Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself

Evidence of Altered Peripheral Nerve Function in a Rodent Model of Diet-Induced Prediabetes.

Peripheral neuropathy (PN) is a debilitating complication of diabetes that affects >50% of patients. Recent evidence suggests that obesity and metabolic disease, which often precede diabetes diagnosis, may influence PN onset and severity. We examined this in a translationally relevant model of prediabetes induced by a cafeteria (CAF) diet in Sprague-Dawley rats (n = 15 CAF versus n = 15 control). Neuropathy phenotyping included nerve conduction, tactile sensitivity, intraepidermal nerve fiber density (IENFD) and nerve excitability testing, an in vivo measure of ion channel function and membrane potential. Metabolic phenotyping included body composition, blood glucose and lipids, plasma hormones and inflammatory cytokines. After 13 weeks diet, CAF-fed rats demonstrated prediabetes with significantly elevated fasting blood glucose, insulin and impaired glucose tolerance as well as obesity and dyslipidemia. Nerve conduction, tactile sensitivity and IENFD did not differ; however, superexcitability was significantly increased in CAF-fed rats. Mathematical modeling demonstrated this was consistent with a reduction in sodium-potassium pump current. Moreover, superexcitability correlated positively with insulin resistance and adiposity, and negatively with fasting high-density lipoprotein cholesterol. In conclusion, prediabetic rats over-consuming processed, palatable foods demonstrated altered nerve function that preceded overt PN. This work provides a relevant model for pathophysiological investigation of diabetic complications

Original Articles National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 -executive summary

Abstract: Various organizations and agencies have issued recommendations for the management of dyslipidemia. Although many commonalities exist among them, material differences are present as well. The leadership of the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel and includes: (1) background and conceptual framework for formulation of the NLA Expert Panel recommendations; (2) screening and classification of lipoprotein lipid levels in adults; (3) targets for intervention in dyslipidemia management; (4) atherosclerotic cardiovascular disease risk assessment and treatment goals based on risk category; (5) atherogenic cholesterol-non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol-as the primary targets of therapy; and (6) lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia. Ó 2014 National Lipid Association. All rights reserved. Various organizations and agencies have issued recommendations for the management of dyslipidemia. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel. The Executive Summary does not include a comprehensive reference list, but citations have been included for several key publications. The full report will include additional details on the rationale for the recommendations and citations to published research considered in the panel's deliberations. A presentation containing the main elements of these recommendations was made available to the public and other organizations involved with the prevention of atherosclerotic cardiovascular disease (ASCVD) to solicit input during an open comment period. Comments and suggestions were received from many members of the NLA as well as other individuals and organizations and were collated for consideration and adjudication by the panel in formulating the final set of recommendations contained herein. Part 1 of the NLA Expert Panel Recommendations for Patient-Centered Management of Dyslipidemia, will cover: Background and conceptual framework for formulation of the NLA Expert Panel recommendations; Screening and classification of lipoprotein lipid levels in adults; Targets for intervention in dyslipidemia management; ASCVD risk assessment and treatment goals based on risk category; Atherogenic cholesterol-non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C)-as the primary targets of therapy; and Lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia

Original Articles National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 -executive summary E M B A R G O E D

Abstract: Various organizations and agencies have issued recommendations for the management of dyslipidemia. Although many commonalities exist among them, material differences are present as well. The leadership of the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel and includes: (1) background and conceptual framework for formulation of the NLA Expert Panel recommendations; (2) screening and classification of lipoprotein lipid levels in adults; (3) targets for intervention in dyslipidemia management; (4) atherosclerotic cardiovascular disease risk assessment and treatment goals based on risk category; (5) atherogenic cholesterol-non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol-as the primary targets of therapy; and (6) lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia. Ó 2014 National Lipid Association. All rights reserved. Various organizations and agencies have issued recommendations for the management of dyslipidemia. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel. The Executive Summary does not include a comprehensive reference list, but citations have been included for several key publications. The full report will include additional details on the rationale for the recommendations and citations to published research considered in the panel's deliberations. A presentation containing the main elements of these recommendations was made available to the public and other organizations involved with the prevention of atherosclerotic cardiovascular disease (ASCVD) to solicit input during an open comment period. Comments and suggestions were received from many members of the NLA as well as other individuals and organizations and were collated for consideration and adjudication by the panel in formulating the final set of recommendations contained herein. Part 1 of the NLA Expert Panel Recommendations for Patient-Centered Management of Dyslipidemia, will cover: Background and conceptual framework for formulation of the NLA Expert Panel recommendations; Screening and classification of lipoprotein lipid levels in adults; Targets for intervention in dyslipidemia management; ASCVD risk assessment and treatment goals based on risk category; Atherogenic cholesterol-non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C)-as the primary targets of therapy; and Lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia

Original Articles National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 -executive summary

Abstract: Various organizations and agencies have issued recommendations for the management of dyslipidemia. Although many commonalities exist among them, material differences are present as well. The leadership of the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel and includes: (1) background and conceptual framework for formulation of the NLA Expert Panel recommendations; (2) screening and classification of lipoprotein lipid levels in adults; (3) targets for intervention in dyslipidemia management; (4) atherosclerotic cardiovascular disease risk assessment and treatment goals based on risk category; (5) atherogenic cholesterol-non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol-as the primary targets of therapy; and (6) lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia. Ó 2014 National Lipid Association. All rights reserved. Various organizations and agencies have issued recommendations for the management of dyslipidemia. The current Executive Summary highlights the major conclusions in Part 1 of the recommendations report of the NLA Expert Panel. The Executive Summary does not include a comprehensive reference list, but citations have been included for several key publications. The full report will include additional details on the rationale for the recommendations and citations to published research considered in the panel's deliberations. A presentation containing the main elements of these recommendations was made available to the public and other organizations involved with the prevention of atherosclerotic cardiovascular disease (ASCVD) to solicit input during an open comment period. Comments and suggestions were received from many members of the NLA as well as other individuals and organizations and were collated for consideration and adjudication by the panel in formulating the final set of recommendations contained herein. Part 1 of the NLA Expert Panel Recommendations for Patient-Centered Management of Dyslipidemia, will cover: Background and conceptual framework for formulation of the NLA Expert Panel recommendations; Screening and classification of lipoprotein lipid levels in adults; Targets for intervention in dyslipidemia management; ASCVD risk assessment and treatment goals based on risk category; Atherogenic cholesterol-non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C)-as the primary targets of therapy; and Lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia

Type 2 diabetes genetic association database manually curated for the study design and odds ratio

<p>Abstract</p> <p>Background</p> <p>The prevalence of type 2 diabetes has reached epidemic proportions worldwide, and the incidence of life-threatening complications of diabetes through continued exposure of tissues to high glucose levels is increasing. Advances in genotyping technology have increased the scale and accuracy of the genotype data so that an association genetic study has expanded enormously. Consequently, it is difficult to search the published association data efficiently, and several databases on the association results have been constructed, but these databases have their limitations to researchers: some providing only genome-wide association data, some not focused on the association but more on the integrative data, and some are not user-friendly. In this study, a user-friend database of type 2 diabetes genetic association of manually curated information was constructed.</p> <p>Description</p> <p>The list of publications used in this study was collected from the HuGE Navigator, which is an online database of published genome epidemiology literature. Because type 2 diabetes genetic association database (T2DGADB) aims to provide specialized information on the genetic risk factors involved in the development of type 2 diabetes, 701 of the 1,771 publications in the type 2 Diabetes case-control study for the development of the disease were extracted.</p> <p>Conclusions</p> <p>In the database, the association results were grouped as either positive or negative. The gene and SNP names were replaced with gene symbols and rsSNP numbers, the association p-values were determined manually, and the results are displayed by graphs and tables. In addition, the study design in publications, such as the population type and size are described. This database can be used for research purposes, such as an association and functional study of type 2 diabetes related genes, and as a primary genetic resource to construct a diabetes risk test in the preparation of personalized medicine in the future.</p

Grifonin-1: A Small HIV-1 Entry Inhibitor Derived from the Algal Lectin, Griffithsin

