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It is commonly known that a number of variables, including price, supply levels, time, and green level, affect how quickly certain things are in demand. Furthermore, the inventory carrying cost is considered to be a nonlinear representation of time and is subject to variation throughout time. More precisely, it rises with time since longer storage times necessitate more costly warehouse space. This study presents a fully backlogged situation inventory system for a single commodity where the product's selling price, green level, and time are used to simultaneously compute the demand rate in accordance with a power pattern. Purchase price is determined by the product's nonlinear green level. Complete backorders are available for shortages. The impact of the product's selling price, green level and time power function are combined to determine the product's demand. Moreover, the holding cost also rises as the product is stored for a longer period of time. The primary goal is to determine the best inventory policy to maximise total profit per unit of time. Though the problem is highly nonlinear in nature. Hence, we cannot solve it analytically. To overcome these difficulties, we have applied several well-known popular metaheuristic algorithms (Water Cycle Algorithm (WCA), Artificial Electric Field Algorithm (AEFA), Teaching Learning Based Optimization Algorithm (TLBOA), Grey Wolf Optimizer Algorithm (GWOA), Sparrow Search Algorithm (SSA), Whale Optimizer Algorithm (WOA), Prairie Dog Optimization Algorithm (PDOA), Gazelle Optimization Algorithm (GOA), A Sinh Cosh Optimizer Algorithm (SCHOA) and White Sherk Optimizer Algorithm (WSOA), Archimedes Optimization Paradigm Algorithm (AOPA), Marine Predator Optimization Algorithm (MPOA), Geyser Inspired Algorithm (GIA), Runge Kutta Optimization Algorithm (RKOA), Lungs Performance-based Optimization Algorithm (LPOA) and Dwarf Mongoose Optimization Algorithm (DMOA)). It is observed that WCA perform better than other algorithms with respect to the convergence rate. A numerical example is taken in order to validate the proposed model. Finally, a post optimality analysis is performed in order to make a fruitful conclusion., (© 2024. The Author(s).)

Background: Management of dementia involves a multidisciplinary approach which also requires active participation from family members and caregivers. Thus, having easy access to information about dementia care is pertinent. Internet-based information is an emerging method for the same., Aim: To perform a comparative assessment of patient-oriented online information available on treatment of dementia over web pages in English and Hindi language., Methods: Observational study was conducted online through a general internet search engine (www.google.com). Web pages containing patient-oriented online information on treatment of dementia in English and Hindi were reviewed to assess their content and quality, esthetics, and interactivity. Appropriate descriptive and inferential statistics were conducted using the Statistical Package for the Social Sciences., Results: A total of 70 web pages met the eligibility criteria. Content quality assessed using the DISCERN score was significantly higher for English web pages compared to Hindi web pages ( P < 0.01). About 72.4% (21/29) of English and only 9.8% (4/41) of Hindi web pages had a total DISCERN score of 40 or above, indicating good quality. For esthetics, the median score for English pages was significantly higher than for Hindi web pages ( P < 0.01). The web pages with Health On Net (HON) certification had significantly better content quality., Conclusion: Our study revealed a scarcity of good quality online information about dementia and its treatment, especially in the Hindi language. English language websites showed better content quality than Hindi websites. HON Code label might be used as an indicator of better content quality for online resources informing on dementia treatment by lay people., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Psychiatry.)

There has been a lot of research on pricing and lot-sizing practices for different payment methods; however, the majority has focused on the buyer's perspective. While accepting buyers' credit conditions positively impacts sales, requesting advance payments from purchasers tends to have a negative effect. Additionally, requiring a down payment has been found to generate interest revenue for the supplier without introducing default risk. However, extending the credit period, along with offering delayed payment options, has the potential to increase sales volume, albeit with an elevated risk of defaults. Taking these payment schemes into account, this study investigates and compares the per-unit profit for sellers across three distinct payment methods: advance payment, cash payment, and credit payment. The consumption rate of the product varies non-linearly not only with the time duration of different payment options but also with the price and the level of greenness of the product. The utmost objective of this work is to determine the optimal duration associated with payment schemes, selling price, green level, and replenishment period to maximize the seller's profit. The Teaching Learning Based Optimization Algorithm (TLBOA) is applied to address and solve three numerical examples, each corresponding to a distinct scenario of the considered payment schemes. Sensitivity analyses confirm that the seller's profit is markedly influenced by the environmental sustainability level of the product. Furthermore, the seller's profitability is more significantly affected by the selling price index compared to the indices of the payment scheme duration and the green level in the demand structure., (© 2024. The Author(s).)

Background and Aims: There is no data on the treatment gap and health care utilization for mental disorders from Punjab. The present study reports on the same by using the data collected during the National Mental Health Survey., Settings and Design: Multisite, multistage, stratified, random cluster sampling study conducted in four districts, namely Faridkot, Moga, Patiala, and Ludhiana (for urban metro areas). Data were collected from October 2015 to March 2016., Materials and Methods: Mini International Neuropsychiatric Interview 6.0.0 and Adapted Fagerstrom Nicotine Dependence Scale were used to diagnose mental and behavioral disorders and tobacco use disorder, respectively. Pathways Interview Schedule of the World Health Organization was applied to persons having any disorder to assess treatment gap and health care utilization. Exploratory focused group discussions (FGDs) were conducted to understand the community perceptions regarding mental and behavioral disorders., Results: The treatment gap for mental and behavioral disorders was 79.59%, and it was higher for common mental disorders than severe mental disorders and higher for alcohol and tobacco use disorders as compared to opioid use disorders. The median treatment lag was 6 months. Only seven patients out of 79 were taking treatment from a psychiatrist, and the average distance traveled by the patient for treatment was 37.61 ± 45.5 km. Many attitudinal, structural, and other barriers leading to high treatment gaps were identified during FGDs in the community, such as stigma, poor knowledge about mental health, deficiency of psychiatrists, and distance from the hospital., Conclusions: Vertical as well as horizontal multisectoral integration is required to reduce the treatment gap and improve healthcare utilization. Increasing mental health literacy, providing high-quality mental health services at the primary-healthcare level and human resources development are the need of the hour., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Psychiatry.)

