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41.
42.
Peristera Paschou Dongmei Yu Gloria Gerber Patrick Evans Fotis Tsetsos Lea K. Davis Iordanis Karagiannidis Jonathan Chaponis Eric Gamazon Kirsten Mueller‐Vahl Manfred Stuhrmann Monika Schloegelhofer Mara Stamenkovic Johannes Hebebrand Markus Noethen Peter Nagy Csaba Barta Zsanett Tarnok Renata Rizzo Christel Depienne Yulia Worbe Andreas Hartmann Danielle C. Cath Cathy L. Budman Paul Sandor Cathy Barr Thomas Wolanczyk Harvey Singer I‐Ching Chou Marco Grados Danielle Posthuma Guy A. Rouleau Harald Aschauer Nelson B. Freimer David L. Pauls Nancy J. Cox Carol A. Mathews Jeremiah M. Scharf 《Annals of neurology》2014,76(2):310-315
Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10−3) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry‐matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10−4) remained significant after Bonferroni correction. Meta‐analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10−7). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case–control status (p = 0.042), suggesting that many of these variants are true TS risk alleles. Ann Neurol 2014;76:310–315 相似文献
43.
Calsequestrin determines the functional size and stability of cardiac intracellular calcium stores: Mechanism for hereditary arrhythmia
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Terentyev D Viatchenko-Karpinski S Györke I Volpe P Williams SC Györke S 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(20):11759-11764
Calsequestrin is a high-capacity Ca-binding protein expressed inside the sarcoplasmic reticulum (SR), an intracellular Ca release and storage organelle in muscle. Mutations in the cardiac calsequestrin gene (CSQ2) have been linked to arrhythmias and sudden death. We have used Ca-imaging and patch-clamp methods in combination with adenoviral gene transfer strategies to explore the function of CSQ2 in adult rat heart cells. By increasing or decreasing CSQ2 levels, we showed that CSQ2 not only determines the Ca storage capacity of the SR but also positively controls the amount of Ca released from this organelle during excitation-contraction coupling. CSQ2 controls Ca release by prolonging the duration of Ca fluxes through the SR Ca-release sites. In addition, the dynamics of functional restitution of Ca-release sites after Ca discharge were prolonged when CSQ2 levels were elevated and accelerated in the presence of lowered CSQ2 protein levels. Furthermore, profound disturbances in rhythmic Ca transients in myocytes undergoing periodic electrical stimulation were observed when CSQ2 levels were reduced. We conclude that CSQ2 is a key determinant of the functional size and stability of SR Ca stores in cardiac muscle. CSQ2 appears to exert its effects by influencing the local luminal Ca concentration-dependent gating of the Ca-release channels and by acting as both a reservoir and a sink for Ca in SR. The abnormal restitution of Ca-release channels in the presence of reduced CSQ2 levels provides a plausible explanation for ventricular arrhythmia associated with mutations of CSQ2. 相似文献
44.
Katalin Gulyas Nora Bodnar Zsofia Nagy Szilvia Szamosi Agnes Horvath Andrea Vancsa Edit Vegh Zoltan Szabo Gabriella Szucs Zoltan Szekanecz Sandor Szanto 《The European journal of health economics》2014,15(1):93-112
Background
Published economic evaluations of trastuzumab for the treatment of HER2-positive metastatic breast cancer have arrived at different conclusions regarding the cost-effectiveness of trastuzumab, despite comparative efficacy being demonstrated by a small set of randomised controlled trials (RCTs).Objectives
This article aims to provide insight into the quality of the evaluations and explore the possible drivers of the conflicting conclusions.Methods
A systematic literature review was conducted to identify all published economic evaluations that compared the incremental costs and outcomes of trastuzumab versus a comparator.Results
Fifteen economic evaluations were identified. In the evaluations that estimated efficacy using an RCT, the key drivers of the conclusions regarding cost-effectiveness were: the approach used to estimate overall survival in the control group given crossover to trastuzumab following progression in the trials; the inclusion of treatment beyond progression; inclusion of wastage due to unused vial portions, adverse events, and the cost of HER2 testing. Four evaluations used non-randomised approaches to estimate efficacy, thus introducing the potential for confounding. As a result these evaluations reported relatively optimistic estimates of comparative effectiveness. Finally the evaluations used different thresholds to determine whether treatment with trastuzumab was cost-effective.Conclusion
There were numerous drivers of the different conclusions regarding the cost-effectiveness of trastuzumab, many of which are due to judgements made by the authors when translating data from RCTs. Many of the potential drivers were not identified by the published systematic reviews of economic evaluations and perhaps more remain unidentified because of inconsistent and limited reporting. 相似文献45.
46.
47.
Russell Lewis McLaughlin Kevin Patrick Kenna Alice Vajda Susan Byrne Daniel G. Bradley Orla Hardiman 《Neurobiology of aging》2014
Mutations in UBQLN2 have been shown to be a cause of dominant X-linked amyotrophic lateral sclerosis (ALS). Occurrences of mutations in this gene vary across ALS populations. We screened UBQLN2 for mutations in a final cohort of 150 Irish ALS patients. Individuals who were from families with male-to-male transmission or who carried pathogenic hexanucleotide repeat expansions in C9orf72 were excluded. Apart from common synonymous variation, no sequence variants in UBQLN2 were observed. Mutations in UBQLN2 are therefore not a frequent cause of ALS in the Irish population. 相似文献
48.
