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1.
J Med Genet ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

3.
J Parkinsons Dis ; 11(4): 1845-1855, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34250953

RESUMO

BACKGROUND: Genetic studies have indicated that variants in several lysosomal genes are risk factors for idiopathic Parkinson's disease (PD). However, the role of lysosomal genes in PD in Asian populations is largely unknown. OBJECTIVE: This study aimed to analyze rare variants in lysosomal related genes in Chinese population with early-onset and familial PD. METHODS: In total, 1,136 participants, including 536 and 600 patients with sporadic early-onset PD (SEOPD) and familial PD, respectively, underwent whole-exome sequencing to assess the genetic etiology. Rare variants in PD were investigated in 67 candidate lysosomal related genes (LRGs), including 15 lysosomal function-related genes and 52 lysosomal storage disorder genes. RESULTS: Compared with the autosomal dominant PD (ADPD) or SEOPD cohorts, a much higher proportion of patients with multiple rare damaging variants of LRGs were found in the autosomal recessive PD (ARPD) cohort. At a gene level, rare damaging variants in GBA and MAN2B1 were enriched in PD, but in SCARB2, MCOLN1, LYST, VPS16, and VPS13C were much less in patients. At an allele level, GBA p. Leu483Pro was found to increase the risk of PD. Genotype-phenotype correlation showed no significance in the clinical features among patients carrying a discrepant number of rare variants in LRGs. CONCLUSION: Our study suggests rare variants in LRGs might be more important in the pathogenicity of ARPD cases compared with ADPD or SEOPD. We further confirm rare variants in GBA are involve in PD pathogenecity and other genes associated with PD identified in this study should be supported with more evidence.

4.
Mol Neurobiol ; 58(7): 3435-3442, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33723766

RESUMO

Functional and genetic studies have identified association between several Zinc finger (ZNF) proteins and Parkinson's disease (PD). However, most of them were still awaiting further replications, especially in the Asian population. Here, we systematically selected PD-relevant ZNF genes and analyzed the genetic associations between these ZNFs and PD in a large Chinese PD cohort. We identified rare variants (minor allele frequency < 0.01) in 743 unrelated patients with early-onset PD (EOPD, age at onset < 50 years) using whole exome sequencing and evaluated the association between rare variants and EOPD at both allele and gene levels. Totally 91 rare variants were identified in ZNF746, ZNF646, ZNF184, ZNF165, ZND219, and GLIS1. One variant p.R373H in ZNF219 and two variants p.G161D and p.R158H in ZNF746 were significantly associated with EOPD, and gene-based burden analysis showed enrichment of rare variants of ZNF746 in EOPD. Our findings build up the connection between ZNF746 and PD from a genetic perspective for the first time, supplement current understanding for the genetic role of ZNFs in EOPD, and broaden the mutation spectrum in PD.

5.
Mol Neurobiol ; 58(4): 1583-1592, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33219486

RESUMO

Recent genetic studies clearly indicate that variants in several lysosomal genes act as risk factors for idiopathic Parkinson's disease (PD). Variants in the co-activator of glucocerebrosidase gene (GBA) and the four active saposins (Sap A-D) which are encoded by the prosaposin gene (PSAP) are of particular interest; however, their genetic roles in PD are unknown. Whole-exome sequencing and Sanger sequencing were used to assess the genetic etiology of 400 autosomal dominant inherited PD (ADPD) and 300 sporadic PD (SPD) patients. Variants from public databases, including Genome Aggregation Database-East Asian (GnomAD_EAS) and Chinese Millionome Database (CMDB), were used as control groups. Burden analysis based on gene and domains level were performed to investigate the role of rare PSAP variants in PD. Six rare and likely pathogenic variants, located in the Sap A-D domains, were identified and accounted for 0.75% (3/400) of ADPD and 1.33% (4/300) of SPD in the Chinese population. Based on the gene or domain, burden analysis showed that damaging missense variants in SapC had statistical significance on the risk of developing PD. Interestingly, rs4747203, an intronic variant potentially linked to PSAP expression, was associated with reduced risk for PD (p = 8.6e-7 in GnomAD EAS and p = 0.002 in Chinese). Clinically, patients carrying the likely pathogenic variants presented typical PD motor symptoms and responded well to levodopa treatment. Six out of seven patients carrying the likely pathogenic variants of PSAP presented slow disease progression, and none of the patients developed cognitive impairment. Our study expands the spectrum of mutations associated with the risk of developing PD and enhances the understanding of the relationship of the clinical phenotype of PD with PSAP variants.

