Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.

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.

Assessment tools for complex post traumatic stress disorder: a systematic review.

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.

Validated and reliable screening tools are required to accurately detect and manage complex post traumatic stress disorder (CPTSD)The International Trauma Questionnaire (ITQ) is the most thoroughly investigated, validated across different populations, and is a freely available and convenient tool for screening within clinical settingsIn circumstances where self-report measures are inappropriate, the ITI, SOTS, and COPISAC are interview tools which detect CPTSD, but require further validation and should be used alongside clinical history and examinationFurther research is needed to ensure appropriate assessment tools for the detection and diagnosis of CPTSD are available.

Demographic and clinical factors associated with psychiatric inpatient admissions during the COVID-19 pandemic.

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.

Prevalence of vitamin D deficiency among psychiatric inpatients: a systematic review.

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.

Psychological stress among anesthesia residents during COVID-19 pandemic and how to mitigate them.

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.

Prevalence of substance use disorders in Punjab: Findings from National Mental Health Survey.

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.

TIMP3 deficiency exacerbates iron overload-mediated cardiomyopathy and liver disease.

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-1ß 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.

Resveratrol mediates therapeutic hepatic effects in acquired and genetic murine models of iron-overload.

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.

Loss of p47phox subunit enhances susceptibility to biomechanical stress and heart failure because of dysregulation of cortactin and actin filaments.

RATIONALE: The classic phagocyte nicotinamide adenine dinucleotide phosphate oxidase (gp91(phox) or Nox2) is expressed in the heart. Nox2 activation requires membrane translocation of the p47(phox) subunit and is linked to heart failure. We hypothesized that loss of p47(phox) subunit will result in decreased reactive oxygen species production and resistance to heart failure. OBJECTIVE: To define the role of p47(phox) in pressure overload-induced biomechanical stress. METHODS AND RESULTS: Eight-week-old male p47(phox) null (p47(phox) knockout [KO]), Nox2 null (Nox2KO), and wild-type mice were subjected to transverse aortic constriction-induced pressure overload. Contrary to our hypothesis, p47(phox)KO mice showed markedly worsened systolic dysfunction in response to pressure overload at 5 and 9 weeks after transverse aortic constriction compared with wild-type-transverse aortic constriction mice. We found that biomechanical stress upregulated N-cadherin and ß-catenin in p47(phox)KO hearts but disrupted the actin filament cytoskeleton and reduced phosphorylation of focal adhesion kinase. p47(phox) interacts with cytosolic cortactin by coimmunoprecipitation and double immunofluorescence staining in murine and human hearts and translocated to the membrane on biomechanical stress where cortactin interacted with N-cadherin, resulting in adaptive cytoskeletal remodeling. However, p47(phox)KO hearts showed impaired interaction of cortactin with N-cadherin, resulting in loss of biomechanical stress-induced actin polymerization and cytoskeletal remodeling. In contrast, Nox2 does not interact with cortactin, and Nox2-deficient hearts were protected from pressure overload-induced adverse myocardial and intracellular cytoskeletal remodeling. CONCLUSIONS: We showed a novel role of p47(phox) subunit beyond and independent of nicotinamide adenine dinucleotide phosphate oxidase activity as a regulator of cortactin and adaptive cytoskeletal remodeling, leading to a paradoxically enhanced susceptibility to biomechanical stress and heart failure.

TIMP2 and TIMP3 have divergent roles in early renal tubulointerstitial injury.

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-ß, 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.

Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor axis.

