Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack ...Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).展开更多
Cardiac amyloidosis(CA)is an infiltrative and restrictive cardiomyopathy that leads to heart failure(HF),decreased quality of life,and death.[1–3]There are two main subtypes of the disease,transthyretin cardiac amylo...Cardiac amyloidosis(CA)is an infiltrative and restrictive cardiomyopathy that leads to heart failure(HF),decreased quality of life,and death.[1–3]There are two main subtypes of the disease,transthyretin cardiac amyloidosis(ATTR-CA)and immunoglobulin light chain CA.The former was further subdivided into wild-type(ATTRwt-CA)and or variant(ATTRv-CA)according to the presence or absence of a mutations in the transthyretin(TTR)gene.展开更多
Objective To examine the association of atherosclerotic cardiovascular disease(ASCVD)and its risk factors with cognitive impairment in older adults.Methods Six hundred and fourteen subjects,aged≥65 years,from one cen...Objective To examine the association of atherosclerotic cardiovascular disease(ASCVD)and its risk factors with cognitive impairment in older adults.Methods Six hundred and fourteen subjects,aged≥65 years,from one center(2016–2018)underwent clinical,laboratory assessments and the Montreal Cognitive Assessment(Mo CA).Using regression analysis,the relationship between ASCVD and its risk factors was evaluated in subjects with and without cognitive impairment(MoCA score<26).Results Older age(b=-1.3 per 5 years,95%CI:-1.7 to-0.9,P<0.001),history of stroke(b=-1.6,95%CI:-3.0 to-0.3,P=0.01),and myocardial infarction(MI;b=-2.2,95%CI:-3.6 to-0.8,P=0.003)were independently associated with lower MoCA scores,whereas more education(b=1.5 per 3 years,95%CI:1.1 to 1.9,P<0.001),higher body mass index(BMI;b=0.5 per 3 kg/m^2,95%CI:0.0 to 1.0,P=0.04),higher estimated glomerular filtration rate(eGFR;b=0.8 per 15 U,95%CI:0.1 to 1.4,P=0.03),left ventricular ejection fraction(LVEF;b=0.4 per 5%,95%CI:0 to 0.8,P=0.04)and statin use(b=1.3,95%CI:0.3 to 2.3,P=0.01)were associated with a higher MoCA score.Cognitive impairment was independently associated with older age(OR=1.51 per 5 yrs,95%CI:1.28 to 1.79,P<0.001),less education(OR=0.55 per 3 years,95%CI:0.45 to 0.68,P<0.001),lower BMI(OR=0.78 per 3 kg/m^2,95%CI:0.62 to 0.98,P=0.03)and higher levels of high sensitivity c-reactive protein(hsCRP;OR=1.08 per 1 mg/L,95%CI:1.02 to 1.15,P=0.01).Conclusions Beyond age,cognitive impairment was associated with prior MI/stroke,higher hsCRP,statin use,less education,lower eGFR,BMI and LVEF.展开更多
p.Tyr329fs is a cytochrome P450c17 mutation among Chinese individuals.However,data on 17-α-hydroxylase deficiency caused by cytochrome P450c17 p.Tyr329fs homozygous mutation are lacking.This paper is a case report of...p.Tyr329fs is a cytochrome P450c17 mutation among Chinese individuals.However,data on 17-α-hydroxylase deficiency caused by cytochrome P450c17 p.Tyr329fs homozygous mutation are lacking.This paper is a case report of three patients homozygous for p.Tyr329fs who were diagnosed with 17-α-hydroxylase deficiency between 2005 and 2019.CASE SUMMARY Case 1 presented with hypertension,hypokalemia,sexual infantilism and delayed bone age.The patient had a 46,XY karyotype,was homozygous for p.Tyr329fs and was recently treated with dexamethasone 0.375 mg qn.Case 2 presented with hypokalemia,sexual infantilism,osteoporosis and delayed bone age.The patient had a 46,XY karyotype,was homozygous for p.Tyr329fs and was treated with dexamethasone 0.75 mg qn at the last follow-up.Serum potassium and blood pressure could be maintained within normal range for cases 1 and 2.Case 3 presented with amenorrhea,sexual infantilism,osteopenia and delayed bone age.The patient had a 46,XX karyotype,was homozygous for p.Tyr329fs and was treated with dexamethasone 0.75 mg qn and progynova 1 mg qd.Outpatient follow-up revealed an adrenocorticotropic hormone(8 AM)of<5.00 pg/mL.CONCLUSION The homozygous p.Tyr329fs mutation usually manifests as a combined deficiency,and definitive diagnosis depends primarily on genetic testing.展开更多
Summary What is already known about this topic?Previous studies have indicated a possible association between reproductive tract infections(RTIs)and highrisk human papillomavirus(HPV)infection,but the evidence is stil...Summary What is already known about this topic?Previous studies have indicated a possible association between reproductive tract infections(RTIs)and highrisk human papillomavirus(HPV)infection,but the evidence is still inconclusive.What is added by this report?This multicenter study found significantly higher positive rates of HPV,including general HPV,highrisk HPV.展开更多
Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(ST...Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.展开更多
In this work,the self-nucleation effect on crystallization was studied for polypropylene with various nucleating agents.The talc was employed to accelerate crystallization of monoclinic α-crystallites,while N,N′-dic...In this work,the self-nucleation effect on crystallization was studied for polypropylene with various nucleating agents.The talc was employed to accelerate crystallization of monoclinic α-crystallites,while N,N′-dicyclohexyl-2,6-naphthalenedicarboxamide TMB-5 was used to accelerate the crystallization kinetics and also induce formation of trigonal β-crystallites.To induce self-nucleation effect,the occurrence criterion was assessed by the transition temperatures from various domains and the available temperature width.More importantly,the resulting influences of self-nucleation effect were quantified by the change of crystallization kinetics and the potential polymorphism variation.It was found that the α-nucleating agents of talc broadened the temperature window for inducing Domain Ⅱ by elevating the transition temperature from Domain Ⅰ to Domain Ⅱ.Although β-nucleating agent(β-NA)of N,N′-dicyclohexyl-2,6-naphthalenedicarboxamide TMB-5 elevated cooling crystallization temperature obviously,the temperature window for Domain Ⅱ was narrowed.It should be emphasized that in presence of β-NA TMB-5,the self-nucleation effect enhances the crystallization of α-crystallite,which show the competition with β-NA TMB-5.At last,the ternary PP/talc/TMB-5 blend was prepared with the same amounts of α-NA talc and β-NA TMB-5 and it exhibits a similar self-nucleation effect of crystallization,indicating the dominant role of β-NA TMB-5.展开更多
Background： Vulvovaginal candidiasis （WC） was a common infection associated with lifelong harassment of woman＇s social and sexual life. The purpose of this study was to describe the species distribution and in vit...Background： Vulvovaginal candidiasis （WC） was a common infection associated with lifelong harassment of woman＇s social and sexual life. The purpose of this study was to describe the species distribution and in vitro antifungal susceptibility of Candida species （Candida spp.） isolated from patients with VVC over 8 years. Methods： Species which isolated from patients with VVC in Peking University First Hospital were identified using chromogenic culture media. Susceptibility to common antifungal agents was determined using agar diffusion method based on CLSI M44-A2 document. SPSS software （version 14.0, Inc., Chicago, IL, USA） was used for statistical analysis, involving statistical description and Chi-square test. Results： The most common strains were Candida （C.） albicans, 80.5% （n = 1775） followed by C. glabrata, 18.1% （n = 400）. Nystatin exhibited excellent activity against all species （〈4% resistant JR]）. Resistance to azole drugs varied among different species. C. albicans： clotrimazole （3.1% R） 〈 fluconazole （ 16.6% R） 〈 itraconazole （51.5% R） 〈 mieonazole （54.0% R）, C. glabrata： miconazole （25.6% R） 〈 clotrimazole （50.5% R） 〈 itraconazole （61.9% R） 〈 fluconazole （73.3% R）; Candida krusei： clotrimazole （0 R） 〈 fluconazole （57.7% R） 〈 miconazole （73.1% R） 〈 itraconazole （83.3% R）. The susceptibility of fluconazole was noticeably decreasing among all species in the study period. Conclusions： Nystatin was the optimal choice for the treatment of VVC at present. The species distribution and in ~＇itro antifungal susceptibility of Candida spp. isolated from patients with VVC had changed over time.展开更多
