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1.
Artigo em Inglês | MEDLINE | ID: mdl-31824749

RESUMO

Background: Genes involved in Tourette syndrome (TS) remain largely unknown. We aimed to identify genetic factors contributing to TS in a French cohort of 120 individuals using a combination of hypothesis-driven and exome-sequencing approaches. Methods: We first sequenced exons of SLITRK1-6 and HDC in the TS cohort and subsequently sequenced the exome of 12 individuals harboring rare variants in these genes to find additional rare variants contributing to the disorder under the hypothesis of oligogenic inheritance. We further screened three candidate genes (OPRK1, PCDH10, and NTSR2) preferentially expressed in the basal ganglia, and three additional genes involved in neurotensin and opioid signaling (OPRM1, NTS, and NTSR1), and compared variant frequencies in TS patients and 788 matched control individuals. We also investigated the impact of altering the expression of Oprk1 in zebrafish. Results: Thirteen ultrarare missense variants of SLITRK1-6 and HDC were identified in 12 patients. Exome sequencing in these patients revealed rare possibly deleterious variants in 3,041 genes, 54 of which were preferentially expressed in the basal ganglia. Comparison of variant frequencies altering selected candidate genes in TS and control individuals revealed an excess of potentially disrupting variants in OPRK1, encoding the opioid kappa receptor, in TS patients. Accordingly, we show that downregulation of the Oprk1 orthologue in zebrafish induces a hyperkinetic phenotype in early development. Discussion: These results support a heterogeneous and complex genetic etiology of TS, possibly involving rare variants altering the opioid pathway in some individuals, which could represent a novel therapeutic target in this disorder.

2.
Mov Disord ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31755599

RESUMO

BACKGROUND: Effects of DBS on freezing of gait and other axial signs in PD patients are unclear. OBJECTIVE: Secondary analysis to assess whether DBS affects these symptoms within a large randomized controlled trial comparing DBS of the STN combined with best medical treatment and best medical treatment alone in patients with early motor complications (EARLYSTIM-trial). METHODS: One hundred twenty-four patients were randomized in the stimulation group and 127 patients in the best medical treatment group. Presence of freezing of gait was assessed in the worst condition based on item-14 of the UPDRS-II at baseline and follow-up. The posture, instability, and gait-difficulty subscore of the UPDRS-III, and a gait test including quantification of freezing of gait and number of steps, were performed in both medication-off and medication-on conditions. RESULTS: Fifty-two percent in both groups had freezing of gait at baseline based on UPDRS-II. This proportion decreased in the stimulation group to 34%, but did not change in the best medical treatment group at 24 months (P = 0.018). The steps needed to complete the gait test decreased in the stimulation group and was superior to the best medical treatment group (P = 0.016). The axial signs improved in the stimulation group compared to the best medical treatment group (P < 0.01) in both medication-off and medication-on conditions. CONCLUSIONS: Within the first 2 years of DBS, freezing of gait and other axial signs improved in the medication-off condition compared to best medical treatment in these patients. © 2019 International Parkinson and Movement Disorder Society.

3.
Genet Med ; 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31578471

RESUMO

PURPOSE: Lamb-Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. METHODS: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types ofSOX5 alterations. Functional consequences of selected substitutions were investigated. RESULTS: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype-phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. CONCLUSIONS: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.

4.
Regul Toxicol Pharmacol ; 108: 104470, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31479718

RESUMO

The European Partnership for Alternative Approaches to Animal Testing (EPAA) convened a Partners' Forum on repeated dose toxicity (RDT) testing to identify synergies between industrial sectors and stakeholders along with opportunities to progress these in existing research frameworks. Although RTD testing is not performed across all industrial sectors, the OECD accepted tests can provide a rich source of information and play a pivotal role for safety decisions relating to the use of chemicals. Currently there are no validated alternatives to repeated dose testing and a direct one-to-one replacement is not appropriate. However, there are many projects and initiatives at the international level which aim to implement various aspects of replacement, reduction and refinement (the 3Rs) in RDT testing. Improved definition of use, through better problem formulation, aligned to harmonisation of regulations is a key area, as is the more rapid implementation of alternatives into the legislative framework. Existing test designs can be optimised to reduce animal use and increase information content. Greater use of exposure-led decisions and improvements in dose selection will be beneficial. In addition, EPAA facilitates sharing of case studies demonstrating the use of Next Generation Risk Assessment applying various New Approach Methodologies to assess RDT.

5.
F1000Res ; 8: 988, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31508215

RESUMO

This is the fifth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2018 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The  highlights from 2019 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the  Tics collection on F1000Research.