RATIONALE: Diabetic cardiovascular complications are reaching epidemic proportions. Angiotensin-converting enzyme-2 (ACE2) is a negative regulator of the renin-angiotensin system. We hypothesize that loss of ACE2 exacerbates cardiovascular complications induced by diabetes. OBJECTIVE: To define the role of ACE2 in diabetic cardiovascular complications. METHODS AND RESULTS: We used the well-validated Akita mice, a model of human diabetes, and generated double-mutant mice using the ACE2 knockout (KO) mice (Akita/ACE2(-/y)). Diabetic state was associated with increased ACE2 in Akita mice, whereas additional loss of ACE2 in these mice leads to increased plasma and tissue angiotensin II levels, resulting in systolic dysfunction on a background of impaired diastolic function. Downregulation of SERCA2 and lipotoxicity were equivalent in Akita and Akita/ACE2KO hearts and are likely mediators of the diastolic dysfunction. However, greater activation of protein kinase C and loss of Akt and endothelial nitric oxide synthase phosphorylation occurred in the Akita/ACE2KO hearts. Systolic dysfunction in Akita/ACE2KO mice was linked to enhanced activation of NADPH oxidase and metalloproteinases, resulting in greater oxidative stress and degradation of the extracellular matrix. Impaired flow-mediated dilation in vivo correlated with increased vascular oxidative stress in Akita/ACE2KO mice. Treatment with the AT1 receptor blocker, irbesartan rescued the systolic dysfunction, normalized altered signaling pathways, flow-mediated dilation, and the increased oxidative stress in the cardiovascular system. CONCLUSIONS: Loss of ACE2 disrupts the balance of the renin-angiotensin system in a diabetic state and leads to an angiotensin II/AT1 receptor-dependent systolic dysfunction and impaired vascular function. Our study demonstrates that ACE2 serves as a protective mechanism against diabetes-induced cardiovascular complications.

Quality of patient-oriented online information on treatment of dementia: A comparative assessment of web pages in English and Hindi language.

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.

Electroconvulsive Therapy in Transgender and Gender Diverse Population: A Case Report and Review of Literature.

Objective: Present a case of a transgender and gender diverse (TGD) individual receiving gender affirming hormone therapy (GAHT) who presented with first episode bipolar mania and received electroconvulsive therapy (ECT). To understand the safety and efficacy of ECT in the TGD population including those receiving GAHT through literature review. Materials and Methods: Case report using informed consent from an individual TGD patient who received ECT. A review of the literature was conducted using PubMed, Embase, and Medline. Results: The case illustrated safe and effective ECT use in a TGD individual receiving GAHT. Eight studies were reviewed. GAHT has been reported to interfere with certain anaesthetic agents used in ECT. ECT appeared to be a safe and effective treatment in the TGD samples in those studies. Conclusion: There is limited literature on the safety and efficacy of ECT for TGD individuals receiving GAHT. More research is required to address mental health inequalities in this population and to support safe and effective gender affirming treatment modalities.

Fishbone perforating Meckel's diverticulum: an acute appendicitis mimicker.

Perforation of Meckel's diverticulum by a foreign body is rare, but when it occurs, it can mimic acute appendicitis, leading to diagnostic challenges. We present a case of a 45-year-old male initially diagnosed with acute appendicitis, but intra-operative exploration revealed a perforated Meckel's diverticulum with a fish bone. Meckel's diverticulum perforation remains diagnostically elusive, highlighting the need for intra-operative vigilance in cases of inconsistent findings like the presence of bilious fluid in the abdominal cavity. This case report underscores the importance of considering perforated Meckel's diverticulum in the differential diagnosis of right iliac fossa pain and the necessity of surgical exploration for atypical presentations to ensure timely diagnosis and appropriate management.

Inventory model for green products with payment strategy, selling price and green level dependent demand using teaching learning based optimization algorithm.

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.

Loss of Timp3 gene leads to abdominal aortic aneurysm formation in response to angiotensin II.