Schizophrenia is considered to be a disorder of brain connectivity, which might result from a disproportionally impaired rich-club organization. The rich-club is composed of highly interconnected hub regions that play...Schizophrenia is considered to be a disorder of brain connectivity, which might result from a disproportionally impaired rich-club organization. The rich-club is composed of highly interconnected hub regions that play crucial roles in integrating information between different brain regions. Few studies have yet investigated whether the structural rich-club organization is impaired in patients and their first-degree relatives. In this study, we established a weighted network model of white matter connections using diffusion tensor imaging of 19 patients and 39 unaffected parents, 22 young healthy controls for the patients, and 25 old healthy controls for the parents. Feeder edges between rich-club nodes and non-rich-club nodes were significantly decreased in both schizophrenic patients and their unaffected parents compared with controls.Furthermore, the feeder edges showed significant positive correlations with the scores in Category Fluency Test—animal naming in the unaffected parents. Specific feeder edges exhibited discriminative power with accuracy of 84.4% in distinguishing unaffected parents from old healthy controls. Our findings suggest that impaired richclub organization, especially impaired feeder edges, may be related to familial vulnerability to schizophrenia,possibly reflecting a genetic predisposition for schizophrenia.展开更多
Several lines of evidence suggest that efficient information integration between brain regions is disrupted in schizophrenia. Abnormalities in white matter tracts that interconnect brain regions may be directly releva...Several lines of evidence suggest that efficient information integration between brain regions is disrupted in schizophrenia. Abnormalities in white matter tracts that interconnect brain regions may be directly relevant to this pathophysiological process. As a complex mental disorder with high heritability, mapping abnormalities in patients and their first- degree relatives may help to disentangle the risk factors for schizophrenia. We established a weighted network model of white matter connections using diffusion tensor imaging in 25 nuclear families with schizophrenic probands （19 patients and 41 unaffected parents） and two unrelated groups of normal controls （24 controls matched with patients and 26 controls matched with relatives）. The patient group showed lower global efficiency and local efficiency. The decreased regional efficiency was localized in hubs such as the bilateral frontal cortices, bilateral anterior cingulate cortices, and left precuneus. The global efficiency was negatively correlated with cognition scores derived from a 5-factor model of schizophrenic psychopathology.We also found that unaffected parents displayed decreased regional efficiency in the right temporal cortices, left supplementary motor area, left superior temporal pole, and left thalamus. The global efficiency tended to be lower in unaffected parents. Our data suggest that （1） the global efficiency loss in neuroanatomical networks may be associated with the cognitive disturbances in schizophrenia; and （2） genetic vulnerability to schizophrenia may influence the anatomical organization of an individual＇s brain networks.展开更多
Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume （GMV） reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV dec...Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume （GMV） reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV decrease in the rostral medial frontal cortex （rMFC, including the anterior cingulate cortex） in the patient group during a 6-week follow-up of 40 patients with schizophrenia and 31 healthy controls well-matched for age, gender, and education. The higher baseline GMV in the rMFC predicted better improvement in the positive score on the Positive and Negative Syndrome Scale （PANSS）, and this might be related to the improved reality-monitoring. Besides, a higher baseline GMV in the posterior rMFC predicted better remission of general symptoms, and a lesser GMV reduction in this region was correlated with better remission of negative symptoms, probably associated with ameliorated self-referential pro- cessing and social cognition. Besides, a shorter disease course and higher educational level contributed to better improvement in the general psychopathological PANSS score, and a family history was negatively associated with improvement of the negative and total PANSS scores. These phenomena might be important for understanding the neuropathological mechanisms underlying the symp- toms of schizophrenia and for making clinical decisions.展开更多
Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) ...Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.展开更多
