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Zhao S.-X.,Shanghai JiaoTong University | Xue L.-Q.,Shanghai JiaoTong University | Liu W.,Shanghai JiaoTong University | Gu Z.-H.,Shanghai JiaoTong University | And 24 more authors.
Human Molecular Genetics | Year: 2013

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identifynewrisk loci forGDandfoundgenome-wide significantassociations in the overall populations forfive novel susceptibility loci: the GPR174-ITM2Aat Xq21.1,C1QTNF6-RAC2 at 22q12.3-13.1,SLAMF 6 at 1q23.2,ABO at 9q34.2 and an intergenic region harboring two non-coding RNA sat 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10-8). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number ofGDloci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD. © The Author 2013. Published by Oxford University Press. All rights reserved.


An S.,Peking University | Chen J.,The Aerospace Corporation | Wang Z.,Peking University | Wang X.,Peking University | And 9 more authors.
FEMS Microbiology Letters | Year: 2012

From February 2010 to July 2011, 183 of 416 presumptive Klebsiella pneumoniae isolates with reduced susceptibility to third-generation cephalosporins from patients with lower respiratory tract infection were collected from seven tertiary hospitals in China. Phenotypic and genotypic methods were employed to characterize 158 extended-spectrum β-lactamase (ESBL)-producers. Among the 158 isolates analyzed, 134 (84.8%) harbored bla CTX-M, within which the most predominant ESBL gene was CTX-M-14 (49.4%), followed by CTX-M-15 (12.0%) and CTX-M-27 (10.8%). Also, 120 (75.9%) harbored bla SHV. One novel SHV variant, bla SHV-142 with T18A and L35Q substitutions, was identified. Ninety-one isolates carried bla TEM-1. An isolate containing bla TEM-135 was first identified in Klebsiella spp. bla KPC-2 was detected in 5 isolates. More than one ESBL combination was detected in 18 isolates (11.4%). Fifty-four (34.2%) isolates demonstrated the multidrug resistant (MDR) phenotype. Seventy-four sequence types (STs) were identified, which showed large genetic background diversity in ESBL-producing K. pneumoniae isolates from the six areas. This is the first report on the high prevalence of CTX-M-27 in China with the possible transmission of a single clone (ST48). The correlated surveillance of organisms with MDR phenotype should be investigated in future. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd.


Chu X.,Shanghai JiaoTong University | Chu X.,Key Laboratory of Health and Disease Genomics | Pan C.-M.,Shanghai JiaoTong University | Zhao S.-X.,Shanghai JiaoTong University | And 46 more authors.
Nature Genetics | Year: 2011

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P combined = 6.85 ×10-10 for rs9355610) and an intergenic region at 4p14 (P combined = 1.08 ×10-13 for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease. © 2011 Nature America, Inc. All rights reserved.


PubMed | Shandong Provincial Hospital, Zhengzhou University, Guangdong General Hospital, PLA Fourth Military Medical University and 29 more.
Type: Journal Article | Journal: Chinese medical journal | Year: 2016

