for those aged 10�24 years, alcohol use for those aged 25�49 years, and high systolic blood pressure for those aged 50�74 years and 75 years and older. Interpretation: Overall, the record for reducing exposure to harmful risks over the past three decades is poor. Success with reducing smoking and lead exposure through regulatory policy might point the way for a stronger role for public policy on other risks in addition to continued efforts to provide information on risk factor harm to the general public. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Protection des données visuelles (analyse des fonctions de hachage perceptuel)

Avec une croissance considérable dans le domaine de la technologie multimédia et de la forte disponibilité des logiciels de traitement d'image, il est désormais facile de manipuler les images numériques. En même temps, il est devenu possible de réaliser des contrefaçons très élaborées, en laissant très peu de traces. Cela présente un grave problème, en particulier, si l'authenticité de l'image numérique est exigée. L'authentification des images devrait se baser sur leurs contenus visuels et non pas sur leurs contenus binaires. Par conséquent, pour authentifier une image, il faut tolérer quelques manipulations acceptables que pourrait subir une image telles que la compression JPEG et l'ajout de bruit Gaussien. En effet, ces manipulations préservent l'aspect visuel de l'image. En même temps un système de hachage perceptuel doit être suffisamment fragile pour détecter les manipulations malveillantes qui modifient l'interprétation du contenu sémantique de l'image comme l'ajout de nouveaux objets, la suppression ou la modification majeure d'objets existants.Dans cette thèse, nous nous intéressons aux fonctions de hachage perceptuel pour l'authentification et le contrôle d'intégrité des images numériques. Dans ce but, nous présentons tous les aspects relatifs aux fonctions de hachage perceptuel. Puis, nous exposons les contraintes qu'un système de hachage perceptuel doit satisfaire pour répondre aux exigences souhaitées au niveau de la robustesse des signatures perceptuelles. Enfin, nous présentons une méthode permettant d'améliorer la robustesse et la sécurité d'un système dehachage perceptuel.The widespread use of multimedia technology has made it relatively easy to manipulate and tamper visual data. In particular, digital image processing and image manipulation tools offer facilities to intentionally alter image content without leaving perceptual traces. This presents a serious problem, particularly if the authenticity of the digital image is required. The image authentication should be based on their visual content and not on their binary content. Therefore, to authenticate an image, some acceptable manipulations that could undergoes an image, such as JPEG compression and Gaussian noise addition, must tolerated. Indeed, these manipulations preserve the visual appearance of the image. At the same time a perceptual hashing system should be sufficiently sensitive to detect malicious manipulations that modify the interpretation of the semantic content of the imagesuch as adding new objects, deleting or major modification of existing objects.In this thesis, we focus on perceptual hash functions for authentication and integrityverification of digital images. For this purpose, we present all aspects of perceptual hashfunctions. Then, we discuss the constraints that perceptual hashing system must satisfy tomeet desired level of robustness of perceptual signatures. Finally, we present a method toimprove the robustness and security of a system of perceptual hashing.MONTPELLIER-BU Sciences (341722106) / SudocSudocFranceF