6.
Chin Med J (Engl) ; 134(6): 690-698, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33234871

RESUMO

BACKGROUND: Sleep disorders are common but under-researched symptoms in patients with multiple system atrophy (MSA). We investigated the frequency and factors associated with sleep-related symptoms in patients with MSA and the impact of sleep disturbances on disease severity. METHODS: This cross-sectional study involved 165 patients with MSA. Three sleep-related symptoms, namely Parkinson's disease (PD)-related sleep problems (PD-SP), excessive daytime sleepiness (EDS), and rapid eye movement sleep behavior disorder (RBD), were evaluated using the PD Sleep Scale-2 (PDSS-2), Epworth Sleepiness Scale (ESS), and RBD Screening Questionnaire (RBDSQ), respectively. Disease severity was evaluated using the Unified MSA Rating Scale (UMSARS). RESULTS: The frequency of PD-SP (PDSS-2 score of ≥18), EDS (ESS score of ≥10), and RBD (RBDSQ score of ≥5) in patients with MSA was 18.8%, 27.3%, and 49.7%, respectively. The frequency of coexistence of all three sleep-related symptoms was 7.3%. Compared with the cerebellar subtype of MSA (MSA-C), the parkinsonism subtype of MSA (MSA-P) was associated with a higher frequency of PD-SP and EDS, but not of RBD. Binary logistic regression revealed that the MSA-P subtype, a higher total UMSARS score, and anxiety were associated with PD-SP; that male sex, a higher total UMSARS score, the MSA-P subtype, and fatigue were associated with EDS; and that male sex, a higher total UMSARS score, and autonomic onset were associated with RBD in patients with MSA. Stepwise linear regression showed that the number of sleep-related symptoms (PD-SP, EDS, and RBD), disease duration, depression, fatigue, and total Montreal Cognitive Assessment score were predictors of disease severity in patients with MSA. CONCLUSIONS: Sleep-related disorders were associated with both MSA subtypes and the severity of disease in patients with MSA, indicating that sleep disorders may reflect the distribution and degree of dopaminergic/non-dopaminergic neuron degeneration in MSA.


Assuntos
Atrofia de Múltiplos Sistemas , Transtorno do Comportamento do Sono REM , Estudos Transversais , Humanos , Masculino , Índice de Gravidade de Doença , Sono
7.
J Int Med Res ; 46(1): 22-32, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28718688

RESUMO

This study was a meta-analysis of randomized controlled trials (RCTs) of ranitidine as an adjunct for antipsychotic-induced weight gain in patients with schizophrenia. RCTs reporting weight gain or metabolic side effects in patients with schizophrenia were included. Case reports/series, non-randomized or observational studies, reviews, and meta-analyses were excluded. The primary outcome measures were body mass index (BMI) (kg/m2) and body weight (kg). Four RCTs with five study arms were identified and analyzed. Compared with the control group, adjunctive ranitidine was associated with marginally significant reductions in BMI and body weight. After removing an outlier study for BMI, the effect of ranitidine remained significant. Adjunctive ranitidine outperformed the placebo in the negative symptom score of the Positive and Negative Syndrome Scale. Although ranitidine was associated with less frequent drowsiness, other adverse events were similar between the two groups. Adjunctive ranitidine appears to be an effective and safe option for reducing antipsychotic-induced weight gain and improving negative symptoms in patients with schizophrenia. Larger RCTs are warranted to confirm these findings. Trial registration PROSPERO: CRD42016039735.


Assuntos
Antipsicóticos/efeitos adversos , Substâncias Protetoras/uso terapêutico , Ranitidina/uso terapêutico , Esquizofrenia/tratamento farmacológico , Ganho de Peso/efeitos dos fármacos , Adulto , Antipsicóticos/antagonistas & inibidores , Índice de Massa Corporal , Peso Corporal/efeitos dos fármacos , Feminino , Humanos , Masculino , Placebos , Ensaios Clínicos Controlados Aleatórios como Assunto , Esquizofrenia/fisiopatologia
8.
PLoS One ; 9(1): e86542, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24466142

RESUMO

The idea of retinal and ex-retinal sources of saccadic suppression has long been established in previous studies. However, how they are implemented in local circuit remains unknown. Researchers have suggested that saccadic suppression was probably achieved by contrast gain control, but this possibility has never been directly tested. In this study, we manipulated contrast gain control by contrast-adapting observers with sinusoidal gratings of different contrasts. Presaccadic and fixational contrast thresholds were measured and compared to give estimates of saccadic suppression at different adaptation states. Our results reconfirmed the selective saccadic suppression in achromatic condition, and further showed that, achromatic saccadic suppression diminished as contrast adaptation was accentuated, whereas no significant chromatic saccadic suppression was induced by greater contrast adaptation. Our data provided evidence for the involvement of contrast gain control in saccadic suppression in achromatic channel. We also discussed how the negative correlation between contrast adaptation and saccadic suppression could be interpreted with contrast gain control.