It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the hu...It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the human MSI2 gene plays a substantial role in stem-cell maintenance,asymmetric division,and differentiation during neurogenesis.Our previous genome-wide association study（GWAS）implied an association of MSI2 with schizophrenia in a Han Chinese population.To further explore this association,three single-nucleotide polymorphisms（SNPs）,rs9892791,rs11657292,and rs1822381,were selected for a replication study involving 921 schizophrenia cases and 1244 controls.After rigorous Bonferroni correction,two of the SNPs（rs9892791 and rs11657292） displayed significant differences in allele and genotype distribution frequencies between the case and control groups.When our GWAS and replication samples were combined,the three MSI2 SNPs were all strongly associated with schizophrenia（rs9892791：allelic P = 1.07E-5;rs11657292：allelic P = 1.95E-12;rs1822381：allelic P = 1.44E-4）.These results indicate that the human MSI2 gene might be a susceptibility gene forschizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.展开更多
The ZNF804 A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting sta...The ZNF804 A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804 A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity（RSFC） between the hippocampus and the dorsolateral prefrontal cortex（DLPFC） in both schizophrenic patients and healthy controls. The homozygous ZNF804 A rs1344706 genotype（AA） conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC（F（2,165） = 13.43,P ／ 0.001）. The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804 A rs1344706 on hippocampalprefrontal RSFC associated with schizophrenia.展开更多
基金supported by the National Natural Science Foundation of China(81825009,82071505,81901358)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2MC&T-B-099,2019-I2M-5–006)+2 种基金the Program of Chinese Institute for Brain Research Beijing(2020-NKX-XM-12)the King’s College London-Peking University Health Science Center Joint Institute for Medical Research(BMU2020KCL001,BMU2019LCKXJ012)the National Key R&D Program of China(2021YFF1201103,2016YFC1307000).
文摘Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).
文摘Cardiac amyloidosis(CA)is an infiltrative and restrictive cardiomyopathy that leads to heart failure(HF),decreased quality of life,and death.[1–3]There are two main subtypes of the disease,transthyretin cardiac amyloidosis(ATTR-CA)and immunoglobulin light chain CA.The former was further subdivided into wild-type(ATTRwt-CA)and or variant(ATTRv-CA)according to the presence or absence of a mutations in the transthyretin(TTR)gene.
基金funded by grants from Beijing Healthcare Committee Fund (19-8)Research Foundation of Beijing Friendship Hospital+1 种基金Capital Medical University (yyqdkt 2017-6)Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201838)。
文摘Objective To examine the association of atherosclerotic cardiovascular disease(ASCVD)and its risk factors with cognitive impairment in older adults.Methods Six hundred and fourteen subjects,aged≥65 years,from one center(2016–2018)underwent clinical,laboratory assessments and the Montreal Cognitive Assessment(Mo CA).Using regression analysis,the relationship between ASCVD and its risk factors was evaluated in subjects with and without cognitive impairment(MoCA score<26).Results Older age(b=-1.3 per 5 years,95%CI:-1.7 to-0.9,P<0.001),history of stroke(b=-1.6,95%CI:-3.0 to-0.3,P=0.01),and myocardial infarction(MI;b=-2.2,95%CI:-3.6 to-0.8,P=0.003)were independently associated with lower MoCA scores,whereas more education(b=1.5 per 3 years,95%CI:1.1 to 1.9,P<0.001),higher body mass index(BMI;b=0.5 per 3 kg/m^2,95%CI:0.0 to 1.0,P=0.04),higher estimated glomerular filtration rate(eGFR;b=0.8 per 15 U,95%CI:0.1 to 1.4,P=0.03),left ventricular ejection fraction(LVEF;b=0.4 per 5%,95%CI:0 to 0.8,P=0.04)and statin use(b=1.3,95%CI:0.3 to 2.3,P=0.01)were associated with a higher MoCA score.Cognitive impairment was independently associated with older age(OR=1.51 per 5 yrs,95%CI:1.28 to 1.79,P<0.001),less education(OR=0.55 per 3 years,95%CI:0.45 to 0.68,P<0.001),lower BMI(OR=0.78 per 3 kg/m^2,95%CI:0.62 to 0.98,P=0.03)and higher levels of high sensitivity c-reactive protein(hsCRP;OR=1.08 per 1 mg/L,95%CI:1.02 to 1.15,P=0.01).Conclusions Beyond age,cognitive impairment was associated with prior MI/stroke,higher hsCRP,statin use,less education,lower eGFR,BMI and LVEF.
