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1.  Clinical and Laboratory Characteristics of Patients with Nontuberculous Mycobacterium Bloodstream Infection in a Tertiary Referral Hospital in Beijing, China 
Chinese Medical Journal  2016;129(18):2220-2225.
Nontuberculous Mycobacterium (NTM) bloodstream infection (BSI) is relatively rare. We aimed in this study to evaluate the clinical characteristics, laboratory evaluation, and outcomes of patients with NTM BSI.
We retrospectively reviewed the clinical records of inpatients with NTM BSI at our institution between January 2008 and January 2015 and recorded clinical parameters including age, gender, underlying disease, clinical manifestation, organs involved with NTM disease, species of NTM, laboratory data, treatment and outcome of these patients. We also reviewed the reported cases and case series of NTM BSI by searching PubMed, EMBASE, and Wanfang databases. Data of normal distribution were expressed by mean ± standard deviation (SD). Data of nonnormal distribution were expressed by median and interquartile range (IQR).
Among the ten patients with NTM BSI, the median age was 51 years (IQR 29–57 years) and three patients were males. Eight patients were immunocompromised, with underlying diseases including human immunodeficiency virus (HIV) infection (one patient), rheumatic diseases (two patients), breast cancer (one patient), myelodysplastic syndrome (two patients), and aplastic anemia (two patients). Other organ(s) involved were lung (two patients), endocardium (two patients), brain, spinal cord, and soft tissue (one each patient). The median lymphocyte was 0.66 × 109/L (IQR 0.24–1.93 × 109/L). The median cluster of differentiation 4 (CD4) cell count was 179/mm3 (IQR 82–619/mm3). Five patients died (three with hematological diseases, one with breast cancer, and one with rheumatic disease), three recovered, and two were lost to follow-up.
We reported all cases in our hospital diagnosed with bloodstream NTM infection that was rarely reported. In this group of patients, patients usually had a high fever and could have multiple organ involvements. All patients with poor prognosis had underlying diseases.
PMCID: PMC5022344  PMID: 27625095
Bloodstream Infection; Hematogenous Disseminated; Nontuberculous Mycobacterium
3.  Diagnostic Value of T-cell Interferon-γ Release Assays on Synovial Fluid for Articular Tuberculosis: A Pilot Study 
Chinese Medical Journal  2016;129(10):1171-1178.
Tuberculosis (TB) remains a major global public health challenge. Articular TB is an important form of extrapulmonary tuberculosis, and its diagnosis is difficult because of the low sensitivity of traditional methods. The aim of this study was to analyze the diagnostic value of T-SPOT.TB on synovial fluid for the diagnosis of articular TB.
Patients with suspected articular TB were enrolled consecutively between August 2011 and December 2015. T-SPOT.TB was performed on both synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs). The final diagnosis of articular TB was independent of the T-SPOT.TB result. The diagnostic sensitivity, specificity, predictive value, and likelihood ratio of T-SPOT.TB on SFMCs and PBMCs were analyzed.
Twenty patients with suspected articular TB were enrolled. Six were diagnosed with articular TB, and 14 patients were diagnosed with other diseases. Sensitivity and specificity were 83% and 86% for T-SPOT.TB on SFMCs, and 67% and 69% for T-SPOT.TB on PBMCs, respectively. The positive predictive value (PPV) and negative predictive value (NPV) of T-SPOT.TB on SFMCs were 71% and 92%, respectively. The PPV and NPV were 50% and 82% for T-SPOT.TB on PBMCs.
Sensitivity, specificity, and NPV of T-SPOT.TB on SFMCs appeared higher than that on PBMCs, indicating that T-SPOT.TB on SFMCs might be a rapid and accurate diagnostic test for articular TB.
PMCID: PMC4878162  PMID: 27174325
Articular Tuberculosis; Diagnosis; Interferon-γ Release Assays; T-SPOT.TB; Sensitivity; Specificity; Synovial Fluid
4.  Correlation of ATP7B genotype with phenotype in Chinese patients with Wilson disease 
World Journal of Gastroenterology  2004;10(4):590-593.
AIM: To determine the mutational characterization of P-type ATP7B gene and to explore the correlation of ATP7B genotype to phenotype in Chinese patients with Wilson disease (WD).
METHODS: Seventy-five patients with WD from 72 no-kinship families, 44 males and 31 females, were enrolled in this study. The age of onset ranged from 4 to 39 years, ≤ 18 years in 72 patients. Some exons of ATP7B gene mutations were analyzed in patients with WD by using biochemical methods, polymerase chain reaction-single strand configuration polymorphism (PCR-SSCP) and DNA sequence analysis. A total of 778 coding regions were identified with restriction enzyme Msp I. The activity of Cu-ATPase was assessed by measuring inorganic phosphorus.
RESULTS: Sixty-six of 75 patients (88%) had with hepatic manifestations, 39 of them had only hepatic manifestations, 27 patients had hepatic and neurological manifestations or other symptoms at the same time (16 patients had associated neurological manifestation, 3 patients had osteopathy, 8 patients had other symptoms). Eight of the 75 patients (10.7%) had only neurological symptoms, one patient (5 years old) had no symptom. Twelve changing patterns were detected in ATP7B gene by DNA sequencing, including seven mutations (R778L, C656X, G943D, V1140A, V1106I V1216M and 1384del17), six polymorphisms (IVS4-5t/c, A2495G, C2310G, IVS18 + 6c/t and IVS20 + 5a/g). R778L occurred in 49/66 patients (74%) with hepatic manifestations, homozygosis of R778L in 16 patients, heterozygosity of R778L in 33 patients. V1106I mutation of ATP7B gene occurred in 2 patients with delaying onset of clinical symptoms. Cu-ATPase activity of three patients with known mutations (R778L/ V1106I/A2495G, R778L/V1216M and R778L/R778L) were determined, and the activity of Cu-ATPase was decreased by 44.55%, 88.23% and 69.49% respectively.
