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Whole Exome Sequencing Identified a Novel Frameshift Mutation in SDR9C7 underlying Autosomal Recessive Congenital Ichthyosis in a Pakistani Family.

Br J Dermatol. 2017 Mar 31;:

Authors: Karim N, Murtaza G, Naeem M

Abstract
Autosomal Recessive Congenital Ichthyosis (ARCI) is a group of cornification disorders (prevalence 1:200,000) broadly divided into three classes namely Harlequin Ichthyosis (HI; OMIM#242500), Lamellar Ichthyosis (LI; OMIM#242304) and Congenital Ichthyosiform Erythroderma (CIE; OMIM#242100). ARCI clinical features include generalized scaling, hypohidrosis and palmo-plantar hyperlinearity although presentation and severity may vary significantly. A large number of affected individuals present with collodion membrane at birth. HI is the most severe and fatal form of the disease and the neonates are born covered with thick, hard, armor-like plates of cornified skin. The classic form of LI present with dark brown, plate-like scales with no erythroderma and CIE with fine and white scales adjoining generalized erythema. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia and palmoplantar keratoderma. Currently, ten genes are reported in association with different ARCI phenotypes: TGM1, ALOX12B, ALOXE3, ABCA12, CYP4F22, NIPAL4, LIPN, CERS3, PNPLA1 and SDR9C7(1,2,3) . Here we report a novel frameshift mutation in SDR9C7 (short-chain dehydrogenase/reductase family 9C member 7) underlying ARCI in a consanguineous Pakistani family. This article is protected by copyright. All rights reserved.

PMID: 28369735 [PubMed - as supplied by publisher]

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Estimating the selective effects of heterozygous protein-truncating variants from human exome data.

Nat Genet. 2017 Apr 03;:

Authors: Cassa CA, Weghorn D, Balick DJ, Jordan DM, Nusinow D, Samocha KE, O'Donnell-Luria A, MacArthur DG, Daly MJ, Beier DR, Sunyaev SR

Abstract
The evolutionary cost of gene loss is a central question in genetics and has been investigated in model organisms and human cell lines. In humans, tolerance of the loss of one or both functional copies of a gene is related to the gene's causal role in disease. However, estimates of the selection and dominance coefficients in humans have been elusive. Here we analyze exome sequence data from 60,706 individuals to make genome-wide estimates of selection against heterozygous loss of gene function. Using this distribution of selection coefficients for heterozygous protein-truncating variants (PTVs), we provide corresponding Bayesian estimates for individual genes. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, Mendelian disease-associated genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that are likely to have crucial functions but have not yet been thoroughly characterized.

PMID: 28369035 [PubMed - as supplied by publisher]

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Genetic disorders of nuclear receptors.

J Clin Invest. 2017 Apr 03;127(4):1181-1192

Authors: Achermann JC, Schwabe J, Fairall L, Chatterjee K

Abstract
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.

PMID: 28368288 [PubMed - in process]

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Genetic Variation in the Exome: Associations With Alcohol and Tobacco Co-Use.

Psychol Addict Behav. 2017 Apr 03;:

Authors: Otto JM, Gizer IR, Ellingson JM, Wilhelmsen KC

Abstract
Shared genetic factors represent one underlying mechanism thought to contribute to high rates of alcohol and tobacco co-use and dependence. Common variants identified by molecular genetic studies tend to confer only small disease risk, and rare protein-coding variants are posited to contribute to disease risk, as well. However, given that genotyping technologies allowing for their inclusion in association studies have only recently become available, the magnitude of their contribution is poorly understood. The current study examined genetic variation in protein-coding regions (i.e., the exome) for associations with measures of lifetime alcohol and tobacco co-use. Participants from the UCSF Family Alcoholism Study (N = 1,862) were genotyped using an exome-focused genotyping array, and assessed for DSM-IV diagnoses of alcohol and tobacco dependence and quantitative consumption measures using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism. Analyses included single variant, gene-based, and pathway-based tests of association. One EMR3 variant and a pathway related to genes upregulated in mesenchymal stem cells during the late phase of adipogenesis met criteria for statistical significance. Suggestive associations were consistent with previous findings from studies of substance use and dependence, including variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster with cigarettes smoked per day. Further, several variants and genes demonstrated suggestive association across phenotypes, suggesting that shared genetic factors may underlie risk for increased levels of alcohol and tobacco use, as well as psychopathology more broadly, providing insight into our understanding of the genetic architecture underlying these traits. (PsycINFO Database Record

PMID: 28368157 [PubMed - as supplied by publisher]

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The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype.