基金Anhui Province Central Guided Local Science and Technology Development Funding Project,No.2017070802D147Anhui Province Key Clinical Specialist Construction Fund.
文摘p.Tyr329fs is a cytochrome P450c17 mutation among Chinese individuals.However,data on 17-α-hydroxylase deficiency caused by cytochrome P450c17 p.Tyr329fs homozygous mutation are lacking.This paper is a case report of three patients homozygous for p.Tyr329fs who were diagnosed with 17-α-hydroxylase deficiency between 2005 and 2019.CASE SUMMARY Case 1 presented with hypertension,hypokalemia,sexual infantilism and delayed bone age.The patient had a 46,XY karyotype,was homozygous for p.Tyr329fs and was recently treated with dexamethasone 0.375 mg qn.Case 2 presented with hypokalemia,sexual infantilism,osteoporosis and delayed bone age.The patient had a 46,XY karyotype,was homozygous for p.Tyr329fs and was treated with dexamethasone 0.75 mg qn at the last follow-up.Serum potassium and blood pressure could be maintained within normal range for cases 1 and 2.Case 3 presented with amenorrhea,sexual infantilism,osteopenia and delayed bone age.The patient had a 46,XX karyotype,was homozygous for p.Tyr329fs and was treated with dexamethasone 0.75 mg qn and progynova 1 mg qd.Outpatient follow-up revealed an adrenocorticotropic hormone(8 AM)of<5.00 pg/mL.CONCLUSION The homozygous p.Tyr329fs mutation usually manifests as a combined deficiency,and definitive diagnosis depends primarily on genetic testing.
文摘Summary What is already known about this topic?Previous studies have indicated a possible association between reproductive tract infections(RTIs)and highrisk human papillomavirus(HPV)infection,but the evidence is still inconclusive.What is added by this report?This multicenter study found significantly higher positive rates of HPV,including general HPV,highrisk HPV.
基金supported by the Key Realm R&D Program of Guangdong Province(2019B030335001)the National Natural Science Foundation of China(82330042,81825009,82071541,81971283,82271576,and 82101570)+2 种基金Changping Laboratory(2021B-01-01)the China Postdoctoral Science Foundation(2021M690421)the Non-profit Central Research Institute Chinese Academy of Medical Sciences(2023-PT320-08).
文摘Synaptic dysfunction is a core component of the pathophysiology of schizophrenia.However,the genetic risk factors and molecular mechanisms related to synaptic dysfunction are still not fully understood.The Stonin 2(STON2)gene encodes a major adaptor for clathrin-mediated endocytosis(CME)of synaptic vesicles.In this study,we showed that the C-C(307Pro-851Ala)haplotype of STON2 increases the susceptibility to schizophrenia and examined whether STON2 variations cause schizophrenia-like behaviors through the regulation of CME.We found that schizophrenia-related STON2 variations led to protein dephosphorylation,which affected its interaction with synaptotagmin 1(Syt1),a calcium sensor protein located in the presynaptic membrane that is critical for CME.STON2307Pro851Ala knockin mice exhibited deficits in synaptic transmission,short-term plasticity,and schizophrenia-like behaviors.Moreover,among seven antipsychotic drugs,patients with the C-C(307Pro-851Ala)haplotype responded better to haloperidol than did the T-A(307Ser-851Ser)carriers.The recovery of deficits in Syt1 sorting and synaptic transmission by acute administration of haloperidol effectively improved schizophrenia-like behaviors in STON2307Pro851Ala knockin mice.Our findings demonstrated the effect of schizophreniarelated STON2 variations on synaptic dysfunction through the regulation of CME,which might be attractive therapeutic targets for treating schizophrenia-like phenotypes.