Aortic aneurysm is dilation of the aorta primarily due to degradation of the aortic wall extracellular matrix (ECM). Tissue inhibitors of metalloproteinases (TIMPs) inhibit matrix metalloproteinases (MMPs), the proteases that degrade the ECM. Timp3 is the only ECM-bound Timp, and its levels are altered in the aorta from patients with abdominal aortic aneurysm (AAA). We investigated the causal role of Timp3 in AAA formation. Infusion of angiotensin II (Ang II) using micro-osmotic (Alzet) pumps in Timp3(-/-) male mice, but not in wild type control mice, led to adverse remodeling of the abdominal aorta, reduced collagen and elastin proteins but not mRNA, and elevated proteolytic activities, suggesting excess protein degradation within 2 weeks that led to formation of AAA by 4 weeks. Intriguingly, despite early up-regulation of MMP2 in Timp3(-/-)Ang II aortas, additional deletion of Mmp2 in these mice (Timp3(-/-)/Mmp2(-/-)) resulted in exacerbated AAA, compromised survival due to aortic rupture, and inflammation in the abdominal aorta. Reconstitution of WT bone marrow in Timp3(-/-)/Mmp2(-/-) mice reduced inflammation and prevented AAA in these animals following Ang II infusion. Treatment with a broad spectrum MMP inhibitor (PD166793) prevented the Ang II-induced AAA in Timp3(-/-) and Timp3(-/-)/Mmp2(-/-) mice. Our study demonstrates that the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and AAA. Hence, replenishing TIMP3, a physiological inhibitor of a number of metalloproteinases, could serve as a therapeutic approach in limiting AAA development or expansion.

Treatment gap for mental and behavioral disorders in Punjab.

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.

Endothelin Receptor Blocker Reverses Breast Cancer-Induced Cardiac Remodeling.

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).

Loss of TIMP3 selectively exacerbates diabetic nephropathy.

Diabetic nephropathy is the most common cause of end-stage renal disease. Polymorphism in the tissue inhibitor of metalloproteinase-3 (TIMP3) gene, and the ECM-bound inhibitor of matrix metalloproteinases (MMPs), has been linked to diabetic nephropathy in humans. To elucidate the mechanism, we generated double mutant mice in which the TIMP3 gene was deleted in the genetic diabetic Akita mouse background. The aggravation of diabetic injury occurred in the absence of worsening of hypertension or hyperglycemia. In fact, myocardial TIMP3 levels were not affected in Akita hearts, and cardiac diastolic and systolic function remained unchanged in the double mutant mice. However, TIMP3 levels increased in Akita kidneys and deletion of TIMP3 exacerbated the diabetic renal injury in the Akita mouse, characterized by increased albuminuria, mesangial matrix expansion, and kidney hypertrophy. The progression of diabetic renal injury was accompanied by the upregulation of fibrotic and inflammatory markers, increased production of reactive oxygen species and NADPH oxidase activity, and elevated activity of TNF-α-converting enzyme (TACE) in the TIMP3(-/-)/Akita kidneys. Moreover, while the elevated phospho-Akt (S473 and T308) and phospho-ERK1/2 in the Akita mice was not detected in the TIMP3(-/-)/Akita kidneys, PKCß1 (but not PKCα) was markedly elevated in the double mutant kidneys. Our data provide definitive evidence for a critical and selective role of TIMP3 in diabetic renal injury consistent with gene expression findings from human diabetic kidneys.

Role of ACE2 in diastolic and systolic heart failure.

A novel angiotensin-converting enzyme (ACE) homolog, named ACE2, is a monocarboxypeptidase which metabolizes several peptides. ACE2 degrades Angiotensin (Ang) II, a peptide with vasoconstrictive/proliferative effects, to generate Ang-(1-7), which acting through its receptor Mas exerts vasodilatory/anti-proliferative actions. In addition, as ACE2 is a multifunctional enzyme and its actions on other vasoactive peptides can also contribute to its vasoactive effects including the apelin-13 and apelin-17 peptides. The discovery of ACE2 corroborates the establishment of two counter-regulatory arms within the renin-angiotensin system. The first one is formed by the classical pathway involving the ACE-Ang II-AT(1) receptor axis and the second arm is constituted by the ACE2-Ang 1-7/Mas receptor axis. Loss of ACE2 enhances the adverse pathological remodeling susceptibility to pressure-overload and myocardial infarction. ACE2 is also a negative regulator of Ang II-induced myocardial hypertrophy, fibrosis, and diastolic dysfunction. The ACE2-Ang 1-7/Mas axis may represent new possibilities for developing novel therapeutic strategies for the treatment of hypertension and cardiovascular diseases. In this review, we will summarize the biochemical and pathophysiological aspects of ACE2 with a focus on its role in diastolic and systolic heart failure.