Neuroscience. 2017 Mar 30;:

Authors: Evely KM, Pryce KD, Bhattacharjee A

Abstract
Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow afterhyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Otahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.

PMID: 28366665 [PubMed - as supplied by publisher]

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Development of an automated assessment tool for MedWatch reports in the FDA adverse event reporting system.

J Am Med Inform Assoc. 2017 Mar 21;:

Authors: Han L, Ball R, Pamer CA, Altman RB, Proestel S

Abstract
Objective: As the US Food and Drug Administration (FDA) receives over a million adverse event reports associated with medication use every year, a system is needed to aid FDA safety evaluators in identifying reports most likely to demonstrate causal relationships to the suspect medications. We combined text mining with machine learning to construct and evaluate such a system to identify medication-related adverse event reports.
Methods: FDA safety evaluators assessed 326 reports for medication-related causality. We engineered features from these reports and constructed random forest, L1 regularized logistic regression, and support vector machine models. We evaluated model accuracy and further assessed utility by generating report rankings that represented a prioritized report review process.
Results: Our random forest model showed the best performance in report ranking and accuracy, with an area under the receiver operating characteristic curve of 0.66. The generated report ordering assigns reports with a higher probability of medication-related causality a higher rank and is significantly correlated to a perfect report ordering, with a Kendall's tau of 0.24 ( P  = .002).
Conclusion: Our models produced prioritized report orderings that enable FDA safety evaluators to focus on reports that are more likely to contain valuable medication-related adverse event information. Applying our models to all FDA adverse event reports has the potential to streamline the manual review process and greatly reduce reviewer workload.

PMID: 28371826 [PubMed - as supplied by publisher]

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Current Status of Parkinsonism-Related Adverse Events and Associated Drugs in Korea.

J Patient Saf. 2017 Apr 01;:

Authors: Kim S, Suh HS

Abstract
OBJECTIVE: The aim of the study was to explore the current status of drug-induced parkinsonism and drugs possibly related to drug-induced parkinsonism in Korea.
METHODS: We conducted a cross-sectional study using the Korea Adverse Event Reporting System database between July 1, 2010, and June 30, 2015. We identified all adverse event reports associated with parkinsonism.
RESULTS: There were 1402 adverse event reports associated with parkinsonism. The number of adverse event reports has increased annually. Among the 1499 drugs associated with parkinsonism, the most common were metoclopramide (49.77%) and paliperidone (16.14%). The major therapeutic groups (the third level of the Anatomical Therapeutic Chemical code) were propulsives (53.87%) and antipsychotics (35.58%). The mean time of onset of parkinsonism was 34.9 days. However, the time of onset of parkinsonism varied by drug, for example, it was 4.6 days for metoclopramide and 37.2 days for paliperidone.
CONCLUSIONS: Metoclopramide and antipsychotics were reported in most adverse event reports associated with parkinsonism in Korea.

PMID: 28368965 [PubMed - as supplied by publisher]

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Natural Compounds As Modulators of Non-apoptotic Cell Death in Cancer Cells.