6.
Nat Commun ; 10(1): 2984, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278295

RESUMO

The oxygen isotope composition of speleothems is a widely used proxy for past climate change. Robust use of this proxy depends on understanding the relationship between precipitation and cave drip water δ18O. Here, we present the first global analysis, based on data from 163 drip sites, from 39 caves on five continents, showing that drip water δ18O is most similar to the amount-weighted precipitation δ18O where mean annual temperature (MAT) is < 10 °C. By contrast, for seasonal climates with MAT > 10 °C and < 16 °C, drip water δ18O records the recharge-weighted δ18O. This implies that the δ18O of speleothems (formed in near isotopic equilibrium) are most likely to directly reflect meteoric precipitation in cool climates only. In warmer and drier environments, speleothems will have a seasonal bias toward the precipitation δ18O of recharge periods and, in some cases, the extent of evaporative fractionation of stored karst water.

7.
Clin Res Cardiol ; 2019 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-31236690

RESUMO

INTRODUCTION: The DANISH trial raised doubts about the effectiveness of primary prevention of sudden cardiac death by ICD implantation among patients with non-ischemic heart failure. We sought to analyse data from the EVITA-HF registry to give an answer from real-world registry data to the DANISH trial. METHODS: 1804 patients were identified from the EVITA-HF registry with chronic heart failure (CHF) due to ischemic or dilated heart disease and reduced left ventricular ejection fraction of ≤ 35%. The patients were divided into two groups: Patients with newly implanted cardioverter-defibrillator (ICD group; mean age 66 ± 12 years, 77% male) and without ICD (no-ICD group; mean age 66 ± 14 years, 77% male). The subgroups were compared with regard to mortality and predictive parameters affecting survival. RESULTS: Cardiovascular risk factors were similar among patients in the non-ICD group (n = 1473) compared to ICD group (n = 331). After 1-year follow-up patients with ischemic heart disease showed a significant improved survival in the ICD group compared to non-ICD group [92.1% vs. 80.6%, HR 0.37 (0.22-0.62)]. Patients with non-ischemic cardiomyopathy did not show a difference with regard to survival between the ICD and the non-ICD group [93.7% vs. 93.1%, HR 0.92 (0.43-1.97)]. The data were stable in a Cox-regression model. CONCLUSION: In a real-world setting, no benefit was evident for patients with non-ischemic cardiomyopathy and reduced left ventricular ejection fraction by adding ICD therapy in a short-term follow-up of 12 months in contrast to patients with ischemic cardiomyopathy.

8.
Ther Innov Regul Sci ; : 2168479019843514, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31084267

RESUMO

The EU is a member of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), and therefore adopts the ICH Guidelines, including the ICH M3 Guideline on Nonclinical Safety Studies. Following the 2016 incident in France with BIA 10-2474, and in light of the substantial evolvement of how early clinical development has been undertaken during the last 10 years, for example, conducting integrated (FIH) studies that include multiple parts (eg, single ascending doses, multiple ascending doses, food effect), EMA decided to update the existing 2007 FIH guideline. The key revisions to the 2007 guideline, now titled "Guideline on Strategies to Identify and Mitigate Risks for First-in-Human and Early Clinical Trials With Investigational Medicinal Products," include additional information. The revision reinforces the importance and impact of pharmacologic data, which supports the intended efficacy of the compound, risk assessment, and protocol design. The updates, effective February 2018, are intended to provide additional guidance and clarity for Sponsors developing FIH and early phase clinical research programs, and ultimately support subject safety. At the 2018 DIA Europe Annual Meeting in Basel, Switzerland, European regulators, industry representatives and academics convened a DIAlogue Session on April 17 to discuss how the revised 2017 guideline is being applied, and to establish recommendations for its application. Using two case studies as examples, the session participants discussed the nonclinical and clinical considerations for applying the newly revised recommendations, and interacted with a panel including regulators and industry representatives. The proceedings from this session reflect practical considerations for the implementation of the revised guideline.

9.
Plant Physiol ; 180(1): 634-653, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30872424

RESUMO

Mitochondria adjust their activities in response to external and internal stimuli to optimize growth via the mitochondrial retrograde response signaling pathway. The Arabidopsis (Arabidopsis thaliana) NAC domain transcription factor ANAC017 has previously been identified as a regulator of the mitochondrial retrograde response. We show here that overexpression of ANAC017 in Arabidopsis leads to growth retardation, altered leaf development with decreased cell size and viability, and early leaf senescence. RNA sequencing analyses revealed that increased ANAC017 expression leads to higher expression of genes related to mitochondrial stress, cell death/autophagy, and leaf senescence under nonlimiting growth conditions as well as extensive repression of chloroplast function. Gene regulatory network analysis indicated that a complex hierarchy of transcription factors exists downstream of ANAC017. These involve a set of up-regulated ANAC and WRKY transcription factors associated with organellar signaling and senescence. The network also includes a number of ethylene- and gibberellic acid-related transcription factors with established functions in stress responses and growth regulation, which down-regulate their target genes. A number of BASIC LEUCINE-ZIPPER MOTIF transcription factors involved in the endoplasmic reticulum unfolded protein response or balancing of energy homeostasis via the SNF1-RELATED PROTEIN KINASE1 were also down-regulated by ANAC017 overexpression. Our results show that the endoplasmic reticulum membrane tethering of the constitutively expressed ANAC017, and its controlled release, are crucial to fine-tune a fast reactive but potentially harmful signaling cascade. Thus, ANAC017 is a master regulator of cellular responses with mitochondria acting as central sensors.

