Present and Future: Pharmacologic Treatment of Obesity

Obesity now presents one of the biggest health problems of our times. Diet and exercise are best for both prevention and treatment; unfortunately, both require much discipline and are difficult to maintain. Medications offer a possible adjunct, but their effect is modest, they are limited by side effects, and the weight loss lasts only as long as the drug is being taken, since as soon as treatment is stopped, the weight is regained. Sibutramine, a sympathomimetic medication which was available for long-term treatment, is the most recent of the drugs to be withdrawn from the market due to side effects; in this case it was an increased risk of cardiovascular events. This paper reviews those medications which are available for treatment of obesity, including many of those recently taken off the market. It also discusses some of the newer treatments that are currently being investigated

A Lion’s Blues: Heroism, Heroic Self-Representations, and Emotional Distress in the Life and Character of Yonatan (Yoni) Netanyahu

The realization that heroism – representing either a trait or a value system – is potentially pernicious is important for both scientific and societal reasons. In this article, we adopt a psychobiographical perspective to analyze the character and life of one of Israel’s greatest heroes, Yonathan (“Yoni”) Netanyahu. Yoni was an illustrious military leader, as well as an outstanding intellectual and adored persona. He served as the commander of the special operation forces spearheading the famous Entebbe Operation during which Israeli commando forces rescued hostages taken captive in Uganda. Yoni was the only military causality in this operation, which was ultimately named after him. Subsequent to his death, his numerous personal letters were made public, allowing further glimpses into his heroic self-representations but also to the emotional distress he suffered. Applying our theory of heroic self-representations (HERS; Shahar, 2013), we analyze Yoni\u27s letters. Our analyses confirm Yoni\u27s tendency to construe himself as a savior and conqueror, and to identify with cultural heroes. The emotional distress Yoni suffered is characterized by depressed and anxious affect, masked by superb functioning. Qualitative analyses of the letters suggest two mechanisms of the effect of heroic self-representations on distress in Yoni\u27s case: compulsive purposefulness and emotional seclusion

The Space of Traces of the Free Group and Free Products of Matrix Algebras

We show that the space of traces of the free group is a Poulsen simplex, i.e., every trace is a pointwise limit of extremal traces. We prove that this fails for many virtually free groups. Using a similar strategy, we show that the space of traces of the free product of matrix algebras $\mathbf{M}_n(\mathbb{C}) * \mathbf{M}_n(\mathbb{C})$ is a Poulsen simplex as well, answering a question of Musat and R{\o}rdam for $n \geq 4$. Similar results are shown for certain faces of the simplices above, most notably, for the face of finite-dimensional traces

Protective effects of SGLT-2 inhibitors across the cardiorenal continuum: two faces of the same coin

The cardiovascular and renal systems are closely interconnected in health and disease. Disorders affecting one of these systems frequently involve the other. Both diseases progress through a continuous chain of events, defined as the ‘cardiorenal continuum’, which is initiated by risk factors that lead to subclinical disease, clinical events, and ultimately to heart failure and end-stage kidney disease. Previous studies have shown that interventions anywhere along this chain of events can interrupt the pathophysiological cascade and provide cardiovascular and/or kidney ‘protection’. More recently, clinical trials with SGLT-2 inhibitors (SGLT2i) have shown a significant reduction in cardiovascular and kidney outcomes. Evidence from EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, VERTIS-CV, CREDENCE, and more recently DAPA-HF, EMPEROR-Reduced, and DAPA-CKD show that the beneficial effects of SGLT2i are observed across all stages of the cardiorenal continuum, ranging from patients with diabetes and multiple risk factors to those with established cardiovascular disease and even independently of diabetes status. This review provides a critical appraisal of the efficacy and safety of SGLT2i, demonstrating that this is a novel way to disrupt the chain of pathological events in the cardiorenal continuum and prevent cardiovascular and kidney disease in patients with and without diabetes

Octreotide, a Somatostatin Analogue, Fails to Inhibit Hypoxia-induced Retinal Neovascularization in the Neonatal Rat