Background: Griffithsin, a 121-residue protein isolated from a red algal Griffithsia sp., binds high mannose N-linked glycans of virus surface glycoproteins with extremely high affinity, a property that allows it to prevent the entry of primary isolates and laboratory strains of T- and M-tropic HIV-1. We used the sequence of a portion of griffithsin's sequence as a design template to create smaller peptides with antiviral and carbohydrate-binding properties. Methodology/Results: The new peptides derived from a trio of homologous β-sheet repeats that comprise the motifs responsible for its biological activity. Our most active antiviral peptide, grifonin-1 (GRFN-1), had an EC50 of 190.8±11.0 nM in in vitro TZM-bl assays and an EC50 of 546.6±66.1 nM in p24gag antigen release assays. GRFN-1 showed considerable structural plasticity, assuming different conformations in solvents that differed in polarity and hydrophobicity. Higher concentrations of GRFN-1 formed oligomers, based on intermolecular β-sheet interactions. Like its parent protein, GRFN-1 bound viral glycoproteins gp41 and gp120 via the N-linked glycans on their surface. Conclusion: Its substantial antiviral activity and low toxicity in vitro suggest that GRFN-1 and/or its derivatives may have therapeutic potential as topical and/or systemic agents directed against HIV-1

Comparison of Antioxidant Effects of Honey, Glibenclamide, Metformin, and Their Combinations in the Kidneys of Streptozotocin-Induced Diabetic Rats

Hyperglycemia-induced increase in oxidative stress is implicated in diabetic complications. This study investigated the effect of metformin and/or glibenclamide in combination with honey on antioxidant enzymes and oxidative stress markers in the kidneys of streptozotocin (60 mg/kg; intraperitoneal)-induced diabetic rats. Diabetic rats were randomized into eight groups of five to seven rats and received distilled water (0.5 mL); honey (1.0 g/kg); metformin (100 mg/kg); metformin (100 mg/kg) and honey (1.0 g/kg); glibenclamide (0.6 mg/kg); glibenclamide (0.6 mg/kg) and honey (1.0 g/kg); metformin (100 mg/kg) and glibenclamide (0.6 mg/kg); or metformin (100 mg/kg), glibenclamide (0.6 mg/kg) and honey (1.0 g/kg) orally once daily for four weeks. Malondialdehyde (MDA) levels, glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities were significantly elevated while catalase (CAT) activity, total antioxidant status (TAS), reduced glutathione (GSH), and GSH:oxidized glutathione (GSSG) ratio was significantly reduced in the diabetic kidneys. CAT, glutathione reductase (GR), TAS, and GSH remained significantly reduced in the diabetic rats treated with metformin and/or glibenclamide. In contrast, metformin or glibenclamide combined with honey significantly increased CAT, GR, TAS, and GSH. These results suggest that combination of honey with metformin or glibenclamide might offer additional antioxidant effect to these drugs. This might reduce oxidative stress-mediated damage in diabetic kidneys

Rationale and study design of a cross sectional study documenting the prevalence of Heart Failure amongst the minority ethnic communities in the UK: the E-ECHOES Study (Ethnic - Echocardiographic Heart of England Screening Study)

Background: Heart failure is an important cause of cardiovascular morbidity and mortality. Studies to date have not established the prevalence heart failure amongst the minority ethnic community in the UK. The aim of the E-ECHOES (Ethnic - Echocardiographic Heart of England Screening Study) is to establish, for the first time, the community prevalence and severity of left ventricular systolic dysfunction (LVSD) and heart failure amongst the South Asian and Black African-Caribbean ethnic groups in the UK.Methods/Design: This is a community based cross-sectional population survey of a sample of South Asian (i.e. those originating from India, Pakistan, Bangladesh) and Black African-Caribbean male and female subjects aged 45 years and over. Data collection undertaken using a standardised protocol comprising a questionnaire incorporating targeted clinical history taking, physical examination, and investigations with resting electrocardiography and echocardiography; and blood sampling with consent. This is the largest study on heart failure amongst these ethnic groups. Full data collection started in September 2006 and will be completed by August 2009.Discussion: The E-ECHOES study will enable the planning and delivery of clinically and cost-effective treatment of this common and debilitating condition within these communities. In addition it will increase knowledge of the aetiology and management of heart failure within minority ethnic communities