Appropriate screening tools are required to accurately detect complex post traumatic stress disorder (CPTSD). This systematic review aimed to assess and compare measurement tools. A literature search using key words 'complex post traumatic stress disorder', 'PTSD', and 'assessment' was undertaken on Embase and PsychINFO during February 2022 by two reviewers. Inclusion criteria included full text papers between 2002-2022 which evaluated CPTSD using assessment tools. Exclusion criteria included reviews, editorials, meta-analyses, or conference abstracts. Twenty-two papers met selection criteria. Thirteen studies used the International Trauma Questionnaire (ITQ). Two studies each evaluated CPTSD with the International Trauma Interview (ITI) or Symptoms of Trauma Scale (SOTS). The Developmental Trauma Inventory (DTI), Cameron Complex Trauma Interview (CCTI), Complex PTSD Item Set additional to the Clinician Administered PTSD Scale (COPISAC), Complex Trauma Questionnaire (ComplexTQ), and Scale 8 of the Minnesota Multiphasic Personality Inventory Scale (MMPI) were used by a single study each. The ITQ was the most thoroughly investigated, validated across different populations, and is a convenient questionnaire for screening within the clinical setting. Where self-report measures are inappropriate, the ITI, SOTS, and COPISAC are interview tools which detect CPTSD. However, they require further validation and should be used alongside clinical history and examination.

Background: Although some cancer therapies have overt and/or subclinical cardiotoxic effects that increase subsequent cardiovascular risk in breast cancer patients, we have recently shown that the breast tumor itself can also induce cardiac hypertrophy through the activation of the endothelin system to contribute to cardiovascular risk. However, the extent to which the suppression of the activation of the endothelin system could improve cardiac remodeling in breast cancer patients has yet to be investigated., Objectives: We aimed to retrospectively assess the cardiac morphology/function in patients with breast cancer before receiving cancer chemotherapy and to investigate if the suppression of the activation of the endothelin system improves cardiac remodeling in a mouse model of breast cancer., Methods: Our study involved 28 previously studied women with breast cancer (including 24 after tumor resection) before receiving adjuvant therapy and 17 control healthy women. In addition, we explored how the endothelin system contributed to breast cancer-induced cardiac remodeling using a mouse model of breast cancer., Results: Our results indicate that before chemotherapy, breast cancer patients already exhibit relative cardiac remodeling and subclinical cardiac dysfunction, which was associated with the activation of the endothelin system. Importantly, our mouse data also show that the endothelin receptor blocker atrasentan significantly lessened cardiac remodeling and improved cardiac function in a preclinical model of breast cancer., Conclusions: Although our findings should be further examined in other preclinical/clinical models, our data suggest that endothelin receptor blockers may play a role in cardiac health in individuals with breast cancer. (Understanding and Treating Heart Failure With Preserved Ejection Fraction: Novel Mechanisms, Diagnostics and Potential Therapeutics [Alberta HEART]; NCT02052804 and Multidisciplinary Team Intervention in Cardio-Oncology [TITAN]; NCT01621659)., Competing Interests: This work was supported by a grant from the Canadian Institutes of Health Research and a grant from the generous supporters of the Lois Hole Hospital for Women through the Women and Children's Health Research Institute, University of Alberta to Dr Dyck. Dr Dyck is a Canada Research Chair in Molecular Medicine. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Pyruvate kinase M2 (PKM2) is a glycolytic enzyme that translocates to the nucleus to regulate transcription factors in different tissues or pathologic states. Although studied extensively in cancer, its biological role in the heart remains unresolved. PKM1 is more abundant than the PKM2 isoform in cardiomyocytes, and thus, we speculated that PKM2 is not genetically redundant to PKM1 and may be critical in regulating cardiomyocyte-specific transcription factors important for cardiac survival. Here, we showed that nuclear PKM2 ( S37 P-PKM2) in cardiomyocytes interacts with prosurvival and proapoptotic transcription factors, including GATA4, GATA6, and P53. Cardiomyocyte-specific PKM2-deficient mice ( Pkm2 Mut Cre + ) developed age-dependent dilated cardiac dysfunction and had decreased amounts of GATA4 and GATA6 (GATA4/6) but increased amounts of P53 compared to Control Cre +  hearts. Nuclear PKM2 prevented caspase-1-dependent cleavage and degradation of GATA4/6 while also providing a molecular platform for MDM2-mediated reduction of P53. In a preclinical heart failure mouse model, nuclear PKM2 and GATA4/6 were decreased, whereas P53 was increased in cardiomyocytes. Loss of nuclear PKM2 was ubiquitination dependent and associated with the induction of the E3 ubiquitin ligase TRIM35. In mice, cardiomyocyte-specific TRIM35 overexpression resulted in decreased S37 P-PKM2 and GATA4/6 along with increased P53 in cardiomyocytes compared to littermate controls and similar cardiac dysfunction to Pkm2 Mut Cre +  mice. In patients with dilated left ventricles, increase in TRIM35 was associated with decreased S37 P-PKM2 and GATA4/6 and increased P53. This study supports a previously unrecognized role for PKM2 as a molecular platform that mediates cell signaling events essential for cardiac survival.

Objectives: Vitamin D deficiency is associated with worse physical and mental health outcomes. Low vitamin D levels are more common among people who experience mental health issues. This is particularly vital due to the outdoor restrictions which arose from the COVID-19 pandemic. This systematic review assessed vitamin D deficiency and insufficiency among psychiatric inpatients. Methods: A literature search was performed using the key words 'vitamin D', 'mental health', 'mental illness' and 'inpatient' and articles were selected by two independent reviewers. Eighteen studies were identified as eligible according to inclusion and exclusion criteria. Results: Vitamin D deficiency (29 - 96%) and insufficiency (20 - 63%) were common among psychiatric inpatients. Over half of the studies recommended or advised consideration of vitamin D level screening among psychiatric inpatients, while nine recommended consideration of vitamin D supplementation. Conclusions: Screening for vitamin D deficiency during psychiatric admission may be clinically indicated and improve patient wellbeing and outcomes.Key pointsLow vitamin D levels are very common among people admitted to inpatient mental health services.Vitamin D level screening upon inpatient psychiatric admission is warranted to optimise general health outcomes.Vitamin D supplementation should be considered among inpatients with vitamin D deficiency or insufficiency.