Objective: Octreotide, a somatostatin analogue, has been shown to prevent angiogenesis in diverse in vitro models. We evaluated its effect on retinal neovascularization in vivo, using a neonatal rat retinopathy model

Metal binding to the dynamic cytoplasmic domain of the cation diffusion facilitator (CDF) protein MamM induces a 'locked-in' configuration

Cation diffusion facilitator (CDF) proteins are a conserved family of transmembrane transporters that ensure cellular homeostasis of divalent transition metal cations. Metal cations bind to CDF protein's cytoplasmic C-terminal domain (CTD), leading to closure from its apo open V-shaped dimer to a tighter packed structure, followed by a conformational change of the transmembrane domain thus enabling transport of the metal cation. By implementing a comprehensive range of biochemical and biophysical methods, we studied the molecular mechanism of metal binding to the magnetotactic bacterial CDF protein MamM CTD. Our results reveal that the CTD is rather dynamic in its apo form, and that two dependent metal binding sites, a single central binding site and two symmetrical, peripheral sites, are available for metal binding. However, only cation binding to the peripheral sites leads to conformational changes that lock the protein in a compact state. Thus, this work reveals how metal binding is regulating the sequential uptakes of metal cations by MamM, and extends our understanding of the complex regulation mechanism of CDF proteins. This article is protected by copyright. All rights reserved

Differences in mtDNA haplogroup distribution among 3 Jewish populations alter susceptibility to T2DM complications

BACKGROUND: Recent genome-wide association studies searching for candidate susceptibility loci for common complex diseases such as type 2 diabetes mellitus (T2DM) and its common complications have uncovered novel disease-associated genes. Nevertheless these large-scale population screens often overlook the tremendous variation in the mitochondrial genome (mtDNA) and its involvement in complex disorders. RESULTS: We have analyzed the mitochondrial DNA (mtDNA) genetic variability in Ashkenazi (Ash), Sephardic (Seph) and North African (NAF) Jewish populations (total n = 1179). Our analysis showed significant differences (p < 0.001) in the distribution of mtDNA genetic backgrounds (haplogroups) among the studied populations. To test whether these differences alter the pattern of disease susceptibility, we have screened our three Jewish populations for an association of mtDNA genetic haplogroups with T2DM complications. Our results identified population-specific susceptibility factors of which the best example is the Ashkenazi Jewish specific haplogroup N1b1, having an apparent protective effect against T2DM complications in Ash (p = 0.006), being absent in the NAF population and under-represented in the Seph population. We have generated and analyzed whole mtDNA sequences from the disease associated haplogroups revealing mutations in highly conserved positions that are good candidates to explain the phenotypic effect of these genetic backgrounds. CONCLUSION: Our findings support the possibility that recent bottleneck events leading to over-representation of minor mtDNA alleles in specific genetic isolates, could result in population-specific susceptibility loci to complex disorders

Insulin therapy in people with type 2 diabetes:opportunities and challenges?

Given the continued interest in defining the optimal management of individuals with type 2 diabetes, the Editor of Diabetes Care convened a working party of diabetes specialists to examine this topic in the context of insulin therapy. This was prompted by recent new evidence on the use of insulin in such people. The group was aware of evidence that the benefits of insulin therapy are still usually offered late, and thus the aim of the discussion was how to define the optimal timing and basis for decisions regarding insulin and to apply these concepts in practice. It was noted that recent evidence had built upon that of the previous decades, together confirming the benefits and safety of insulin therapy, albeit with concerns about the potential for hypoglycemia and gain in body weight. Insulin offers a unique ability to control hyperglycemia, being used from the time of diagnosis in some circumstances, when metabolic control is disturbed by medical illness, procedures, or therapy, as well as in the longer term in ambulatory care. For those previously starting insulin, various other forms of therapy can be added later, which offer complementary effects appropriate to individual needs. Here we review current evidence and circumstances in which insulin can be used, consider individualized choices of alternatives and combination regimens, and offer some guidance on personalized targets and tactics for glycemic control in type 2 diabetes