10.
Am J Psychiatry ; 176(3): 217-227, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818990

RESUMO

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

12.
Neurology ; 92(10): e1109-e1120, 2019 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-30737338

RESUMO

OBJECTIVE: To investigate predictors for improvement of disease-specific quality of life (QOL) after deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson disease (PD) with early motor complications. METHODS: We performed a secondary analysis of data from the previously published EARLYSTIM study, a prospective randomized trial comparing STN-DBS (n = 124) to best medical treatment (n = 127) after 2 years follow-up with disease-specific QOL (39-item Parkinson's Disease Questionnaire summary index [PDQ-39-SI]) as the primary endpoint. Linear regression analyses of the baseline characteristics age, disease duration, duration of motor complications, and disease severity measured at baseline with the Unified Parkinson's Disease Rating Scale (UPDRS) (UPDRS-III "off" and "on" medications, UPDRS-IV) were conducted to determine predictors of change in PDQ-39-SI. RESULTS: PDQ-39-SI at baseline was correlated to the change in PDQ-39-SI after 24 months in both treatment groups (p < 0.05). The higher the baseline score (worse QOL) the larger the improvement in QOL after 24 months. No correlation was found for any of the other baseline characteristics analyzed in either treatment group. CONCLUSION: Impaired QOL as subjectively evaluated by the patient is the most important predictor of benefit in patients with PD and early motor complications, fulfilling objective gold standard inclusion criteria for STN-DBS. Our results prompt systematically including evaluation of disease-specific QOL when selecting patients with PD for STN-DBS. CLINICALTRIALSGOV IDENTIFIER: NCT00354133.


Assuntos
Estimulação Encefálica Profunda , Doença de Parkinson/psicologia , Doença de Parkinson/terapia , Qualidade de Vida , Seguimentos , Humanos , Prognóstico
14.
Neuroimaging Clin N Am ; 28(4): 639-648, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30322599

RESUMO

Given the need for early restoration of blood flow and preservation of partially damaged brain cells after ischemic stroke, the noninterventional treatment of stroke relies heavily on the speedy recognition and classification of the clinical syndrome. Initiation of systemic thrombolysis with careful observation of contraindications within the 3.0 (4.5)-hour time window is the approved therapy of choice. Management of hemorrhagic complications and resumption of oral anticoagulation if indicated are also discussed in this article.

15.
Commun Biol ; 1: 154, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30302398

RESUMO

Our meagre understanding of CFTR misfolding and its reversal by small-molecule correctors hampers the development of mechanism-based therapies of cystic fibrosis. Here we exploit a helical-hairpin construct-the simplest proxy of membrane-protein tertiary contacts-containing CFTR's transmembrane helices 3 and 4 and its corresponding disease phenotypic mutant V232D to gain molecular-level insights into CFTR misfolding and drug rescue by the corrector Lumacaftor. Using a single-molecule FRET approach to study hairpin conformations in lipid bilayers, we find that the wild-type hairpin is well folded, whereas the V232D mutant assumes an open conformation in bilayer thicknesses mimicking the endoplasmic reticulum. Addition of Lumacaftor reverses the aberrant opening of the mutant hairpin to restore a compact state as in the wild type. The observed membrane escape of the V232D hairpin and its reversal by Lumacaftor complement cell-based analyses of the full-length protein, thereby providing in vivo and in vitro correlates of CFTR misfolding and drug-action mechanisms.

16.
F1000Res ; 7: 1122, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30210792

RESUMO

This is the fourth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The  highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research.