The impact of the novel coronavirus disease 19 (COVID-19) has overburdened the anesthesia fraternity both physically and mentally. The academic and training schedule of the medical residents in the last year was also disrupted. Since we are in the early phase of the second peak of the COVID-19 pandemic, it is time to reconsider the causes of stress in anesthesia residents and methods to mitigate them. In this non-systematic review, authors have included articles from PubMed, Medline, and Google scholar with keywords "identify strategies" "preventing and treating psychological disorders," and "medical students" from year 2010 onwards were included. Apart from these keywords, we have included the coping strategies and early psychiatric consultation methods. This review article aims at early identification, workplace environment changes, and implementation of early coping strategies in anesthesia residents during this second peak of COVID-19., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Anaesthesiology Clinical Pharmacology.)

Background: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics., Methods: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations., Results: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain ( MYH7 ) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations., Conclusions: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.

Objective: The COVID-19 pandemic may cause a major mental health impact. We aimed to identify demographic or clinical factors associated with psychiatric admissions where COVID-19 was attributed to contribute to mental state, compared to admissions which did not., Methods: A retrospective cohort study was undertaken of inpatients admitted to Northern Psychiatric Unit 1, Northern Hospital in Melbourne, Victoria, Australia during 27/02/2020 to 08/07/2020. Data were extracted for participants who identified COVID-19 as a stressor compared to participants who did not. Fisher's exact test and Mann-Whitley rank sum test were used., Results: Thirty six of 242 inpatients reported the COVID-19 pandemic contributed to mental ill health and subsequent admission. Reasons given included social isolation, generalized distress about the pandemic, barriers to support services, disruption to daily routine, impact on employment, media coverage, re-traumatization, cancelled ECT sessions, loss of loved ones, and increased drug use during the lockdown. Chronic medical conditions or psychiatric multimorbidity were positively associated and smoking status was negatively associated with reporting the COVID-19 pandemic as a contributor to mental ill health., Conclusion: Screening and identifying vulnerable populations during and after the global disaster is vital for timely and appropriate interventions to reduce the impact of the pandemic worldwide.

An epithelial-to-mesenchymal transition (EMT) phenotype with cancer stem cell-like properties is a critical feature of aggressive/metastatic tumors, but the mechanism(s) that promote it and its relation to metabolic stress remain unknown. Here we show that Collapsin Response Mediator Protein 2A (CRMP2A) is unexpectedly and reversibly induced in cancer cells in response to multiple metabolic stresses, including low glucose and hypoxia, and inhibits EMT/stemness. Loss of CRMP2A, when metabolic stress decreases (e.g., around blood vessels in vivo) or by gene deletion, induces extensive microtubule remodeling, increased glutamine utilization toward pyrimidine synthesis, and an EMT/stemness phenotype with increased migration, chemoresistance, tumor initiation capacity/growth, and metastatic potential. In a cohort of 27 prostate cancer patients with biopsies from primary tumors and distant metastases, CRMP2A expression decreases in the metastatic versus primary tumors. CRMP2A is an endogenous molecular brake on cancer EMT/stemness and its loss increases the aggressiveness and metastatic potential of tumors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess stress, coping, and resilience among home-quarantined individuals via a community survey during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In this cross-sectional study, a combined list was generated of all contacts of positive COVID-19 cases, traced by a contact tracing team, and international travelers who had entered the country after March 8, 2020 (2 weeks before the air travel shutdown on March 22, 2020 in India). This community-based study was conducted among people who were quarantined in their homes and international travelers who arrived in the country after declaration of lockdown. Stress and coping were assessed via the 12-item General Health Questionnaire, 10-item Perceived Stress Scale, and Brief Resilient Coping Scale. The participants with higher perceived stress scores (≥ 14) were asked to seek help from telemedicine services. Study data were collected from April 8, 2020, to May 20, 2020., Results: The mean age of the 153 study participants was 40.10 years, and 41.8% were women. Poor coping was identified in 25.5% of the sample, and moderate/high stress was present in 49.7%. Significantly higher stress was noted in women ( P  = .007). Higher age, joint family structure, and contacts of COVID cases were significant predictors of moderate/severe perceived stress in the logistic regression., Conclusions: Adequate psychological supportive services should be provided to home-quarantined persons through provision of information, rapid communication, and timely supplies of general and medical items., (© Copyright 2022 Physicians Postgraduate Press, Inc.)

Background: Health-care providers (HCP) engaged in demanding work like being involved in the care of COVID-19 positive and suspected cases are likely to have a lot of stress, anxiety, depression, and other mental health issues. It will be noteworthy to have an idea about the magnitude of the mental health problems in them to formulate effective intervention strategies for their well-being., Aims and Objectives: The aim of this study is to determine whether frontline HCP engaged in the treatment and care of COVID-19 positive and suspect cases experienced increased mental health problems., Methodology: Two hundred and fifty-one frontline HCPs engaged in COVID-19 duty and 97 nonfrontline (controls) HCP were assessed and compared using tools like General Health Questionnaire 12, Hamilton Anxiety Rating Scale, and Hamilton Depression Rating Scale. Appropriate statistical tools such as analysis of variance and Chi-square were used., Results: Frontline HCP who were directly involved in COVID-19 duty had a higher proportion (28.3%) of psychological morbidities as compared to 19.6% among controls; HCP-frontline had significantly 2.17 times chances of having psychological distress compared to HCP controls. Among, HCP-frontline 13.1% had clinical depression, whereas in the HCP control, this was 6.2%. Further, 20.3% of HCP frontline and 10.3% of HCP control had clinical anxiety, and the difference between the two groups was statistically significant ( P = 0.0011)., Conclusion: Frontline HCPs working in demanding work such as COVID-19 patient care are susceptible to psychological distress, anxiety, and depression which warrant urgent attention., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Industrial Psychiatry Journal.)

The prospect of using metal-cored wires instead of solid wires during gas metal arc welding (GMAW) of 2.25 Cr-1.0 Mo steels embraces several challenges. The in-service requirements for the equipment made up of these steels are stringent. The major challenge faced by the manufacturers is temper embrittlement. In the current study, the temper embrittlement susceptibility of the welded joint was ascertained by subjecting it to step cooling heat treatment. A 25 mm thick 2.25 Cr-1.0 Mo weld joint was prepared using a combination of the regulated metal deposition (RMD) and GMAW processes incorporating metal-cored wires. After welding the plates were exposed to post-weld heat treatment followed by a rigorous step cooling heat treatment prescribed by API standards. The temper embrittlement susceptibility of the weld joint was ascertained by Bruscato X-factor as well as by formulating ductile-to-brittle transition temperature (DBTT) curves by carrying out the impact toughness testing at various temperatures. Detailed microscopy and hardness studies were also carried out. It was established from the study that the X-factor value for the welded joint was 15.4. The DBTT for the weld joint was found to occur at -37 °C which was well below 10 °C. Optical microscopy and scanning electron microscopy indicated the presence of carbides and the energy dispersive X-ray spectrometry studies indicated the presence of chromium and manganese-rich carbides along with the presence of sulfur near the grain boundaries. This study establishes a base for the usage of metal-cored wires particularly in high temperature and pressure application of Cr-Mo steels.