Assuntos
Adaptação Fisiológica , Sensibilidades de Contraste , Movimentos Sacádicos/fisiologia , Adulto , Feminino , Humanos , Masculino , Estimulação Luminosa
9.
Zhonghua Yi Xue Za Zhi ; 90(23): 1631-4, 2010 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-20979754

RESUMO

OBJECTIVE: The aim of this research is to observe whether esmolol infusion as an adjunct to propofol can affect BIS index, reduce anesthetic dose and decrease emergence time. METHOD: Sixty ASA I-II patients, age 18-35, undergoing uterine dilatation and curettage surgery were studied. They were randomized into two groups. Before induction, patients in esmolol group (Group E) were received 1 mg/kg esmolol intravenously and followed by esmolol 150 microg x kg(-1) x min(-1) intravenous infusion; patients in group C received normal saline instead of esmolol. Fentanyl (1 microg/kg) and propofol (2 mg/kg) were used as induction drugs. The change of BIS index, heart rate and MAP during operation; total amount of propofol; time when patients opened eyes and time when patients reached the standard for discharge from hospital were recorded. RESULTS: BIS and heart rate of Group C at 1,2,3 minute after surgery started, increased significantly compared with the time after induction and those in Group E (P < 0.05). The time patients reached the score of discharging from hospital in Group C is longer than that in Group E (P < 0.05). CONCLUSION: Esmolol combined with propofol administering in minor ambulatory operations can control the increase of BIS index caused by surgical nociceptive stimulus. Meanwhile the combination could reduce the dose of sedatives and decrease anesthesia emergence time.


Assuntos
Procedimentos Cirúrgicos Ambulatórios/métodos , Anestesia/métodos , Anestésicos Intravenosos/uso terapêutico , Propanolaminas/uso terapêutico , Aborto Induzido , Adolescente , Adulto , Período de Recuperação da Anestesia , Eletroencefalografia , Feminino , Humanos , Gravidez , Propofol/uso terapêutico , Adulto Jovem
10.
Zhonghua Yi Xue Za Zhi ; 90(11): 760-2, 2010 Mar 23.
Artigo em Chinês | MEDLINE | ID: mdl-20627022

RESUMO

OBJECTIVE: To evaluate whether administration of flurbiprofen axetil before elective laparoscopic cholecystectomy can affect the BIS index and hemodynamics. METHOD: Sixty patients scheduled for elective laparoscopic cholecystectomy were randomized into two groups. Flurbiprofen axetil 1 mg/kg was used intravenous 15 minutes before induction of general anesthesia in group B, while group A without premedication. Total intravenous anesthesia was maintained with propofol TCI. BIS index, blood pressure and heart rate were recorded at the time just before induction, after endotracheal intubation, 5 minutes before incision, incision, 5, 10, 15, 20 and 25 mins after incision. RESULT: There were no significant difference between two groups in BIS index during period of anesthesia and awareness (all P > 0.05). Compared with group A, both systolic and diastolic blood pressure in group B at time of incision (T(1)) are apparently lower (P < 0.05). While, blood pressures were no significant different at other time (all P > 0.05). CONCLUSION: In this study, administration of flurbiprofen before surgery of laparoscopic cholecystectomy did not alter BIS and the degree of sedation during total intravenous anesthesia. But it can reduce the harmful stimulation to cardiovascular reaction from surgery and make hemodynamic status more stable. Flurbiprofen can be safely and effectively used on elective laparoscopic cholecystectomy.


Assuntos
Anestesia Intravenosa/métodos , Anestésicos Intravenosos/uso terapêutico , Colecistectomia Laparoscópica/métodos , Flurbiprofeno/análogos & derivados , Adolescente , Adulto , Idoso , Feminino , Flurbiprofeno/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Pré-Medicação , Adulto Jovem
11.
Zhonghua Yi Xue Za Zhi ; 87(20): 1425-6, 2007 May 29.
Artigo em Chinês | MEDLINE | ID: mdl-17785070

RESUMO

OBJECTIVE: To introduce an effective method for preventing bile duct injury in laparoscopic cholecystectomy. METHODS: From January 2003 to October 2005, laparoscopic cholecystectomy was performed on 629 patients, 335 males and 294 females, aged 46.3 (14 - 81). The common hepatic duct was exposed by blunt dissection routinely before transecting the cystic duct. RESULTS: No bile duct injury occurred. 7 cases were converted to open procedure, 5 cases for severe abdominal adhesion, one for internal fistula of bile duct to intestinal tract, and another 1 for gall bladder cancer. 2 patients had postoperative complications, one with raw surface bleeding, and the other with incision bleeding. CONCLUSION: Exposing common hepatic duct by blunt dissection in laparoscopic cholecystectomy can prevent intraoperative bile duct injury. Such procedure is simple, easy to learn and easy to apply.


Assuntos
Colecistectomia Laparoscópica/métodos , Ducto Hepático Comum/cirurgia , Complicações Intraoperatórias/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ductos Biliares/lesões , Colecistectomia Laparoscópica/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
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