17.
EMBO Mol Med ; 10(11)2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30224383

RESUMO

The beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) initiates the generation of amyloid-ß (Aß), and the amyloid cascade leading to amyloid plaque deposition, neurodegeneration, and dementia in Alzheimer's disease (AD). Clinical failures of anti-Aß therapies in dementia stages suggest that treatment has to start in the early, asymptomatic disease states. The BACE-1 inhibitor CNP520 has a selectivity, pharmacodynamics, and distribution profile suitable for AD prevention studies. CNP520 reduced brain and cerebrospinal fluid (CSF) Aß in rats and dogs, and Aß plaque deposition in APP-transgenic mice. Animal toxicology studies of CNP520 demonstrated sufficient safety margins, with no signs of hair depigmentation, retina degeneration, liver toxicity, or cardiovascular effects. In healthy adults ≥ 60 years old, treatment with CNP520 was safe and well tolerated and resulted in robust and dose-dependent Aß reduction in the cerebrospinal fluid. Thus, long-term, pivotal studies with CNP520 have been initiated in the Generation Program.

18.
Nat Methods ; 15(9): 669-676, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30171252

RESUMO

Single-molecule Förster resonance energy transfer (smFRET) is increasingly being used to determine distances, structures, and dynamics of biomolecules in vitro and in vivo. However, generalized protocols and FRET standards to ensure the reproducibility and accuracy of measurements of FRET efficiencies are currently lacking. Here we report the results of a comparative blind study in which 20 labs determined the FRET efficiencies (E) of several dye-labeled DNA duplexes. Using a unified, straightforward method, we obtained FRET efficiencies with s.d. between ±0.02 and ±0.05. We suggest experimental and computational procedures for converting FRET efficiencies into accurate distances, and discuss potential uncertainties in the experiment and the modeling. Our quantitative assessment of the reproducibility of intensity-based smFRET measurements and a unified correction procedure represents an important step toward the validation of distance networks, with the ultimate aim of achieving reliable structural models of biomolecular systems by smFRET-based hybrid methods.

19.
IEEE Trans Med Imaging ; 37(9): 2033-2043, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29993599

RESUMO

The brain is composed of several neural circuits which may be seen as anatomical complexes composed of grey matter structures interconnected by white matter tracts. Grey and white matter components may be modeled as 3-D surfaces and curves, respectively. Neurodevelopmental disorders involve morphological and organizational alterations which cannot be jointly captured by usual shape analysis techniques based on single diffeomorphisms. We propose a new deformation scheme, called double diffeomorphism, which is a combination of two diffeomorphisms. The first one captures changes in structural connectivity, whereas the second one recovers the global morphological variations of both grey and white matter structures. This deformation model is integrated into a Bayesian framework for atlas construction. We evaluate it on a data-set of 3-D structures representing the neural circuits of patients with Gilles de la Tourette syndrome (GTS). We show that this approach makes it possible to localise, quantify, and easily visualise the pathological anomalies altering the morphology and organization of the neural circuits. Furthermore, results also indicate that the proposed deformation model better discriminates between controls and GTS patients than a single diffeomorphism.

20.
Dev Med Child Neurol ; 60(9): 942-950, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29748952

RESUMO

AIM: To explore the heterogeneity of Tourette syndrome as part of a neurodevelopmental spectrum. METHOD: Using hierarchical ascendant clustering based on tic symptoms, developmental milestones, and neurodevelopmental comorbidities, we analyzed the heterogeneity of Tourette syndrome phenotypes in a sample of 174 children and adolescents with Tourette syndrome referred to a tertiary university clinic. RESULTS: The model yielded three distinct clusters characterized as follows. In cluster 1, we found many neurodevelopmental comorbidities (including intellectual disabilities, autism spectrum disorder, attention-deficit-hyperactivity disorder [ADHD], and learning disabilities) and academic impairments. In cluster 2, patients had no other neurodevelopmental comorbidities. In cluster 3, patients had higher intelligence, a high frequency of attentional impairment, school problems related to both ADHD and unspecific attention difficulties, and handwriting problems related to the tics themselves. Interestingly, clusters did not differ in terms of family history or anxious-depressive comorbidities. The only other differences that emerged were related to prenatal or perinatal risk factors (more represented in cluster 1) and treatment profiles (higher rates of stimulants in cluster 1). INTERPRETATION: We conclude that from a phenotypical perspective, Tourette syndrome is a heterogeneous syndrome with at least three main clusters that may help in addressing the etiological basis of Tourette syndrome and specific rehabilitative and therapeutic approaches. WHAT THIS PAPER ADDS: The clustering of Tourette syndrome based on comorbidity with other neurodevelopmental conditions reveals three clusters. A group of patients with Tourette syndrome show school difficulties related to non-specific attention and writing problems. Analysing only children and adolescents helps to distinguish between developmental comorbid conditions and coexistent disorders.


Assuntos
Transtornos do Neurodesenvolvimento/epidemiologia , Síndrome de Tourette/classificação , Síndrome de Tourette/complicações , Adolescente , Criança , Análise por Conglomerados , Estudos de Coortes , Feminino , França , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Síndrome de Tourette/psicologia
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