Objective: The objective of the study is to predict the early changes in electroencephalography (EEG) at 1 week and its correlation to clinical response at 6 weeks after treatment with atomoxetine in children with ADHD. Method: In 50 children (6-14 years) with ADHD ( Diagnostic and Statistical Manual of Mental Disorders [5th ed.; DSM-5 ]), Vanderbilt ADHD Parent Rating Scale (VADPRS) and Vanderbilt ADHD Teachers Rating Scale (VADTRS) were applied at baseline, 1, 4, and 6 weeks. EEG was recorded using International 10-20 System of electrode placement at baseline and at 1 week after atomoxetine treatment. EEG changes at 1 week after atomoxetine therapy was correlated to clinical response at 6 weeks. Results: Patients were classified as responders or nonresponders based on the VADPRS/VADTRS findings. After 1 week of treatment, responders' theta cordance values were decreased, whereas nonresponders' values didn't decrease significantly. Conclusion: Patients with decreased theta cordance values, especially in the left temporoparietal region, at 1 week were likely to respond to atomoxetine while those without any such change were likely to be nonresponders.

Background: Pain and depression are associated, but it is uncertain if effective pain relief during labor by labor analgesia reduces the incidence of postpartum depression (PPD). This randomized, controlled study assessed whether combined spinal-epidural (CSE) labor analgesia is associated with a decreased risk of PPD. Other reported risk factors for PPD were also assessed., Materials and Methods: Parturients were randomly assigned to either CSE labor analgesia or normal vaginal delivery ( n = 65 each). CSE parturients received 0.5 ml of 0.5% hyperbaric bupivacaine intrathecally and PCEA with continuous infusion of 0.1% levobupivacaine and 2 μg/ml fentanyl @5 ml/h along with patient-controlled boluses with a lockout interval of 15 min. Parturients of both the groups were assessed using Edinburgh Postnatal Depression Scale (EPDS) for depressive symptoms at day 3 and PPD at 6 weeks (primary outcome; defined as EPDS score ≥10 at 6 weeks postpartum). Secondary outcomes included pain scores, maternal satisfaction, and Apgar scores at 1 and 5 min. Parturients were also screened for several risk factors for PPD., Results: Incidence of PPD was 22.3%. The difference in incidence of PPD between the CSE group vs. control group was not significant (27.7% vs. 16.9%; Fisher's exact P = 0.103). Of all the risk factors analyzed in logistic regression model, perceived stress during pregnancy was the only significant predictor of the development of PPD (adjusted Odds Ratio 11.17, 95% Confidence interval 2.86-43.55; P = 0.001)., Conclusion: CSE analgesia in laboring parturients does not reduce PPD at 6 weeks. Instead, perceived high stress during pregnancy appears to be the most important factor., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Saudi Journal of Anesthesia.)

Single ventricle heart defects (SVDs) are congenital disorders that result in a variety of complications, including increased ventricular mechanical strain and mixing of oxygenated and deoxygenated blood, leading to heart failure without surgical intervention. Corrective surgery for SVDs are traditionally handled by the Fontan procedure, requiring a vascular conduit for completion. Although effective, current conduits are limited by their inability to aid in pumping blood into the pulmonary circulation. In this report, we propose an innovative and versatile design strategy for a tissue engineered pulsatile conduit (TEPC) to aid circulation through the pulmonary system by producing contractile force. Several design strategies were tested for production of a functional TEPC. Ultimately, we found that porcine extracellular matrix (ECM)-based engineered heart tissue (EHT) composed of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and primary cardiac fibroblasts (HCF) wrapped around decellularized human umbilical artery (HUA) made an efficacious basal TEPC. Importantly, the TEPCs showed effective electrical and mechanical function. Initial pressure readings from our TEPC in vitro (0.68 mmHg) displayed efficient electrical conductivity enabling them to follow electrical pacing up to a 2 Hz frequency. This work represents a proof of principle study for our current TEPC design strategy. Refinement and optimization of this promising TEPC design will lay the groundwork for testing the construct's therapeutic potential in the future. Together this work represents a progressive step toward developing an improved treatment for SVD patients. STATEMENT OF SIGNIFICANCE: Single Ventricle Cardiac defects (SVD) are a form of congenital disorder with a morbid prognosis without surgical intervention. These patients are treated through the Fontan procedure which requires vascular conduits to complete. Fontan conduits have been traditionally made from stable or biodegradable materials with no pumping activity. Here, we propose a tissue engineered pulsatile conduit (TEPC) for use in Fontan circulation to alleviate excess strain in SVD patients. In contrast to previous strategies for making a pulsatile Fontan conduit, we employ a modular design strategy that allows for the optimization of each component individually to make a standalone tissue. This work sets the foundation for an in vitro, trainable human induced pluripotent stem cell based TEPC., (Copyright © 2019. Published by Elsevier Ltd.)

Competing Interests: There are no conflicts of interest.

Background & Objectives: Substance use disorders are a major public health concern in Punjab. However, reliable estimates of prevalence of substance use disorders are not available for the State. The present study reports estimates of prevalence of substance use disorders in Punjab, conducted as part of National Mental Health Survey, India., Methods: Using multistage stratified random cluster sampling, 2895 individuals from 719 households of 60 clusters (from 4 districts of Punjab) were interviewed. Mini International Neuropsychiatric Interview and Fagerstrom nicotine dependence scale were used to assess substance use disorders., Results: The sample comprised almost equal numbers of males and females. Nearly 80 per cent had less than or equal to high school education, and 70 per cent were married. The weighted prevalence of alcohol and other substance use disorders was 7.9 and 2.48 per cent, respectively. The prevalence of tobacco dependence was 5.5 per cent; 35 per cent households had one person with substance use disorder. The prevalence was highest in the productive age group (30-39 yr), urban metro and less educated persons. The prevalence of alcohol and other substance use disorders was much higher in Punjab as compared to other States where survey was done. Tobacco dependence was lowest in Punjab. Majority (87%) of the persons with substance use disorders did not suffer from any other mental disorder. Treatment gap was 80 per cent., Interpretation & Conclusions: Punjab has a high burden of substance use disorders. The estimates will help clinicians and policymakers to plan the strategies against the menace of substance use disorders effectively., Competing Interests: None

