Myocardial Delivery of Lipidoid Nanoparticle Carrying modRNA Induces Rapid and Transient Expression.

Nanoparticle-based delivery of nucleotides offers an alternative to viral vectors for gene therapy. We report highly efficient in vivo delivery of modified mRNA (modRNA) to rat and pig myocardium using formulated lipidoid nanoparticles (FLNP). Direct myocardial injection of FLNP containing 1-10 μg eGFPmodRNA in the rat (n = 3 per group) showed dose-dependent enhanced green fluorescent protein (eGFP) mRNA levels in heart tissue 20 hours after injection, over 60-fold higher than for naked modRNA.

Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.

A hallmark of human and experimental heart failure is deficient sarcoplasmic reticulum (SR) Ca-uptake reflecting impaired contractile function. This is at least partially attributed to dephosphorylation of phospholamban by increased protein phosphatase 1 (PP1) activity. Indeed inhibition of PP1 by transgenic overexpression or gene-transfer of constitutively active inhibitor-1 improved Ca-cycling, preserved function and decreased fibrosis in small and large animal models of heart failure, suggesting that inhibitor-1 may represent a potential therapeutic target.

Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.

The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats.

The impact and treatment of obesity in kidney transplant candidates and recipients.

The prevalence of obesity in patients with chronic kidney failure and renal transplant candidates has paralleled the epidemic in the general population. The associated risks of surgical complications and long-term cardiovascular death are significant: most transplant centers consider obesity a relative contra-indication for transplant. Few studies have focused on conservative weight loss strategies in transplant patients.

Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility.

Aims: Impaired sarcoplasmic reticulum (SR) Ca(2+) cycling and depressed contractility, a hallmark of human and experimental heart failure, has been partially attributed to increased protein phosphatase 1 (PP-1) activity, associated with down-regulation of its endogenous inhibitor-1. The levels and activity of inhibitor-1 are reduced in failing hearts, contributing to dephosphorylation and inactivation of key calcium cycling proteins. Therefore, we investigated the mechanisms that mediate decreases in inhibitor-1 by post-transcriptional modification.

High-dose chloroquine is metabolically cardiotoxic by inducing lysosomes and mitochondria dysfunction in a rat model of pressure overload hypertrophy.

Autophagy, macroautophagy and chaperone-mediated autophagy (CMA), are upregulated in pressure overload (PO) hypertrophy. In this study, we targeted this process at its induction using 3 methyladenine and at the lysosomal level using chloroquine and evaluated the effects of these modulations on cardiac function and myocyte ultrastructure. Sprague-Dawley rats weighing 200 g were subjected to ascending aortic banding.

Labeling galectin-3 for the assessment of myocardial infarction in rats.

Background: Galectin-3 is a ß-galactoside-binding lectin expressed in most of tissues in normal conditions and overexpressed in myocardium from early stages of heart failure (HF). It is an established biomarker associated with extracellular matrix (ECM) turnover during myocardial remodeling. The aim of this study is to test the ability of (123)I-galectin-3 (IG3) to assess cardiac remodeling in a model of myocardial infarction (MI) using imaging techniques.

Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure.

Decreased activity and expression of the cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a), a critical pump regulating calcium cycling in cardiomyocyte, are hallmarks of heart failure. We have previously described a role for the small ubiquitin-like modifier type 1 (SUMO-1) as a regulator of SERCA2a and have shown that gene transfer of SUMO-1 in rodents and large animal models of heart failure restores cardiac function. Here, we identify and characterize a small molecule, N106, which increases SUMOylation of SERCA2a.

Effectiveness of gene delivery systems for pluripotent and differentiated cells.

Human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) assert a great future for the cardiovascular diseases, both to study them and to explore therapies. However, a comprehensive assessment of the viral vectors used to modify these cells is lacking. In this study, we aimed to compare the transduction efficiency of recombinant adeno-associated vectors (AAV), adenoviruses and lentiviral vectors in hESC, hiPSC, and the derived cardiomyocytes.

Increased stiffness is the major early abnormality in a pig model of severe aortic stenosis and predisposes to congestive heart failure in the absence of systolic dysfunction.

Background: It remains unclear whether abnormal systolic function and relaxation are essential for developing heart failure in pathophysiology of severe aortic stenosis.

Methods And Results: Yorkshire pigs underwent surgical banding of the ascending aorta. The animals were followed for up to 5 months after surgery, and cardiac function was assessed comprehensively by invasive pressure-volume measurements, 3-dimensional echocardiography, echocardiographic speckle-tracking strain, and postmortem molecular and histological analyses.

Combination proximal pulmonary artery coiling and distal embolization induces chronic elevations in pulmonary artery pressure in Swine.