Senka Bla?eti? Irena Labak Barbara Viljeti? Marta Balog Sandor G. Vari Zora Krivo?íková Martin Gajdo? Patrícia Kramárová Anton Kebis Rosemary Vukovi? Livia Puljak Elizabeta Has-Sch?n Marija Heffer 《Croatian medical journal》2014,55(3):228-238
Aim
To evaluate in a rat animal model whether ovariectomy, high fat diet (HFD), and physical activity in the form of running affect leptin receptor (Ob-R) distribution in the brain and white fat tissue compared to sham (Sh) surgery, standard diet (StD), and sedentary conditions.Methods
The study included 48 female laboratory Wistar rats (4 weeks old). Following eight weeks of feeding with standard or HFD, rats were subjected to either OVX or Sh surgery. After surgery, all animals continued StD or HFD for the next 10 weeks. During these 10 weeks, ovariectomy and Sh groups were subjected to physical activity or sedentary conditions. Free-floating immunohistochemistry and Western blot methods were carried out to detect Ob-R in the brain and adipose tissue.Results
StD-ovariectomy-sedentary group had a greater number of Ob-R positive neurons in lateral hypothalamic nuclei than StD-Sh-sedentary group. There was no difference in Ob-R positive neurons in arcuatus nuclei between all groups. Ob-R distribution in the barrel cortex was higher in HFD group than in StD group. Ob-R presence in perirenal and subcutaneous fat was decreased in StD-ovariectomy group.Conclusion
HFD and ovariectomy increased Ob-R distribution in lateral hypothalamic nuclei, but there was no effect on arcuatus nuclei. Our results are first to suggest that HFD, ovariectomy, and physical activity affect Ob-R distribution in the barrel cortex, which might be correlated with the role of Ob-R in election of food in rats.Obesity is one of the leading health issues worldwide, associated with an increased risk of morbidity and mortality (1). In 1997, the World Health Organization (WHO) formally recognized obesity as a global epidemic (2). Increase in body fat stores and obesity is caused by an imbalance between energy intake and energy expenditure (3,4). Since childhood obesity is a predictor of an increased death rate, the “obesity epidemic” may reverse the current declining rate of death from cardiovascular diseases (5). Factors that contribute to obesity can be environmental (6), social (7), behavioral (8), psychological (9), and genetic (10,11).Women generally have more body fat than men (12). Nevertheless similar odds ratios were recorded in women and men for the association of abdominal obesity with acute myocardial infarction (13). Weight gain is common after menopause, indicating an association between hormones and fat stores (14). A large scale observational study found that both the body mass index and the level of physical activity were independent predictors of mortality and that a higher level of physical activity did not eliminate the risk associated with adiposity. At the same time, women who were both lean and physically active had the lowest mortality (15). In animal studies menopause can be induced by ovariectomy (OVX) (16).Obesity can also be called a disorder of appetite and it is controlled by complex homeostatic mechanisms involving the hypothalamus and brainstem (17). Many gut peptides like cholecystokinin, ghrelin, glucagon-like peptide-1 (GLP-1), and -2 and peptide YY (PYY) act on the brain to control eating behavior (18). There are two different system for controlling feeding behavior: short-term and long-term (19). Short-term regulation involves neural signals from the GI tract and its hormones, like insulin, glucagon, and ghrelin (20). A hormone that functions mainly within long-term regulation is leptin (16 kD), a hormonal product of the obesity (ob) gen, primarily secreted by adipocytes (21) and released in the brain. It generates a feeling of satisfaction and acts like an appetite-suppressing agent. Circulating leptin levels are lower in ovariectomized rats (22).Food intake is regulated via neural circuits located in the hypothalamus (23). Leptin acts via its leptin or Ob receptors (Ob-R) and is primarily expressed in hypothalamic neurons (19) especially in arcuate, ventromedial, and dorsomedial nuclei (24). Leptin is transported across the blood-brain barrier (BBB) by a saturable transporter (25). Ob-R is also detected in nonhypothalamic areas in the mice and in human brain neocortex, cerebellum, entorinal cortex, amygdale, and rostral medulla (26). Adipocytes, endothelial cells, and macrophages also have leptin receptor at its surface, which suggests autocrine and paracrine action for leptin in human adipose tissue (27). Association between the expression of Ob-R in target tissues and physiological and hormonal controlled processes is still unclear. Leptin receptors mRNA is found in each of the major components of the CNS “feeding” circuitry – the brainstem, hypothalamus, and is distributed reward centers (Allan brain) (28). Therefore, the aim of the current study was to evaluate whether HFD affects Ob-R distribution compared with StD specifically in the barrel field and piriform cortex compared to standard feeding centers in the hypothalamus. We supposed that the combination of OVX and HFD is interesting for further research on selected brain regions, which might be alleviated by physical activity. We also supposed that changes in Ob-R level in white fat tissue would correlate with the changes in brain regions. 相似文献49.
50.
Cathy L. Barr Karen G. Wigg Elizabeth Zovko Paul Sandor Lap-Chee Tsui 《American journal of medical genetics. Part A》1996,67(3):301-305
Gilles de la Tourette Syndrome (TS) is a neuropsychiatric disorder characterized by both motor and vocal tics affecting approximately 1/10,000 females and 1/2000 males. Because of the success of neuroleptics and other agents interacting with the dopaminergic system in the suppression of tics, a defect in the dopamine system has been hypothesized in the etiology of TS. In this paper we test the hypothesis that the dopamine D4 receptor (DRD4) is linked to the genetic susceptibility to TS in five families. We tested three polymorphisms in the DRD4 gene and a polymorphism in the closely linked locus, tyrosine hydroxylase (TH). We found no evidence for linkage of DRD4 or TH to TS using an autosomal dominant model with reduced penetrance or using non-parametric methods. The presence of a mutation that results in a truncated non-functional D4 receptor protein was also tested for, but was not observed in these families. © 1996 Wiley-Liss, Inc. 相似文献