Undiagnosed liver disease remains an unmet medical need in pediatric hepatology, including children with high gamma-glutamyltransferase (GGT) cholestasis. Here, we report whole-exome sequencing of germline DNA from 2 unrelated children, both offspring of consanguineous union, with neonatal cholestasis and high GGT of unclear etiology. Both children had a rare homozygous damaging mutation (p.Arg219* and p.Val204Met) in kinesin family member 12 ( KIF12 ). Furthermore, an older sibling of the child homozygous for p.Val204Met missense mutation, who was also found to have cholestasis, had the same homozygous mutation, thus identifying the cause of the underlying liver disease. Conclusion : Our findings implicate rare homozygous mutations in KIF12 in the pathogenesis of cholestatic liver disease with high GGT in 3 previously undiagnosed children.

Understanding the burden and pattern of mental disorders as well as mapping the existing resources for delivery of mental health services in India, has been a felt need over decades. Recognizing this necessity, the Ministry of Health and Family Welfare, Government of India, commissioned the National Mental Health Survey (NMHS) in the year 2014-15. The NMHS aimed to estimate the prevalence and burden of mental health disorders in India and identify current treatment gaps, existing patterns of health-care seeking, service utilization patterns, along with an understanding of the impact and disability due to these disorders. This paper describes the design, steps and the methodology adopted for phase 1 of the NMHS conducted in India. The NMHS phase 1 covered a representative population of 39,532 from 12 states across 6 regions of India, namely, the states of Punjab and Uttar Pradesh (North); Tamil Nadu and Kerala (South); Jharkhand and West Bengal (East); Rajasthan and Gujarat (West); Madhya Pradesh and Chhattisgarh (Central) and Assam and Manipur (North East). The NMHS of India (2015-16) is a unique representative survey which adopted a uniform and standardized methodology which sought to overcome limitations of previous surveys. It employed a multi-stage, stratified, random cluster sampling technique, with random selection of clusters based on Probability Proportionate to Size. It was expected that the findings from the NMHS 2015-16 would reveal the burden of mental disorders, the magnitude of the treatment gap, existing challenges and prevailing barriers in the mental-health delivery systems in the country at a single point in time. It is hoped that the results of NMHS will provide the evidence to strengthen and implement mental health policies and programs in the near future and provide the rationale to enhance investment in mental health care in India. It is also hoped that the NMHS will provide a framework for conducting similar population based surveys on mental health and other public health problems in low and middle-income countries., Competing Interests: The authors have declared that no competing interests exist.

Background: Mental illness results in a plethora of distressing issues, has tremendous socio-economic impact and causes socio-occupational dysfunction in the individual as well as the caregivers. There is a felt need to explore the disability caused by mental illness and the associated socio-economic impact at the population level in a developing nation like India., Aims: To elucidate the disability and socio-economic impact associated with mental illness at the individual and household levels for the state of Punjab in India., Method: This was a multisite cross-sectional study carried out during 2015-2016 (as a part of the National Mental Health Survey of India) in three districts and one urban metro area of Punjab. The sample was selected using multi-stage, stratified, random cluster sampling technique, with random selection based on Probability Proportionate to Size (PPS) at different stages. A validated set of questions was used to assess the socio-economic impact of mental illness and the Sheehan Disability Scale was used to document self-perceived disability among individuals with mental morbidity. Median (IQR) and proportions were used to summarize quantitative and qualitative data, respectively Results: Subjects with any mental morbidity reported disability of varying severities across different domains of life; family life was affected the most (70.1%). One in every six persons reported that their mental illness interfered with their daily activities to a large extent. Economic burden was high and a typical family would spend about INR 1500/month (US$23) towards the treatment of its member with mental morbidity. Family members had to forego their work for at least 7 days in 3 months to take care of their relative with mental illness., Conclusion: Mental illness causes disability in the individual and has tremendous socio-economic impact on the family, incapacitating a family's productivity to a large extent and thus affecting the society.

Background: The need for effective and accepted method for opioid detoxification is ever increasing. Sublingual buprenorphine and oral clonidine have been effective in opioid detoxification. As often, there is a great variation in the dosage of buprenorphine and clonidine prescribed by the clinicians; hence, there is a felt need to find an effective dosage for a favorable outcome of opioid detoxification., Objective: The objective of this study was to compare the effectiveness of different doses of sublingual buprenorphine and clonidine in opioid detoxification., Materials and Methods: A total of 100 patients with the diagnosis of opioid dependence as per the international classification of diseases-10 criteria were recruited for this study. Participants were assigned randomly into four groups - low-dose clonidine, high-dose clonidine, low-dose sublingual buprenorphine, and high sublingual dose buprenorphine using a computer-generated random number table, resulting in 25, 26, 23, and 26 patients in each group, respectively., Results: The four groups had comparable scores on all the items of "stages of change readiness and treatment eagerness scale" for the assessment of motivation at baseline. Progressive decrease in withdrawal score was seen in all the groups on "clinical opiate withdrawal scale" and "subjective opiate withdrawal scale.", Conclusion: From the current study, we can infer that both low and high doses of buprenorphine and clonidine are comparable regarding controlling withdrawal., Competing Interests: There are no conflicts of interest.