Curr Genomics. 2017 Apr;18(2):132-155

Authors: Guamán-Ortiz LM, Orellana MI, Ratovitski EA

Abstract
Cell death is an innate capability of cells to be removed from microenvironment, if and when they are damaged by multiple stresses. Cell death is often regulated by multiple molecular pathways and mechanism, including apoptosis, autophagy, and necroptosis. The molecular network underlying these processes is often intertwined and one pathway can dynamically shift to another one acquiring certain protein components, in particular upon treatment with various drugs. The strategy to treat human cancer ultimately relies on the ability of anticancer therapeutics to induce tumor-specific cell death, while leaving normal adjacent cells undamaged. However, tumor cells often develop the resistance to the drug-induced cell death, thus representing a great challenge for the anticancer approaches. Numerous compounds originated from the natural sources and biopharmaceutical industries are applied today in clinics showing advantageous results. However, some exhibit serious toxic side effects. Thus, novel effective therapeutic approaches in treating cancers are continued to be developed. Natural compounds with anticancer activity have gained a great interest among researchers and clinicians alike since they have shown more favorable safety and efficacy then the synthetic marketed drugs. Numerous studies in vitro and in vivo have found that several natural compounds display promising anticancer potentials. This review underlines certain information regarding the role of natural compounds from plants, microorganisms and sea life forms, which are able to induce non-apoptotic cell death in tumor cells, namely autophagy and necroptosis.

PMID: 28367073 [PubMed - in process]

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Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction-A prospective, randomized, double-blind, placebo-controlled clinical trial.

Maturitas. 2017 May;99:20-26

Authors: Kamenov Z, Fileva S, Kalinov K, Jannini EA

Abstract
OBJECTIVE: The primary objectives were to compare the efficacy of extracts of the plant Tribulus terrestris (TT; marketed as Tribestan), in comparison with placebo, for the treatment of men with erectile dysfunction (ED) and with or without hypoactive sexual desire disorder (HSDD), as well as to monitor the safety profile of the drug. The secondary objective was to evaluate the level of lipids in blood during treatment.
PARTICIPANTS AND DESIGN: Phase IV, prospective, randomized, double-blind, placebo-controlled clinical trial in parallel groups. This study included 180 males aged between 18 and 65 years with mild or moderate ED and with or without HSDD: 90 were randomized to TT and 90 to placebo. Patients with ED and hypertension, diabetes mellitus, and metabolic syndrome were included in the study. In the trial, an herbal medicine intervention of Bulgarian origin was used (Tribestan(®), Sopharma AD). Each Tribestan film-coated tablet contains the active substance Tribulus terrestris, herba extractum siccum (35-45:1) 250mg which is standardized to furostanol saponins (not less than 112.5mg). Each patient received orally 3×2 film-coated tablets daily after meals, during the 12-week treatment period. At the end of each month, participants' sexual function, including ED, was assessed by International Index of Erectile Function (IIEF) Questionnaire and Global Efficacy Question (GEQ). Several biochemical parameters were also determined. The primary outcome measure was the change in IIEF score after 12 weeks of treatment. Complete randomization (random sorting using maximum allowable% deviation) with an equal number of patients in each sequence was used. This randomization algorithm has the restriction that unequal treatment allocation is not allowed; that is, all groups must have the same target sample size. Patients, investigational staff, and data collectors were blinded to treatment. All outcome assessors were also blinded to group allocation.
RESULTS: 86 patients in each group completed the study. The IIEF score improved significantly in the TT group compared with the placebo group (Р<0.0001). For intention-to-treat (ITT) there was a statistically significant difference in change from baseline of IIEF scores. The difference between TT and placebo was 2.70 (95% CI 1.40, 4.01) for the ITT population. A statistically significant difference between TT and placebo was found for Intercourse Satisfaction (p=0.0005), Orgasmic Function (p=0.0325), Sexual Desire (p=0.0038), Overall Satisfaction (p=0.0028) as well as in GEQ responses (p<0.0001), in favour of TT. There were no differences in the incidence of adverse events (AEs) between the two groups and the therapy was well tolerated. There were no drug-related serious AEs. Following the 12-week treatment period, significant improvement in sexual function was observed with TT compared with placebo in men with mild to moderate ED. TT was generally well tolerated for the treatment of ED.

PMID: 28364864 [PubMed - in process]

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Safety of Denosumab Versus Zoledronic Acid in Patients with Bone Metastases: A Meta-Analysis of Randomized Controlled Trials.