Over the years, the mechanical ventilation (MV) strategy has changed worldwide. The aim of the present study was to describe the ventilation practices, particularly lung-protective ventilation (LPV), among brain-injured patients in China.This study was a multicenter, 1-day, cross-sectional study in 47 Intensive Care Units (ICUs) across China. Mechanically ventilated patients (18 years and older) with brain injury in a participating ICU during the time of the study, including traumatic brain injury, stroke, postoperation with intracranial tumor, hypoxic-ischemic encephalopathy, intracranial infection, and idiopathic epilepsy, were enrolled. Demographic data, primary diagnoses, indications for MV, MV modes and settings, and prognoses on the 60th day were collected. Multivariable logistic analysis was used to assess factors that might affect the use of LPV.A total of 104 patients were enrolled in the present study, 87 (83.7%) of whom were identified with severe brain injury based on a Glasgow Coma Scale 8 points. Synchronized intermittent mandatory ventilation (SIMV) was the most frequent ventilator mode, accounting for 46.2% of the entire cohort. The median tidal volume was set to 8.0 ml/kg (interquartile range [IQR], 7.0-8.9 ml/kg) of the predicted body weight; 50 (48.1%) patients received LPV. The median positive end-expiratory pressure (PEEP) was set to 5 cmH2O (IQR, 5-6 cmH2O). No PEEP values were higher than 10 cmH2O. Compared with partially mandatory ventilation, supportive and spontaneous ventilation practices were associated with LPV. There were no significant differences in mortality and MV duration between patients subjected to LPV and those were not.Among brain-injured patients in China, SIMV was the most frequent ventilation mode. Nearly one-half of the brain-injured patients received LPV. Patients under supportive and spontaneous ventilation were more likely to receive LPV.ClinicalTrials.org NCT02517073 https://clinicaltrials.gov/ct2/show/NCT02517073.


PubMed | Linyi Peoples Hospital, Tongji University, Fujian Province Hospital, Shanghai JiaoTong University and 4 more.
Type: Clinical Trial | Journal: PloS one | Year: 2014

In our previous studies, we presumed subtypes of Graves disease (GD) may be caused by different major susceptibility genes or different variants of a single susceptibility gene. However, more evidence is needed to support this hypothesis. Single-nucleotide polymorphism (SNP) rs2476601 in PTPN22 is the susceptibility loci of GD in the European population. However, this polymorphism has not been found in Asian populations. Here, we investigate whether PTPN22 is the susceptibility gene for GD in Chinese population and further determine the susceptibility variant of PTPN22 in GD. We conducted an imputation analysis based on the results of our genome-wide association study (GWAS) in 1,536 GD patients and 1,516 control subjects. Imputation revealed that 255 common SNPs on a linkage disequilibrium (LD) block containing PTPN22 were associated with GD (P<0.05). Nine tagSNPs that captured the 255 common variants were selected to be further genotyped in a large cohort including 4,368 GD patients and 4,350 matched controls. There was no significant difference between the nine tagSNPs (P>0.05) in either the genotype distribution or allelic frequencies between patients and controls in the replication study. Although the combined analysis exhibited a weak association signal (P(combined) = 0.003263 for rs3811021), the false positive report probability (FPRP) analysis indicated it was most likely a false positive finding. Our study did not support an association of common SNPs in PTPN22 LD block with GD in Chinese Han population. This suggests that GD in different ethnic population is probably caused by distinct susceptibility genes.


Lu T.,Mayo Medical School | Chai Q.,Mayo Medical School | Chai Q.,Shandong Academy of Sciences | Yu L.,Mayo Medical School | And 5 more authors.
Diabetes | Year: 2012

Activity of the vascular large conductance Ca 2+-activated K + (BK) channel is tightly regulated by its accessory β 1 subunit (BK-β 1). Downregulation of BK-β 1 expression in diabetic vessels is associated with upregulation of the forkhead box O subfamily transcription factor-3a (FOXO-3a)-dependent F-box-only protein (FBXO) expression. However, the upstream signaling regulating this process is unclear. Overproduction of reactive oxygen species (ROS) is a common finding in diabetic vasculopathy. We hypothesized that ROS signaling cascade facilitates the FOXO-3a/FBXO-mediated BK-β 1 degradation and leads to diabetic BK channel dysfunction. Using cellular biology, patch clamp, and videomicroscopy techniques, we found that reduced BK-β 1 expression in streptozotocin (STZ)-induced diabetic mouse arteries and in human coronary smooth muscle cells (SMCs) cultured with high glucose was attributable to an increase in protein kinase C (PKC)-β and NADPH oxidase expressions and accompanied by attenuation of Akt phosphorylation and augmentation of atrogin-1 expression. Treatment with ruboxistaurin (a PKCβ inhibitor) or with GW501516 (a peroxisome proliferator-activated receptor δ activator) reduced atrogin-1 expression and restored BK channel-mediated coronary vasodilation in diabetic mice. Our results suggested that oxidative stress inhibited Akt signaling and facilitated the FOXO-3a/FBXO-dependent BK-β 1 degradation in diabetic vessels. Suppression of the FOXO-3a/FBXO pathway prevented vascular BK-β 1 degradation and protected coronary function in diabetes. © 2012 by the American Diabetes Association.


