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81.
Nitric oxide synthase genes and their interactions with environmental factors in Parkinson’s disease
Nitric oxide synthase (NOS) genes (NOS1, NOS2A, and NOS3) may create excess nitric oxide that contributes to neurodegeneration in Parkinson’s disease (PD). NOS genes might also interact
with one another or with environmental factors in PD. Coding and tagging single nucleotide polymorphisms (SNPs) (27 NOS1, 18 NOS2A, and five NOS3 SNPs) were genotyped in families with PD (1,065 cases and 1,180 relative and other controls) and were tested for allelic
associations with PD using the association in the presence of linkage test and the pedigree disequilibrium test (PDT), allelic
associations with age-at-onset (AAO) using the quantitative transmission disequilibrium test, and interactions using the multifactor
dimensionality reduction—PDT. Gene–environment interactions involving cigarette smoking, caffeine, nonsteroidal anti-inflammatory
drugs, and pesticides were examined using generalized estimating equations in participants with environmental data available.
Significant associations with PD were detected for the NOS1 SNPs rs3782218, rs11068447, rs7295972, rs2293052, rs12829185, rs1047735, rs3741475, and rs2682826 (range of p = 0.00083–0.046) and the NOS2A SNPs rs2072324, rs944725, rs12944039, rs2248814, rs2297516, rs1060826, and rs2255929 (range of p = 0.0000040–0.047) in earlier-onset families with sporadic PD, and some SNPs were also associated with earlier AAO. There
was no compelling statistical evidence for gene–gene interactions. However, of the significantly associated SNPs, interactions
were found between pesticides and the NOS1 SNPs rs12829185, rs1047735, and rs2682826 (range of p = 0.012–0.034) and between smoking and the NOS2A SNPs rs2248814 (p = 0.021) and rs1060826 (p = 0.013). These data implicate NOS1 and NOS2A as genetic risk factors for PD and demonstrate that their interactions with established environmental factors may modulate
the environmental effects. 相似文献
82.
Hortobágyi T Troakes C Nishimura AL Vance C van Swieten JC Seelaar H King A Al-Sarraj S Rogelj B Shaw CE 《Acta neuropathologica》2011,121(4):519-527
Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression.
OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS).
OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance
of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial
ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions
were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot
of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared
to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in
FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimer’s disease (AD)
cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity
in Huntington’s disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau
and α-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43
positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the
pathogenesis of ALS, FTLD or any other neurodegenerative disorder. 相似文献
83.
D. A. Solomon J.C. Mitchell M.‐T. Salcher‐Konrad C.A. Vance S. Mizielinska 《Neuropathology and applied neurobiology》2019,45(1):58-80
Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development. 相似文献
84.
McCorquodale DS Montenegro G Peguero A Carlson N Speziani F Price J Taylor SW Melanson M Vance JM Züchner S 《Journal of neurology》2011,258(7):1234-1239
Charcot-Marie-Tooth (CMT) disease is among the most common inherited neurological disorders. Mutations in the gene mitofusin 2 (MFN2) cause the axonal subtype CMT2A, which has also been shown to be associated with optic atrophy, clinical signs of first motor
neuron involvement, and early onset stroke. Mutations in MFN2 account for up to 20–30% of all axonal CMT type 2 cases. To further investigate the prevalence of MFN2 mutations and to add to the genotypic spectrum, we sequenced all exons of MFN2 in a cohort of 39 CMT2 patients. We identified seven variants, four of which are novel. One previously described change was co-inherited with a PMP22 duplication,
which itself causes the demyelinating form CMT1A. Another mutation was a novel in frame deletion, which is a rare occurrence
in the genotypic spectrum of MFN2 characterized mainly by missense mutations. Our results confirm a MFN2 mutation rate of ~15–20% in CMT2. 相似文献
85.
Excel97在药物分析中的应用 总被引:1,自引:0,他引:1
目的:在药物分析中,电子表格软件MicrosoftExce197for Windows。方法:利用Excel的数据处理功能,进行药物的图表绘制、数据计算和统计处理,回归分析,特别是计算分析,并可建立分析数据库。结果和结论:Excel操作简单,功能强大,数据分析工作直观。 相似文献
86.
Adeno-associated virus(AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes. We studied AAV transduction in the context of prior exposure of AAV serotype 8(AAV8) to environmental p H within the range encountered during endosomal endocytosis(p H 7.4 to p H 4.4), during which low p H-triggered structural and autoproteolytic changes to the viral capsid are believed to be necessary for endosome escape and virus uncoating. Due to the fundamental nature of these processes, we hypothesized that premature exposure of AAV8 particles to acidic p H would decrease viral transduction of HT1080 cells in vitro, as measured by fluorescent reporter gene expression using high-content imaging analysis. We found that increasingly acidic incubation conditions were associated with concomitant reductions in transduction efficiency, and that quantitative levels of reporter gene expression in transduced cells were similarly decreased. The biggest decrease in transduction occurred between p H 7.4 and p H 6.4, suggesting the possible co-occurrence of a p H-associated event and viral inactivation within that range. Taken together, these findings indicate that exposure of AAV8 to acidic p H for as little as 1 hour is deleterious to transduction ability. Future studies are necessary to understand the p H-associated causative mechanisms involved. This study was approved by the University of Miami Institutional Animal Care and Use Committee, USA(Protocol #18-108-LF) on July 12, 2018. 相似文献
87.
PLS—紫外分光光度法同时测定复方阿斯匹林片中三组分含量 总被引:7,自引:0,他引:7
本文研究了复方阿斯匹林片中阿斯匹林、非那西丁和咖啡因含量同时测定的紫外分光光度法的最佳实验条件,并简述偏最小二乘法(PLS)在多组分同时测定中的基本原理和应用。三组分模拟试样回收率平均值的置信区间分别为100.1±0.23%,100.0±0.25%和100.1±0.33%(置信度95%)。PLS法是一种理想的多组分测定方法,计算速度较快,结果更准确可靠,尤其适用于成批试样的分析,为微机控制的紫外可见分光光度计提供了一种新方法。 相似文献
88.
89.
Vance DE Burgio LD Roth DL Stevens AB Fairchild JK Yurick A 《The journals of gerontology. Series B, Psychological sciences and social sciences》2003,58(2):P129-P137
Agitation in nursing home residents presents a serious challenge to caregivers and may place residents at risk for harm. Understanding the etiology of agitation can assist clinicians in developing nonpharmacologic interventions for preventing and treating this problem. The purpose of this study was to examine independent and common predictors of resident agitation with structural equation modeling. Agitation was measured with both a standardized staff report rating scale and direct behavioral observation. No indirect or mediating effects were found. Cognitive impairment, vision and hearing impairment, and gender were found to be independent predictors of agitation as measured by direct behavioral observation. Only cognitive impairment was found to be predictive of agitation as measured by the standardized staff report scale. An unexpected finding was that vision impairment appeared to exert a protective effect for agitation in these severely cognitively impaired residents. The clinical implications of these findings are discussed as well as the relative merits of the two methods of measuring agitation. 相似文献
90.
Cushing's disease and its associated clinical syndrome reflect the effects of excess cortisol on the individual. The cause of Cushing's disease is ordinarily an ACTH-secreting benign pituitary adenoma. The diagnosis of Cushing's disease is established by sophisticated endocrine testing and comprehensive imaging studies. Because of the devastating effects of excess cortisol, therapy that provides prompt and effective normalization of serum cortisol is essential. Currently this goal is best achieved by transsphenoidal microsurgery. This paper reviews the clinical presentation, laboratory analysis, surgical management and outcome in patients with Cushing's disease. 相似文献