基金financially supported by the National Natural Science Foundation of China(No.52022065).
文摘In this work,the self-nucleation effect on crystallization was studied for polypropylene with various nucleating agents.The talc was employed to accelerate crystallization of monoclinic α-crystallites,while N,N′-dicyclohexyl-2,6-naphthalenedicarboxamide TMB-5 was used to accelerate the crystallization kinetics and also induce formation of trigonal β-crystallites.To induce self-nucleation effect,the occurrence criterion was assessed by the transition temperatures from various domains and the available temperature width.More importantly,the resulting influences of self-nucleation effect were quantified by the change of crystallization kinetics and the potential polymorphism variation.It was found that the α-nucleating agents of talc broadened the temperature window for inducing Domain Ⅱ by elevating the transition temperature from Domain Ⅰ to Domain Ⅱ.Although β-nucleating agent(β-NA)of N,N′-dicyclohexyl-2,6-naphthalenedicarboxamide TMB-5 elevated cooling crystallization temperature obviously,the temperature window for Domain Ⅱ was narrowed.It should be emphasized that in presence of β-NA TMB-5,the self-nucleation effect enhances the crystallization of α-crystallite,which show the competition with β-NA TMB-5.At last,the ternary PP/talc/TMB-5 blend was prepared with the same amounts of α-NA talc and β-NA TMB-5 and it exhibits a similar self-nucleation effect of crystallization,indicating the dominant role of β-NA TMB-5.
基金Acknowledgements The authors are thankful to all the clinicians and microbiologists for referring vulvovaginal yeast isolates to the mycology reference laboratory. Excellent technical support received from Min Zhao is acknowledged.Financial support and sponsorship This study was supported by a grant from the National Natural Science Foundation of China （No. 81571394）.
文摘Background： Vulvovaginal candidiasis （WC） was a common infection associated with lifelong harassment of woman＇s social and sexual life. The purpose of this study was to describe the species distribution and in vitro antifungal susceptibility of Candida species （Candida spp.） isolated from patients with VVC over 8 years. Methods： Species which isolated from patients with VVC in Peking University First Hospital were identified using chromogenic culture media. Susceptibility to common antifungal agents was determined using agar diffusion method based on CLSI M44-A2 document. SPSS software （version 14.0, Inc., Chicago, IL, USA） was used for statistical analysis, involving statistical description and Chi-square test. Results： The most common strains were Candida （C.） albicans, 80.5% （n = 1775） followed by C. glabrata, 18.1% （n = 400）. Nystatin exhibited excellent activity against all species （〈4% resistant JR]）. Resistance to azole drugs varied among different species. C. albicans： clotrimazole （3.1% R） 〈 fluconazole （ 16.6% R） 〈 itraconazole （51.5% R） 〈 mieonazole （54.0% R）, C. glabrata： miconazole （25.6% R） 〈 clotrimazole （50.5% R） 〈 itraconazole （61.9% R） 〈 fluconazole （73.3% R）; Candida krusei： clotrimazole （0 R） 〈 fluconazole （57.7% R） 〈 miconazole （73.1% R） 〈 itraconazole （83.3% R）. The susceptibility of fluconazole was noticeably decreasing among all species in the study period. Conclusions： Nystatin was the optimal choice for the treatment of VVC at present. The species distribution and in ~＇itro antifungal susceptibility of Candida spp. isolated from patients with VVC had changed over time.