Hu R.-F.,Fujian Medical University | Jiang X.-Y.,Fujian Medical University | Hegadoren K.M.,University of Alberta | Zhang Y.-H.,Fujian Province Hospital
Critical Care | Year: 2015

Introduction: Intensive care unit (ICU) environmental factors such as noise and light have been cited as important causes of sleep deprivation in critically ill patients. Previous studies indicated that using earplugs and eye masks can improve REM sleep in healthy subjects in simulated ICU environment, and improve sleep quality in ICU patients. This study aimed to determine the effects of using earplugs and eye masks with relaxing background music on sleep, melatonin and cortisol levels in ICU patients. Methods: Fifty patients who underwent a scheduled cardiac surgery and were expected to stay at least 2 nights in Cardiac Surgical ICU (CSICU) were included. They were randomized to sleep with or without earplugs and eye masks combined with 30-minute relaxing music during the postoperative nights in CSICU. Urine was analyzed for nocturnal melatonin and cortisol levels. Subjective sleep quality was evaluated using the Chinese version of Richards-Campbell Sleep Questionnaire (a visual analog scale, ranging 0-100). Results: Data from 45 patients (20 in intervention group, 25 in control group) were analyzed. Significant differences were found between groups in depth of sleep, falling asleep, awakenings, falling asleep again after awakening and overall sleep quality (P < 0.05). Perceived sleep quality was better in the intervention group. No group differences were found in urinary melatonin levels and cortisol levels for the night before surgery, and the first and second nights post-surgery (P > 0.05). The urinary melatonin levels of the first and second postoperative nights were significantly lower than those of the night before surgery (P = 0.01). The opposite pattern was seen with urinary cortisol levels (P = 0.00). Conclusion: This combination of non-pharmacological interventions is useful for promoting sleep in ICU adult patients; however, any influence on nocturnal melatonin levels and cortisol level may have been masked by several factors such as the timing of surgery, medication use and individual differences. Larger scale studies would be needed to examine the potential influences of these factors on biological markers and intervention efficacy on sleep. Trial registration: Chinese Clinical Trial Registry: ChiCTR-IOR-14005511. Registered 21 November 2014. © Hu et al.; licensee BioMed Central.


Hu R.-F.,Fujian Medical University | Jiang X.-Y.,Fujian Medical University | Zeng Y.-M.,Second Affiliated Hospital | Chen X.-Y.,Second Affiliated Hospital | Zhang Y.-H.,Fujian Province Hospital
Critical Care | Year: 2010

Introduction: Environmental stimulus, especially noise and light, is thought to disrupt sleep in patients in the intensive care unit (ICU). This study aimed to determine the physiological and psychological effects of ICU noise and light, and of earplugs and eye masks, used in these conditions in healthy subjects.Methods: Fourteen subjects underwent polysomnography under four conditions: adaptation, baseline, exposure to recorded ICU noise and light (NL), and NL plus use of earplugs and eye masks (NLEE). Urine was analyzed for melatonin and cortisol levels. Subjects rated their perceived sleep quality, anxiety levels and perception of environmental stimuli.Results: Subjects had poorer perceived sleep quality, more light sleep, longer rapid eye movement (REM) latency, less REM sleep when exposed to simulated ICU noise and light (P < 0.05). Nocturnal melatonin (P = 0.007) and cortisol secretion levels (P = 0.004) differed significantly by condition but anxiety levels did not (P = 0.06). Use of earplugs and eye masks resulted in more REM time, shorter REM latency, less arousal (P < 0.05) and elevated melatonin levels (P = 0.002).Conclusions: Earplugs and eye masks promote sleep and hormone balance in healthy subjects exposed to simulated ICU noise and light, making their promotion in ICU patients reasonable. © 2010 Hu et al.; licensee BioMed Central Ltd.