Chronic iron overload results in heart and liver diseases and is a common cause of morbidity and mortality in patients with genetic hemochromatosis and secondary iron overload. We investigated the role of tissue inhibitor of metalloproteinase 3 (TIMP3) in iron overload-mediated tissue injury by subjecting male mice lacking Timp3 ( Timp3 -/- ) and wild-type (WT) mice to 12 wk of chronic iron overload. Whereas WT mice with iron overload developed diastolic dysfunction, iron-overloaded Timp3 -/- mice showed worsened cardiac dysfunction coupled with systolic dysfunction. In the heart, loss of Timp3 was associated with increased myocardial fibrosis, greater Timp1, matrix metalloproteinase ( Mmp) 2, and Mmp9 expression, increased active MMP-2 levels, and gelatinase activity. Iron overload in Timp3 -/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin. Loss of Timp3 enhanced the hepatic inflammatory response to iron overload, leading to greater neutrophil and macrophage infiltration and increased hepatic fibrosis. Expression of inflammation-related MMPs (MMP-12 and MMP-13) and inflammatory cytokines (IL-1β and monocyte chemoattractant protein-1) was elevated to a greater extent in iron-overloaded Timp3 -/- livers. Gelatin zymography demonstrated equivalent increases in MMP-2 and MMP-9 levels in WT and Timp3 -/- iron-overloaded livers. Loss of Timp3 enhanced the susceptibility to iron overload-mediated heart and liver injury, suggesting that Timp3 is a key protective molecule against iron-mediated pathology. NEW & NOTEWORTHY In mice, loss of tissue inhibitor of metalloproteinase 3 ( Timp3) was associated with systolic and diastolic dysfunctions, twofold higher hepatic iron accumulation (attributable to constituently lower levels of ferroportin), and increased hepatic inflammation. Loss of Timp3 enhanced the susceptibility to iron overload-mediated injury, suggesting that Timp3 plays a key protective role against iron-mediated pathology.

Background: A substantial proportion of euthymic bipolar disorder patients have neuropsychological impairment which can have a significant impact on the overall functional recovery., Materials and Methods: A total of 60 bipolar disorder patients, currently in euthymic phase for the last 3 months with minimum duration of illness 2 years and current Young Mania Rating Scale <7 and Hamilton Depression Rating Scale <6, currently on medications were administrated various neuropsychological tests., Results: Approximately half of the patients have neuropsychological impairments in the areas of mental speed, sustained attention, verbal fluency, working memory, set shifting, verbal and visual memory, and visual-constructional ability., Conclusion: Findings of the current study provides evidence of neuropsychological impairment in euthymic bipolar disorder patients, and type of medications also has an impact on neuropsychological functions., Competing Interests: There are no conflicts of interest.

Iron-overload cardiomyopathy is prevalent on a worldwide basis and is a major comorbidity in patients with genetic hemochromatosis and secondary iron overload. Therapies are limited in part due to lack of a valid preclinical model, which recapitulates advanced iron-overload cardiomyopathy. Male hemojuvelin (HJV) knockout (HJVKO) mice, which lack HJV, a bone morphogenetic co-receptor protein required for hepcidin expression and systemic iron homeostasis, were fed a high-iron diet starting at 4 weeks of age for a duration of 1 year. Aged HJVKO mice in response to iron overload showed increased myocardial iron deposition and mortality coupled with oxidative stress and myocardial fibrosis culminating in advanced iron-overload cardiomyopathy. In a parallel group, iron-overloaded HJVKO mice received resveratrol (240 mg/day) at 9 months of age until 1 year of age. Echocardiography and invasive pressure-volume (PV) loop analyses revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. In addition, myocardial sarcoplasmic reticulum Ca 2+ ATPase (SERCa2a) levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCa2a levels and suppressed up-regulation of the sodium-calcium exchanger (NCX1). Further, iron-mediated oxidative stress and myocardial fibrosis were suppressed by resveratrol treatment with concomitant activation of the p-Akt and p-AMP-activated protein kinase (AMPK) signaling pathways. A combination of ageing and high-iron diet in male HJVKO mice results in a valid preclinical model that recapitulates iron-overload cardiomyopathy in humans. Resveratrol therapy resulted in normalization of cardiac function demonstrating that resveratrol represents a feasible therapeutic intervention to reduce the burden of iron-overload cardiomyopathy., (© 2018 The Author(s).)

Background: Knowledge of the prevalence of mental disorders is essential for setting up services and allocation of resources. Existing studies suffer from methodological problems which limit their utility and generalizability. There was a long felt need to conduct a scientifically robust study in different regions of India to have national prevalence rates., Aims: This study aims to estimate the prevalence of mental disorders in a representative population of Punjab as a part of the National Mental Health Survey., Settings and Design: Community-based survey carried out in rural and urban areas of Punjab using multistage, stratified, random cluster sampling technique and random selection was based on Probability Proportion to Size., Materials and Methods: The survey was conducted in 60 clusters of 4 districts (Faridkot, Ludhiana, Moga, and Patiala) of Punjab. Mini-International Neuropsychiatric Interview adult version 6.0 for mental morbidity, case definition for generalized tonic-clonic seizure, an expansion of the Fagerström Nicotine Dependence Scale for tobacco use and screener for intellectual disability were used. Appropriate statistical methods were applied., Results: A total of 2895 respondents aged >18 years from 719 households were interviewed. The prevalence of lifetime and current mental morbidity was 17.94% and 13.42%, respectively. Higher prevalence of mental morbidity was found among persons aged >60 years and those belonging to lower income group and rural population., Conclusions: The prevalence of mental morbidity is high in the population. The findings give a clear picture of magnitude of the problem and will help policy planners to tackle the situation which looks grave and warrants immediate intervention., Competing Interests: There are no conflicts of interest.

Objectives: To compare the efficacy and tolerability of clozapine and quetiapine in patients with treatment-resistant schizophrenia (TRS)., Patients and Methods: In this prospective, randomized, open label study of 14 weeks, 53 patients with schizophrenia diagnosed as per ICD-10 and fulfilling the modified version of Conley and Kelly's criteria of TRS were randomly assigned to receive clozapine or quetiapine as per a computer-generated random table. After 2-weeks of dose-titration phase, doses were fixed at minimum therapeutic dose and subsequently adjusted according to the clinical improvement. All patients received dosage of respective drug in therapeutic range. 13 patients were lost to follow up. Treatment efficacy and side effects were evaluated with standardized rating scales., Results: Clozapine group (reduction in total score: mean=14.45, SD=10.39) had significantly greater reductions (P=0.004; CI=3.541-17.059) in the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive subscale and PANSS general psychopathology subscale at 14 weeks in comparison to the quetiapine group (reduction in total score: mean=4.15, SD=10.71). Significant reduction in PANSS negative subscale was seen with both drugs but no significant difference was present between the two drugs. At 14 weeks, 30% patients in clozapine group and 15% patients in quetiapine group showed response. Clozapine led to significantly greater side effects (P< 0.001, CI=2.241-6.059) on Glassgow Antipsychotic Side-effect Scale (GASS) than quetiapine., Conclusions: Clozapine was found to be more efficacious than quetiapine in patients with TRS but was associated with greater side effects. Both the drugs were found to be equally effective in reducing the negative symptoms., Competing Interests: There are no conflicts of interest.