Oncol Res Treat. 2016;39(7-8):453-9

Authors: Chen F, Pu F

Abstract
INTRODUCTION: Bone metastases lead to local bone destruction and skeletal complications. Bisphosphonates, particlulaly zoledronic acid (ZA), play a central role in the treatment of bone metastases. Some studies have shown that denosumab may delay and prevent SREs in metastatic bone disease more effectively than ZA; therefore, we systematically reviewed and assessed the safety of denosumab and ZA.
METHODS: The PubMed, EMBASE, Cochrane Library, Web of Science with Conference Proceedings, Elsevier, and China National Knowledge Infrastructure (CNKI) databases were searched up to October 2015. 2 independent reviewers extracted data from each eligible study using a standard protocol, and both fixed-effects and random-effects models were used to analyze and evaluate the data extracted from eligible articles.
RESULTS: 6 randomized controlled trials enrolling 13,733 patients were included. Occurrences of adverse events were generally similar between the denosumab and ZA groups except anemia and anorexia in patients with bone metastases and back pain and bone pain. However, occurrences of serious adverse events such as hypocalcaemia , renal adverse events , and new primary malignancy were significantly different between the denosumab and ZA groups. Only the occurrence of osteonecrosis of the jaw showed no significant difference between the denosumab and ZA groups in patients with bone metastases.
CONCLUSION: Denosumab was safer in delaying or preventing skeletal-related events in patients with bone metastases and prevented pain progression compared to ZA in this meta-analysis.

PMID: 27487236 [PubMed - indexed for MEDLINE]

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[Pharmacokinetic and pharmacodynamic effects of psychotropic medications: Differences between sexes].

Psychiatriki. 2016 Apr-Jun;27(2):118-26

Authors: Bergiannaki JD, Kostaras P

Abstract
The gender based or gender sensitive pharmacology is a new research area. Differences among sexes are observed in several parameters of their pharmacokinetic which may relate to alteration of their pharmacodynamic as well. Most psychotropics are given per os, and the greater part of their absorption takes place in the small intestine. Premenopausal women have slower gastric emptying times and lower gastrointestinal blood flow which probably reduces the extent of drug absorption. The distribution of drugs is influenced by the relative lower body mass index, the lower blood volume and flow and the greater percentage of body fat of women. Further, the elimination and renal clearance is reduced in women and the hepatic metabolism differ between sexes. Besides, women differ from men in physiological conditions which may have an impact on the psychotropic medication and dosage required for efficacy and response. Women are exposed to monthly hormonal fluctuations (menstruation), pregnancy, puerperium, menopause and use of contraceptives or synthetic hormonal replacement therapies. Throughout of these conditions changes may occur in total body water, in renal clearance, cardiovascular and autoimmune system, which may cause fluctuations in the activity of the psychotropics, changes in the central neurotransmitters, in the number and sensitivity of the receptors, and the general metabolism as well. Despite the fact that women are the primer consumers of psychotropic medication, taking more psychotropics as well as more multiple medications than men, little attention has been paid to sex differences in psychopharmacology. Till recently women were under-represented or excluded from most of the pharmacological clinical trials. The treatment guidelines for psychotropic medication are based on studies verified and investigated almost exclusively in men. Results from such studies were generalized and recommended for use in the clinical practice without any critique and justification between the sexes. In conclusion, women compared to men, tend to have a greater bioavailability and slower elimination of drugs leading to higher concentrations of free circulating drugs in serum and causing more side effects and adverse reactions to the psychotropic medication than men do. In general, women require lower doses of antidepressants, antipsychotics and benzodiazepines than men. For safety and efficacy reasons and despite the fact that research is still being carried out to determine the exact differences in pharmacodynamic of several psychotropics between genders, the clinician must be aware of the reported effect of the recommended medications on serum levels and organ tissues both for men and women.

PMID: 27467032 [PubMed - indexed for MEDLINE]

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Improving Care in Older Patients with Diabetes: A Focus on Glycemic Control.

