Cathepsin S As an Inhibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease

Cardiovascular disease (CVD) is responsible for the majority of deaths in the developed world. Particularly, in patients with chronic kidney disease (CKD), the imbalance of calcium and phosphate may lead to the acceleration of both vascular and valve inflammation and calcification. One in two patients with CKD are reported as dying from cardiovascular causes due to the resulting acceleration in the development of atherosclerosis plaques. In addition, CKD patients on hemodialysis are prone to aortic valve calcification and often need valve replacement before kidney transplantation. The lysosomal proteases, cathepsins, are composed of 11 cysteine members (cathepsin B, C, F, H, K, L, O, S, V, W, and Z), as well as serine proteases cathepsin A and G, which cleave peptide bonds with serine as the amino acid, and aspartyl proteases D and E, which use an activated water molecule bound to aspartate to break peptide substrate. Cysteine proteases, also known as thiol proteases, degrade protein via the deprotonation of a thiol and have been found to play a significant role in autoimmune disease, atherosclerosis, aortic valve calcification, cardiac repair, and cardiomyopathy, operating within extracellular spaces. This review sought to evaluate recent findings in this field, highlighting how among cathepsins, the inhibition of cathepsin S in particular, could play a significant role in diminishing the effects of CVD, especially for patients with CKD

Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice

Background—Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6Chigh monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E–deficient (apoE−/−) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset–targeted RNAi altered infarct inflammation and healing. Methods and Results—Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE−/− mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18–labeled positron emission tomography agent (18F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas 18F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05). Conclusion—CCR2-targeted RNAi reduced recruitment of Ly-6Chigh monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.National Heart, Lung, and Blood InstituteUnited States. Dept. of Health and Human Services (contract No. HHSN268201000044C)National Institutes of Health (U.S.) (grant R01-HL096576)National Institutes of Health (U.S.) (grant R01-HL095629)National Institutes of Health (U.S.) (grant T32-HL094301)Deutsche Forschungsgemeinschaft (HE-6382/1-1

A Health Technician-delivered Brief Intervention linked to AUDIT for reduction of alcohol use in Chilean primary care: a randomized controlled trial

Abstract Background Because of the shortage of health professionals in Chilean primary care, Health Technicians (HT) are providing Brief Interventions (BI) for risky alcohol consumption. We compared the efficacy of two AUDIT-linked interventions provided by HTs: an informative leaflet and a BI plus leaflet. Methods This is a parallel-group randomized controlled trial with 1:1 randomization. Participants were identified through screening with the Alcohol Use Disorders Identification Test (AUDIT) at five primary care centers between March 2016 and July 2017. People older than 18 years at intermediate-risk (AUDIT score 8 to 15, inclusive) were randomized to receive either an HT-delivered BI (n = 174) or an informative leaflet (n = 168). Only data from participants (n = 294) who completed the 6-month assessment were analyzed. The leaflet was delivered without further advice. It contains alcohol consumption limits, a change planner, and strategies to decrease drinking. The BI was a 5-min discussion on the leaflet´s content plus normative feedback, tailored information on alcohol and health, and a change plan. The change in the AUDIT risk category six months after randomization (primary outcome) was compared among groups with a Chi-squared test. Changes in the secondary outcomes, which were scores on the AUDIT and the AUDIT´s consumption items (AUDIT-C), were compared with T-tests. Mixed-effects linear models adjusted for potential confounders. Outcome adjudicators were blinded to group assignment. Results At 6-month follow-up, low-risk alcohol consumption was observed in 119 (80%) participants in the BI group, and in 103 (71%) in the leaflet group, with no difference among groups ( $$\chi 2$$ χ 2 [1, N = 294] = 2.6, p = 0.1; adjusted odds ratio 0.6; 95% confidence interval [CI] 0.34, 1.05). The mean AUDIT score decreased by 5.76 points in the BI group, and by 5.07 in the leaflet group, which represents a 0.86 AUDIT point reduction attributable to the BI (secondary outcome) (T = 2.03, p = 0.043; adjusted mean difference 0.86 CI 0.06, 1.66). Conclusions The AUDIT-linked BI delivered by HTs was not associated with a greater reduction of risky alcohol consumption than an informative leaflet. Delivering a leaflet could be more efficient than a BI when provided by HTs; however, more research on the effectiveness of the leaflet is needed. Trial registration ClinicalTrials.gov NCT02642757 (December 30, 2015) https://clinicaltrials.gov/ct2/show/NCT02642757

Stigma towards mental illness and substance use issues in primary health care: Challenges and opportunities for Latin America