Background: Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood., Methods and Results: Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17β-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury., Conclusions: Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17β-estradiol therapy was protective in male iron-overloaded mice., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in developed countries. NAFLD describes a wide range of liver pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is distinguished from simple steatosis by inflammation, cell death and fibrosis. In this study we found that mice lacking triacylglycerol hydrolase (TGH, also known as carboxylesterase 3 or carboxylesterase 1d) are protected from high-fat diet (HFD) - induced hepatic steatosis via decreased lipogenesis, increased fatty acid oxidation and improved hepatic insulin sensitivity. To examine the effect of the loss of TGH function on the more severe NAFLD form NASH, we ablated Tgh expression in two independent NASH mouse models, Pemt(-/-) mice fed HFD and Ldlr(-/-) mice fed high-fat, high-cholesterol Western-type diet (WTD). TGH deficiency reduced liver inflammation, oxidative stress and fibrosis in Pemt(-/-) mice. TGH deficiency also decreased NASH in Ldlr(-/-) mice. Collectively, these findings indicate that TGH deficiency attenuated both simple hepatic steatosis and irreversible NASH.

Background & Aims: Abnormal iron metabolism and hepatic iron-overload is a major cause of liver injury and in the development of chronic liver diseases. Iron-overload-mediated liver disease leads to end-stage cirrhosis and/or hepatocellular carcinoma., Methods: Using a genetic hemochromatosis (hemojuvelin knockout mice) and non-genetic (secondary iron-overload) murine models of hepatic iron-overload, we elucidated the mechanism of hepatic iron injury and the therapeutic effects of resveratrol., Results: Hepatic iron-overload was associated with hepatosplenomegaly, increased oxidative stress, hepatic fibrosis, and inflammation, and a pro-apoptotic state which was markedly corrected by resveratrol therapy. Importantly our aging studies with the hemojuvelin knockout mice showed advanced liver disease in association with steatosis in the absence of a diabetic state which recapitulates the essential pathological features seen in clinical iron-overload. Chronic hepatic iron-overload showed increased nuclear localization of acetylated Forkhead fox-O-1 (FoxO1) transcription factor whereas resveratrol dietary intervention reversed the acetylation of FoxO1 in association with increased SIRT1 levels which together with its pleotropic antioxidant properties are likely key mechanisms of its therapeutic action. Importantly, resveratrol treatment did not affect the degree of hepatic iron-overload but rather direct protects the liver from iron-mediated injury., Conclusions: Our findings illustrate a novel and definitive therapeutic action of resveratrol and represent an economically feasible therapeutic intervention to treat hepatic iron-overload and liver disease., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Iron-overload cardiomyopathy is a prevalent cause of heart failure on a world-wide basis and is a major cause of mortality and morbidity in patients with secondary iron-overload and genetic hemochromatosis. We investigated the therapeutic effects of resveratrol in acquired and genetic models of iron-overload cardiomyopathy. Murine iron-overload models showed cardiac iron-overload, increased oxidative stress, altered Ca(2+) homeostasis and myocardial fibrosis resulting in heart disease. Iron-overload increased nuclear and acetylated levels of FOXO1 with corresponding inverse changes in SIRT1 levels in the heart corrected by resveratrol therapy. Resveratrol, reduced the pathological remodeling and improved cardiac function in murine models of acquired and genetic iron-overload at varying stages of iron-overload. Echocardiography and hemodynamic analysis revealed a complete normalization of iron-overload mediated diastolic and systolic dysfunction in response to resveratrol therapy. Myocardial SERCA2a levels were reduced in iron-overloaded hearts and resveratrol therapy restored SERCA2a levels and corrected altered Ca(2+) homeostasis. Iron-mediated pro-oxidant and pro-fibrotic effects in human and murine cardiomyocytes and cardiofibroblasts were suppressed by resveratrol which correlated with reduction in iron-induced myocardial oxidative stress and myocardial fibrosis. Resveratrol represents a clinically and economically feasible therapeutic intervention to reduce the global burden from iron-overload cardiomyopathy at early and chronic stages of iron-overload.

Unlabelled: Activation of the angiotensin 1-7/Mas receptor (MasR) axis counteracts angiotensin II (Ang II)-mediated cardiovascular disease. Recombinant human angiotensin-converting enzyme 2 (rhACE2) generates Ang 1-7 from Ang II. We hypothesized that the therapeutic effects of rhACE2 are dependent on Ang 1-7 action. Wild type male C57BL/6 mice (10-12 weeks old) were infused with Ang II (1.5 mg/kg/d) and treated with rhACE2 (2 mg/kg/d). The Ang 1-7 antagonist, A779 (200 ng/kg/min), was administered to a parallel group of mice. rhACE2 prevented Ang II-induced hypertrophy and diastolic dysfunction while A779 prevented these beneficial effects and precipitated systolic dysfunction. rhACE2 effectively antagonized Ang II-mediated myocardial fibrosis which was dependent on the action of Ang 1-7. Myocardial oxidative stress and matrix metalloproteinase 2 activity was further increased by Ang 1-7 inhibition even in the presence of rhACE2. Activation of Akt and endothelial nitric oxide synthase (eNOS) by rhACE2 were suppressed by the antagonism of Ang 1-7 while the activation of pathological signaling pathways was maintained. Blocking Ang 1-7 action prevents the therapeutic effects of rhACE2 in the setting of elevated Ang II culminating in systolic dysfunction. These results highlight a key cardioprotective role of Ang 1-7, and increased Ang 1-7 action represents a potential therapeutic strategy for cardiovascular diseases., Key Messages: Activation of the renin-angiotensin system (RAS) plays a key pathogenic role in cardiovascular disease. ACE2, a monocarboxypeptidase, negatively regulates pathological effects of Ang II. Antagonizing Ang 1-7 prevents the therapeutic effects of recombinant human ACE2. Our results highlight a key protective role of Ang 1-7 in cardiovascular disease.