Perm J. Summer 2016;20(3):51-6

Authors: Lee EA, Gibbs NE, Martin J, Ziel F, Polzin JK, Palmer-Toy D

Abstract
Diabetes affects more than 25% of Americans older than age 65 years. The medical care of older patients must differ from the care of their younger counterparts. Older patients are at high risk of drug toxicity. A hemoglobin A1c (HbA1c) level less than 7.0% has historically been the goal of all patients with diabetes, regardless of age. Recent research has demonstrated that using medications to achieve such tight glycemic control is not necessary and is often not safe.This article discusses the seminal research findings that strongly suggest that HbA1c goals should be relaxed in older patients. The authors then recommend an age-specific and functionally appropriate HbA1c reference range for patients receiving medications to improve glycemic control. Other interventions are suggested that should make diabetes care safer in older patients receiving hypoglycemic medications.

PMID: 27352408 [PubMed - indexed for MEDLINE]

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A Questionnaire Study to Assess the Value of the Vulnerable Elders Survey, G8, and Predictors of Toxicity as Screening Tools for Frailty and Toxicity in Geriatric Cancer Patients.

Oncol Res Treat. 2016;39(4):210-6

Authors: Hentschel L, Rentsch A, Lenz F, Hornemann B, Schmitt J, Baumann M, Ehninger G, Schuler M

Abstract
BACKGROUND: The aim of this study was to identify an appropriate screening instrument for the identification of frail elderly patients in a tertiary cancer center. In order to improve cancer care for older patients, the use of a geriatric assessment (GA) has been proposed to identify frail patients or those who are at a higher risk for chemotherapy-related toxicities. In busy clinical routine, an appropriate screening instrument could be used to spare time- and resource-consuming application of GA.
PATIENTS AND METHODS: We administered the Vulnerable Elders Survey (VES-13), G8 questionnaire, and Predictors of Toxicity (POT) as well as a GA at the first visit of 84 consecutive patients at a single Comprehensive Cancer Center. Analysis for patients' characteristics as well as sensitivity, specificity, and positive and negative predictive value (npv) was conducted.
RESULTS: The median age of the patients was 73 years (range 63-93 years), 61.9% were male, most (63%) suffered from gastrointestinal tumors, 39.3% had a multiple cancer diagnosis, and 53.6% had metastasis. 30 (35.7%) individuals were classified as 'frail' by the GA. Sensitivity of G8 was 38.3%, and the npv was 63.8%. Sensitivity for VES-13 was 57.1%, and npv was 76.3%. Sensitivity of POT was 72.7%, and the npv was 80.6%.
CONCLUSION: For the first time, the VES-13, G8, and POT are compared in a sample of older German patients. The POT seems to be a sufficient screening tool to identify frail patients in a tertiary referral cancer center and helps to save time and resources compared with a complete GA.

PMID: 27160741 [PubMed - indexed for MEDLINE]

Funding Opportunity PAR-17-249 from the NIH Guide for Grants and Contracts. The purpose of this Funding Opportunity Announcement (FOA) is to transition the core resources and biomedical research activities of Centers of Biomedical Research Excellence (COBRE) into independence and sustainability.

Funding Opportunity PA-17-247 from the NIH Guide for Grants and Contracts. This Funding Opportunity Announcement (FOA) invites U18 cooperative agreement applications to stimulate innovative and collaborative research by utilizing new health information technology (IT) strategies for collecting and using patient-reported outcome (PRO) measures in primary care and other ambulatory care settings.

Funding Opportunity RFA-HL-18-013 from the NIH Guide for Grants and Contracts. The objective of this research career program is to create a national Consortium that focuses on career development of the next generation of biomedical investigators in glycosciences. The ultimate goal of the Consortium is to transform and democratize glycosciences from a super-specialized research domain into the mainstream of biology and clinical translation such that glycans become an integral component of future scholars'/investigators' scientific thinking, thus creating a pathway for major scientific breakthroughs specifically in heart, lung, blood and sleep (HLBS) sciences.

Notice NOT-MH-17-017 from the NIH Guide for Grants and Contracts

Notice NOT-AI-17-022 from the NIH Guide for Grants and Contracts

Notice NOT-AI-17-021 from the NIH Guide for Grants and Contracts

Notice NOT-OD-17-052 from the NIH Guide for Grants and Contracts