基金supported by grants from the National Basic Research Program of China(2011CB707805)the National Natural Science Foundation of China(81370032,91232305,81361120395,and 91432304)the International Science and Technology Cooperation Program of China(2010DFB30820)
文摘Schizophrenia is considered to be a disorder of brain connectivity, which might result from a disproportionally impaired rich-club organization. The rich-club is composed of highly interconnected hub regions that play crucial roles in integrating information between different brain regions. Few studies have yet investigated whether the structural rich-club organization is impaired in patients and their first-degree relatives. In this study, we established a weighted network model of white matter connections using diffusion tensor imaging of 19 patients and 39 unaffected parents, 22 young healthy controls for the patients, and 25 old healthy controls for the parents. Feeder edges between rich-club nodes and non-rich-club nodes were significantly decreased in both schizophrenic patients and their unaffected parents compared with controls.Furthermore, the feeder edges showed significant positive correlations with the scores in Category Fluency Test—animal naming in the unaffected parents. Specific feeder edges exhibited discriminative power with accuracy of 84.4% in distinguishing unaffected parents from old healthy controls. Our findings suggest that impaired richclub organization, especially impaired feeder edges, may be related to familial vulnerability to schizophrenia,possibly reflecting a genetic predisposition for schizophrenia.
基金supported by grants from the National Basic Research Program of China (2011CB707805)the National Natural Science Foundation of China (81370032, 91232305, 81361120395, and 91432304)the International Science & Technology Cooperation Program of China (2010DFB30820)
文摘Several lines of evidence suggest that efficient information integration between brain regions is disrupted in schizophrenia. Abnormalities in white matter tracts that interconnect brain regions may be directly relevant to this pathophysiological process. As a complex mental disorder with high heritability, mapping abnormalities in patients and their first- degree relatives may help to disentangle the risk factors for schizophrenia. We established a weighted network model of white matter connections using diffusion tensor imaging in 25 nuclear families with schizophrenic probands （19 patients and 41 unaffected parents） and two unrelated groups of normal controls （24 controls matched with patients and 26 controls matched with relatives）. The patient group showed lower global efficiency and local efficiency. The decreased regional efficiency was localized in hubs such as the bilateral frontal cortices, bilateral anterior cingulate cortices, and left precuneus. The global efficiency was negatively correlated with cognition scores derived from a 5-factor model of schizophrenic psychopathology.We also found that unaffected parents displayed decreased regional efficiency in the right temporal cortices, left supplementary motor area, left superior temporal pole, and left thalamus. The global efficiency tended to be lower in unaffected parents. Our data suggest that （1） the global efficiency loss in neuroanatomical networks may be associated with the cognitive disturbances in schizophrenia; and （2） genetic vulnerability to schizophrenia may influence the anatomical organization of an individual＇s brain networks.
基金supported by the National Basic Research Development Program of China(2011CB707805)the National Natural Science Foundation of China(91232305,81361120395,91432304,81370032,and 81601171)the National Key Technology R&D Program of China(2015BAI13B01)
文摘Cross-sectional and longitudinal studies have identified widespread and progressive grey matter volume （GMV） reductions in schizophrenia, especially in the frontal lobe. In this study, we found a progressive GMV decrease in the rostral medial frontal cortex （rMFC, including the anterior cingulate cortex） in the patient group during a 6-week follow-up of 40 patients with schizophrenia and 31 healthy controls well-matched for age, gender, and education. The higher baseline GMV in the rMFC predicted better improvement in the positive score on the Positive and Negative Syndrome Scale （PANSS）, and this might be related to the improved reality-monitoring. Besides, a higher baseline GMV in the posterior rMFC predicted better remission of general symptoms, and a lesser GMV reduction in this region was correlated with better remission of negative symptoms, probably associated with ameliorated self-referential pro- cessing and social cognition. Besides, a shorter disease course and higher educational level contributed to better improvement in the general psychopathological PANSS score, and a family history was negatively associated with improvement of the negative and total PANSS scores. These phenomena might be important for understanding the neuropathological mechanisms underlying the symp- toms of schizophrenia and for making clinical decisions.