Pulmonary hypertension (PH) is associated with aberrant vascular remodeling and right ventricular (RV) dysfunction that contribute to early mortality. Large animal models that recapitulate human PH are essential for mechanistic studies and evaluating novel therapies; however, these models are not readily accessible to the field owing to the need for advanced surgical techniques or hypoxia. In this study, we present a novel swine model that develops cardiopulmonary hemodynamics and structural changes characteristic of chronic PH.

Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy.

A number of genetic mutations is associated with cardiomyopathies. A mutation in the coding region of the phospholamban (PLN) gene (R14del) is identified in families with hereditary heart failure. Heterozygous patients exhibit left ventricular dilation and ventricular arrhythmias.

International palliative care: Middle East experience as a model for global palliative care.

Care for elderly people with life-limiting illness cannot be delivered primarily by geriatricians or palliative care practitioners. The role of these clinicians is to help carers become adept in palliative care medicine. In a culture in which family ties run deep, the offer of palliative care from an outsider may be met with suspicion.

Incorporating geriatrics into undergraduate medical education in Lebanon.

Background: Although the proportion of older adults in Lebanon is expected to increase rapidly over the next few decades, the current healthcare workforce is unprepared to address the needs of this population. Currently, emphasis on geriatrics is lacking in medical education curricula of most universities in Lebanon, and there is a shortage of geriatricians in the country.

Methods: In this paper we present specific methods of integrating geriatrics into the undergraduate medical curriculum based on the experience of medical schools in the United States.

Psychological first aid training for Lebanese field workers in the emergency context of the Syrian refugees in Lebanon.

The Syrian refugee crisis in Lebanon required a fast and efficient comprehensive rescue strategy. Professionals working in emergency response were neither prepared to provide psychological first aid nor prepared to screen for mental health disorders in child refugees. This article examines the efficacy of a national training program in psychological first aid (PFA) to enhance the readiness of mental health field workers in the Syrian refugee response.

Adeno-associated virus-mediated gene therapy in cardiovascular disease.

Purpose Of Review: The use of adeno-associated virus (AAV) as an efficient, cardiotropic, and safe vector, coupled with the identification of key molecular targets, has placed gene-based therapies within reach of cardiovascular diseases. The purpose of this review is to provide a focused update on the current advances related to AAV-mediated gene therapy in cardiovascular diseases, and particularly in heart failure (HF), wherein gene therapy has recently made important progress.

Recent Findings: Multiple successful preclinical studies suggest a potential utility of AAV gene therapy for arrhythmias and biological heart pacing, as well as RNA overexpression.

An international definition for "nursing home".

There is much ambiguity regarding the term "nursing home" in the international literature. The definition of a nursing home and the type of assistance provided in a nursing home is quite varied by country. The International Association of Gerontology and Geriatrics and AMDA foundation developed a survey to assist with an international consensus on the definition of "nursing home.

Abnormalities of capillary microarchitecture in a rat model of coronary ischemic congestive heart failure.

The aim of the present study is to explore the role of capillary disorder in coronary ischemic congestive heart failure (CHF). CHF was induced in rats by aortic banding plus ischemia-reperfusion followed by aortic debanding. Coronary arteries were perfused with plastic polymer containing fluorescent dye.

Altered myocardial calcium cycling and energetics in heart failure--a rational approach for disease treatment.

Cardiomyocyte function depends on coordinated movements of calcium into and out of the cell and the proper delivery of ATP to energy-utilizing enzymes. Defects in calcium-handling proteins and abnormal energy metabolism are features of heart failure. Recent discoveries have led to gene-based therapies targeting calcium-transporting or -binding proteins, such as the cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a), leading to improvements in calcium homeostasis and excitation-contraction coupling.

Integration of complementary medicine in supportive cancer care: survey of health-care providers' perspectives from 16 countries in the Middle East.

Introduction: In this multinational Middle-Eastern study, we assessed health-care providers' (HCPs) perspectives on their patients' use of complementary and traditional medicine (CTM) and identified the leading barriers to CTM integration in supportive cancer care.

Methods: A 17-item questionnaire was developed and administered to HCPs attending palliative medicine workshops conducted across the Middle East by the Middle East Cancer Consortium.

Results: 339 HCPs from 16 countries across the Middle East completed the questionnaire (80.

Guidelines for translational research in heart failure.

Heart failure (HF) remains a major cause of death and hospitalization worldwide. Despite medical advances, the prognosis of HF remains poor and new therapeutic approaches are urgently needed. The development of new therapies for HF is hindered by inappropriate or incomplete preclinical studies.

High capsid-genome correlation facilitates creation of AAV libraries for directed evolution.

Directed evolution of adeno-associated virus (AAV) through successive rounds of phenotypic selection is a powerful method to isolate variants with improved properties from large libraries of capsid mutants. Importantly, AAV libraries used for directed evolution are based on the "natural" AAV genome organization where the capsid proteins are encoded in cis from replicating genomes. This is necessary to allow the recovery of the capsid DNA after each step of phenotypic selection.