Chen J.,Fuzhou University | Chen J.,Fujian University of Traditional Chinese Medicine | Wang J.,Fuzhou University | Shao J.,Fuzhou University | And 5 more authors.
Medicinal Research Reviews | Year: 2014

Mifepristone (RU486) is a born-for-woman molecule discovered three decades ago. Unlike those antihypertensive and antipsychotic pharmaceutical blockbusters, this abortifacient offers relatively low profit potential. Current understanding of mechanism of action of mifepristone and its on-going clinical trials are changing our views on the drug beyond its abortifacient scope. Here we briefly review its metabolism and pharmacokinetic properties including its unique enterohepatic circulation, its mechanisms of actions involving antiprogesterone and antiglucocorticoid, growth inhibition of various cancer cell lines, suppression of invasive and metastatic cancer potential, downregulation of Cdk2, Bcl-2, and NF-kappa B, interference of heterotypic cell adhesion to basement membrane, and cell migration. We comprehensively analyze recent results from preclinical and clinical studies using mifepristone as an anticancer drug for breast, meningioma, and gliomas tumors in the central nervous system, prostate cancer, ovarian and endometrial cancer, and gastric adenocarcinoma. Although mifepristone has more benefits for global public health than we originally thought, its effect as a postmetastatic chemotherapeutic agent is limited. Nonetheless, owing to its unique safe, metabolism and other pharmacological properties, metapristone (the primary metabolite of mifepristone) may have potential for cancer metastatic chemoprevention. © 2014 Wiley Periodicals, Inc.


PubMed | Fujian Medical University, Fujian Province Hospital and University of Alberta
Type: | Journal: Critical care (London, England) | Year: 2015

Intensive care unit (ICU) environmental factors such as noise and light have been cited as important causes of sleep deprivation in critically ill patients. Previous studies indicated that using earplugs and eye masks can improve REM sleep in healthy subjects in simulated ICU environment, and improve sleep quality in ICU patients. This study aimed to determine the effects of using earplugs and eye masks with relaxing background music on sleep, melatonin and cortisol levels in ICU patients.Fifty patients who underwent a scheduled cardiac surgery and were expected to stay at least 2 nights in Cardiac Surgical ICU (CSICU) were included. They were randomized to sleep with or without earplugs and eye masks combined with 30-minute relaxing music during the postoperative nights in CSICU. Urine was analyzed for nocturnal melatonin and cortisol levels. Subjective sleep quality was evaluated using the Chinese version of Richards-Campbell Sleep Questionnaire (a visual analog scale, ranging 0-100).Data from 45 patients (20 in intervention group, 25 in control group) were analyzed. Significant differences were found between groups in depth of sleep, falling asleep, awakenings, falling asleep again after awakening and overall sleep quality (P<0.05). Perceived sleep quality was better in the intervention group. No group differences were found in urinary melatonin levels and cortisol levels for the night before surgery, and the first and second nights post-surgery (P>0.05). The urinary melatonin levels of the first and second postoperative nights were significantly lower than those of the night before surgery (P=0.01). The opposite pattern was seen with urinary cortisol levels (P=0.00).This combination of non-pharmacological interventions is useful for promoting sleep in ICU adult patients; however, any influence on nocturnal melatonin levels and cortisol level may have been masked by several factors such as the timing of surgery, medication use and individual differences. Larger scale studies would be needed to examine the potential influences of these factors on biological markers and intervention efficacy on sleep.Chinese Clinical Trial Registry: ChiCTR-IOR-14005511 . Registered 21 November 2014.

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