Stigma towards mental illness and addictive disorders is a global problem and one of the main obstacles in tackling this issue remains the effective integration of mental health services into primary health care (PHC). In Latin America, information has significantly increased on the existence of stigma; however, little is known about effective interventions to prevent stigma and promote recovery-oriented practices in PHC. The aim of this study is to understand the existing evidence regarding mental health stigma in PHC with a special focus on the Latin American region. A scoping review of the literature related to mental health stigma in PHC was conducted. Two hundred and seventeen articles were evaluated; 74 met inclusion criteria and 14 additional articles were selected from references of search results. Results were subdivided into five different perspectives: users, family members and significant others, health professionals, contextual factors, and potential effective interventions. Only nine studies were based in Latin America, and only one described an intervention to reduce stigma in mental health services, not specifically in PHC. We found an urgent need to develop interventions to understand and reduce stigma in PHC settings, especially in Latin America

Dedifferentiated liposarcoma of the gallbladder: first reported case

Abstract Background Liposarcoma of the gallbladder is an extremely rare sarcoma, with only five cases reported in the literature according to our knowledge. Case presentation A 71-year-old woman was referred to the Surgical Oncology Division of Napoleão Laureano Hospital (João Pessoa, PB, Brazil) due to a solid mass at the right side of the abdomen and fever, with no signs of jaundice. Abdominal ultrasonography and computed tomography (CT) evidenced an extensive gallbladder lobular formation adhered to the inferior border of the right hepatic lobe and cholelithiasis. The CT report suggested gallbladder liposarcoma. A cholecystectomy associated with resection of segments IV-B and V of the liver were performed. Intraoperative frozen sections were compatible with gallbladder sarcoma. Anatomopathological examination and immunohistochemistry confirmed dedifferentiated liposarcoma with foci of heterologous leiomyosarcomatous differentiation and undifferentiated fusocellular areas of high histological grade. Conclusion This is the first case of dedifferentiated liposarcoma of the gallbladder to be reported

Diversity matters:opportunities in the study of the genetics of psychotic disorders in low-and middle-income countries in Latin America

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America’s particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies

Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy

The aging myopathy manifests itself with diastolic dysfunction and preserved ejection fraction. We raised the possibility that, in a mouse model of physiological aging, defects in electromechanical properties of cardiomyocytes are important determinants of the diastolic characteristics of the myocardium, independently from changes in structural composition of the muscle and collagen framework. Here we show that an increase in the late Na+ current (INaL) in aging cardiomyocytes prolongs the action potential (AP) and influences temporal kinetics of Ca2+ cycling and contractility. These alterations increase force development and passive tension. Inhibition of INaL shortens the AP and corrects dynamics of Ca2+ transient, cell contraction and relaxation. Similarly, repolarization and diastolic tension of the senescent myocardium are partly restored. Thus, INaL offers inotropic support, but negatively interferes with cellular and ventricular compliance, providing a new perspective of the biology of myocardial aging and the aetiology of the defective cardiac performance in the elderly

PET/MRI of inflammation in myocardial infarction

ObjectivesThe aim of this study was to explore post–myocardial infarction (MI) myocardial inflammation.BackgroundInnate immune cells are centrally involved in infarct healing and are emerging therapeutic targets in cardiovascular disease; however, clinical tools to assess their presence in tissue are scarce. Furthermore, it is currently not known if the nonischemic remote zone recruits monocytes.MethodsAcute inflammation was followed in mice with coronary ligation by 18-fluorodeoxyglucose (18FDG) positron emission tomography/magnetic resonance imaging, fluorescence-activated cell sorting, polymerase chain reaction, and histology.ResultsGd-DTPA–enhanced infarcts showed high 18FDG uptake on day 5 after MI. Cell depletion and isolation data confirmed that this largely reflected inflammation; CD11b+ cells had 4-fold higher 18FDG uptake than the infarct tissue from which they were isolated (p < 0.01). Surprisingly, there was considerable monocyte recruitment in the remote myocardium (approximately 104/mg of myocardium, 5.6-fold increase; p < 0.01), a finding mirrored by macrophage infiltration in the remote myocardium of patients with acute MI. Temporal kinetics of cell recruitment were slower than in the infarct, with peak numbers on day 10 after ischemia. Quantitative polymerase chain reaction showed a robust increase of recruiting adhesion molecules and chemokines in the remote myocardium (e.g., 12-fold increase of monocyte chemoattractant protein-1), although levels were always lower than in the infarct. Finally, matrix metalloproteinase activity was significantly increased in noninfarcted myocardium, suggesting that monocyte recruitment to the remote zone may contribute to post-MI dilation.ConclusionsThis study shed light on the innate inflammatory response in remote myocardium after MI