基金supported by the National Natural Science Foundation of China Key Project(91332205,81130024,81630030to T.L.)National Natural Science Foundation of China(8157051859 to W.D.et al.)+3 种基金National Key Technology R&D Program of the Ministry of Science and Technology of China(2016YFC0904300 to T.L.)National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme(8141101084 to T.L.)Sichuan Science&Technology Department(2015JY0173 to Q.W.)1.3.5 Project for disciplines of excellence,West China Hospital of Sichuan University(ZY2016103,ZY2016203 to T.L.)
文摘Antipsychotic-induced metabolic disturbance(AIMD) is a common adverse effect of antipsychotics with genetics partly underpinning variation in susceptibility among schizophrenia patients. Melanocortin4 receptor(MC4 R) gene, one of the candidate genes for AIMD, has been under-studied in the Chinese patients. We conducted a pharmacogenetic study in a large cohort of Chinese patients with schizophrenia. In this study, we investigated the genetic variation of MC4 R in Chinese population by genotyping two SNPs(rs489693 and rs17782313) in 1,991 Chinese patients and examined association of these variants with the metabolic effects that were often observed to be related to AIMD. Metabolic measures, including body mass index(BMI), waist circumference(WC), glucose, triglyceride, high-density lipoprotein(HDL), and low-density lipoprotein(LDL) levels were assessed at baseline and after 6-week antipsychotic treatment. We found that interaction of SNP×medication status(drug-na?ve/medicated) was significantly associated with BMI, WC, and HDL change %, respectively. Both SNPs were significantly associated with baseline BMI and WC in the medicated group. Moderate association of rs489693 with WC, Triglyceride, and HDL change % were observed in the whole sample. In the drug-na?ve group, we found recessive effects of rs489693 on BMI gain more than 7%, WC and Triglyceride change %, with AA incurring more metabolic adverse effects. In conclusion, the association between rs489693 and the metabolic measures is ubiquitous but moderate. Rs17782313 is less involved in AIMD. Two SNPs confer risk of AIMD to patients treated with different antipsychotics in a similar way.
文摘It has been suggested that altered neurogenesis may be involved in the etiology of schizophrenia,so genes impacting on neurogenesis could be potential candidates for schizophrenia.A member of the Musashi family,the human MSI2 gene plays a substantial role in stem-cell maintenance,asymmetric division,and differentiation during neurogenesis.Our previous genome-wide association study（GWAS）implied an association of MSI2 with schizophrenia in a Han Chinese population.To further explore this association,three single-nucleotide polymorphisms（SNPs）,rs9892791,rs11657292,and rs1822381,were selected for a replication study involving 921 schizophrenia cases and 1244 controls.After rigorous Bonferroni correction,two of the SNPs（rs9892791 and rs11657292） displayed significant differences in allele and genotype distribution frequencies between the case and control groups.When our GWAS and replication samples were combined,the three MSI2 SNPs were all strongly associated with schizophrenia（rs9892791：allelic P = 1.07E-5;rs11657292：allelic P = 1.95E-12;rs1822381：allelic P = 1.44E-4）.These results indicate that the human MSI2 gene might be a susceptibility gene forschizophrenia and encourage future research on the functional relationship between this gene and schizophrenia.
基金supported by the National Key Research and Development Program of China (2016YFC1307000 and 2015BAI13B01)the National Natural Science Foundation of China (91432304, 81370032, 81571313 and 81221002)+1 种基金Capital Health Development Research (2016-2-4112)Beijing Nova Program Interdisciplinary Studies Cooperative Project (Z161100004916038)
文摘The ZNF804 A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804 A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity（RSFC） between the hippocampus and the dorsolateral prefrontal cortex（DLPFC） in both schizophrenic patients and healthy controls. The homozygous ZNF804 A rs1344706 genotype（AA） conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC（F（2,165） = 13.43,P ／ 0.001）. The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804 A rs1344706 on hippocampalprefrontal RSFC associated with schizophrenia.