Background: Depression is common among diabetes, and is associated with poor outcomes. However, the data on this important relationship are limited from India., Objective: The aim was to estimate the prevalence of depression in patients with diabetes and to determine the association of depression with age, sex, and other related parameters., Materials and Methods: The study was cross-sectional carried out in endocrinology clinic of tertiary care hospital in North India. Cases were patients with type 2 diabetes mellitus (T2DM) above 30 years of age. Depression was assessed using the patient health questionairre-9 (PHQ-9). The relationship with sociodemographic profile, duration of diabetes, hypertension and microvascular complications was also analyzed., Results: Seventy-three subjects (57.5% females) with mean age 50.8 ± 9.2 years were evaluated. The prevalence of depression was 41%. Severe depression (PHQ score ≥15) was present in 3 (4%) subjects, moderate depression (PHQ score ≥10) in 7 (10%) subjects, and mild depression was present in 20 (27%) of subjects. Depression was significantly more prevalent in rural subjects (57%) when compared to urban ones (31%, P = 0.049). Depression increased with presence of microvascular complications, fasting plasma glucose, hypertension, but the differences were not statistically significant., Conclusions: Our study demonstrates higher prevalence of depression in patients with type 2 diabetes. Apart from being belonging to the rural area, no other factor was significantly associated with depression. Therefore, depression should be assessed in each and every patient, irrespective of other factors.

Background: Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload-induced HF and identified physiological and molecular mechanisms contributing to this., Methods and Results: C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment., Conclusions: Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism., (© 2014 American Heart Association, Inc.)

Objective: Population-based information on causes of death (CoD) by age, sex, and area is critical for countries with limited resources to identify and address key public health issues. This study analysed the demographic surveillance and verbal autopsy (VA) data to estimate age- and sex-specific mortality rates and cause-specific mortality fractions in two well-defined rural populations within the demographic surveillance system in Abhoynagar and Mirsarai subdistricts, located in different climatic zones., Design: During 2004-2010, the sample demographic surveillance system registered 1,384 deaths in Abhoynagar and 1,847 deaths in Mirsarai. Trained interviewers interviewed the main caretaker of the deceased with standard VA questionnaires to record signs and symptoms of diseases or conditions that led to death and health care experiences before death. The computer-automated InterVA-4 method was used to analyse VAs to determine probable CoD., Results: Age- and sex-specific death rates revealed a higher neonatal mortality rate in Abhoynagar than Mirsarai, and death rates and sex ratios of male to female death rates were higher in the ages after infancy. Communicable diseases (CDs) accounted for 16.7% of all deaths in Abhoynagar and 21.2% in Mirsarai--the difference was due mostly to more deaths from acute respiratory infections, pneumonia, and tuberculosis in Mirsarai. Non-communicable diseases (NCDs) accounted for 56.2 and 55.3% of deaths in each subdistrict, respectively, with leading causes being stroke (16.5-19.3%), neoplasms (13.2% each), cardiac diseases (8.9-11.6%), chronic obstructive pulmonary diseases (5.1-6.3%), diseases of the digestive system (3.1-4.1%), and diabetes (2.8-3.5%), together accounting for 49.2-51.2% points of the NCD deaths in the two subdistricts. Injury and other external causes accounted for another 7.5-7.7% deaths, with self-harm being higher among females in Abhoynagar., Conclusions: The computer-automated coding of VA to determine CoD reconfirmed that NCDs were the leading CoD with some differences between the sites. Incorporating VA into the national sample vital registration system can help policy makers to identify the leading CoDs for public health planning.

Drug-induced galactorrhea has been reported with agents such as antidopaminergic antiemetics, antipsychotics, etc., with few case reports of galactorrhea with selective serotonin reuptake inhibitors, including paroxetine, being reported in last few decades. Prolactin levels have been found to be either raised or normal in these cases. We here report a case of paroxetine induced galactorrhea in a 48-year-old female patient of obsessive compulsive disorder, having hyperprolactinemic and euprolactinemic galactorrhea at different time with a pituitary incidentaloma.

Context: Attitude of fresh graduates toward psychiatric patients is important to bridge the treatment gap due to mental illness. Psychiatry as a subject has been neglected in the undergraduates of MBBS., Aims: (1) To compare the attitude of medical students and interns in a medical college toward mental illness and psychiatry. (2) To assess the impact of psychiatric training on attitude toward the mentally ill person and mental illness., Settings and Design: Cross-sectional, single assessment study conducted at a tertiary hospital., Subjects and Methods: Participants consisted of medical students of 1(st) and 2(nd) year who didn't have any exposure to psychiatry and interns, who had completed their compulsory 2 week clinical posting in psychiatry. Participants were individually administered sociodemographic proforma, General Health Questionnaire-12 (GHQ-12), opinion about mental illness (OMI) scale, and attitude to psychiatry-29 (ATP-29) scale., Statistical Analysis: Standard descriptive statistics (mean, percentage), Chi-square test., Results: A total of 135 participants formed the study sample, with 48, 47, and 40 participants from 1(st) year, 2(nd) year and interns, respectively. Mean GHQ score was 14.03 for the entire sample. There was better outlook of interns toward psychiatry and patients with mental disorders in comparison to fresh graduate students in some areas. Overall, negative attitude toward mental illness and psychiatry was reflected., Conclusions: Exposure to psychiatry as per the current curriculum seems to have a limited influence in bringing a positive change in OMI and psychiatry.

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs). While TIMP2 and TIMP3 inhibit MMPs, TIMP3 also inhibits activation of pro-MMP2, whereas TIMP2 promotes it. Here we assessed the differential role of TIMP2 and TIMP3 in renal injury using the unilateral ureteral obstruction model. Gene microarray assay showed that post obstruction, the lack of TIMP3 had a greater impact on gene expression of intermediate, late injury- and repair-induced transcripts, kidney selective transcripts, and solute carriers. Renal injury in TIMP3(-/-), but not in TIMP2(-/-), mice increased the expression of collagen type I/III, connective tissue growth factor, transforming growth factor-β, and the downstream Smad2/3 pathway. Interestingly, ureteral obstruction markedly increased MMP2 activation in the kidneys of TIMP3(-/-) mice, which was completely blocked in the kidneys of TIMP2(-/-) mice. These changes are consistent with enhanced renal tubulointerstitial fibrosis in TIMP3(-/-) and its reduction in TIMP2(-/-) mice. The activities of tumor necrosis factor-α-converting enzyme, caspase-3, and mitogen-activated kinases were elevated in the kidneys of TIMP3(-/-) mice but not TIMP2(-/-) mice, suggesting enhanced activation of apoptotic and pathological signaling pathways only in the obstructed kidney of TIMP3(-/-) mice. Thus, TIMP2 and TIMP3 play differential and contrasting roles in renal injury: TIMP3 protects from damage, whereas TIMP2 promotes injury through MMP2 activation.