CONCLUSION: 1384del17bp is a novel mutation found in WD patients. R778L is the most common mutation of ATP7B gene. There is a correlation between R778L and hepatic manifestations in WD patient.
PMCID: PMC4716986  PMID: 14966923
5.  Combination of icotinib, surgery, and internal-radiotherapy of a patient with lung cancer severely metastasized to the vertebrae bones with EGFR mutation: a case report 
OncoTargets and therapy  2015;8:1271-1276.
A 48-year-old Chinese female was referred to us regarding EGFR-mutated advanced non-small cell lung cancer, and metastasis to left scapula and vertebrae bones which caused pathological fracture at T8 and T10 thoracic vertebrae. An aggressive combined therapy with icotinib, vertebrae operation, and radioactive particle implantation and immunotherapy was proposed to prevent paraplegia, relieve pain, and control the overall and local tumor lesions. No postoperative symptoms were seen after surgery, and the pain was significantly relieved. Icotinib merited a 31-month partial response with grade 1 diarrhea as its drug-related adverse event. High dose of icotinib was administered after pelvis lesion progression for 3 months with good tolerance. Combination therapy of icotinib, surgery, and internal radiation for metastases of the vertebrae bones from non-small cell lung cancer seems to be a very promising technique both for sufficient pain relief and for local control of the tumor, vertebrae operation can be an encouraging option for patients with EFGR positive mutation and good prognosis indicator.
PMCID: PMC4459626  PMID: 26082644
lung cancer; spinal metastasis; pathological fracture; spinal canal stenosis; icotinib
6.  Identity-by-descent mapping for diastolic blood pressure in unrelated Mexican Americans 
BMC Proceedings  2016;10(Suppl 7):263-267.
Population-based identity by descent (IBD) mapping is a statistical method for detection of genetic loci that share an ancestral segment among “unrelated” pairs of individuals for a disease. As a complementary method to genome-wide association studies, IBD mapping is robust to allelic heterogeneity and may identify rare inherited variants when combined with sequence data.
Our objective is to identify the causal genes for diastolic blood pressure (DBP). We applied a population-based IBD mapping method to 105 unrelated individuals selected from the family data provided for the Genetic Analysis Workshop 19. Using the genome-wide association study data (ie, the microarray data), chromosome 3 was scanned for IBD sharing segments among all pairs of these individuals. At the chromosomal region with the most significant relationship between IBD sharing and DBP, the whole genome sequence data were examined to identify the risk variants for DBP.
The most significant chromosomal region that was identified to have a relationship between the IBD sharing and DBP was at 3q12.3 (p = 0.0016), although it did not achieve the chromosome-wide significance level (p = 0.00012). This chromosomal region contains 1 gene, ZPLD1, which has been reported to be associated with cerebral cavernous malformations, a disease with enlarged small blood vessels (capillaries) in the brain. Although 24 deleterious variants were identified at this region, no significant association was found between these variants and DBP (p = 0.40).
We presented a mapping strategy which combined a population-based IBD mapping method with sequence data analyses. One gene was located at a chromosomal region identified by this method for DBP. However, further study with a large sample size is needed to assess this result.
PMCID: PMC5133517  PMID: 27980647
7.  Clinical and Laboratory Diagnosis of Intestinal Tuberculosis 
Chinese Medical Journal  2016;129(11):1330-1333.
Tuberculosis (TB) remains a worldwide problem. Intestinal TB (ITB) constitutes a major public health problem in developing countries and has been associated with significant morbidity and mortality. The aim of this study was to characterize the clinical, radiological, endoscopic, and pathological features of ITB and to define the strategy for establishing the diagnosis.
A retrospective study (from January 2000 to June 2015) was carried out in Peking Union Medical College Hospital and all hospitalized cases were diagnosed as ITB during the study period were included. The relevant clinical information, laboratory results, microbiological, and radiological investigations were recorded.
Of the 85 cases, 61 cases (71.8%) were ranged from 20 to 50 years. The ileocecal region was involved in about 83.5% (71/85) of patients. About 41.2% (35/85) of patients had co-existing extra ITB, especially active pulmonary TB. Abdominal pain (82.4%) was the most common presenting symptom followed by weight loss (72.9%) and fever (64.7%). Both T-cell spot of TB test (T-SPOT.TB) and purified protein derivatives (PPD) tests were performed in 26 patients: 20 (76.9%) positive T-SPOT.TB and 13 (50.0%) positive PPD were detected, with a statistical significant difference (P = 0.046). Twenty cases (23.5%) were histopathology and/or pathogen confirmed TB; 27 cases (31.8%) were diagnosed by clinical manifestation consistent with ITB and evidence of active extra ITB; 38 cases (44.7%) were diagnosed by good response to diagnostic anti-TB therapy.
ITB is difficult to diagnose even with modern medical techniques due to its nonspecific clinical and laboratory features. At present, combination of clinical, endoscopic, radiological, and pathological features continues to be the key to the diagnosis of ITB.
PMCID: PMC4894044  PMID: 27231171
Diagnosis; Intestinal Tuberculosis; Extra-intestinal Tuberculosis
8.  Interactions among Lung Cancer Cells, Fibroblasts, and Macrophages in 3D Co-Cultures and the Impact on MMP-1 and VEGF Expression 
PLoS ONE  2016;11(5):e0156268.
In vitro cell-based models of lung cancer are frequently employed to study invasion and the mechanisms behind metastasis. However, these models often study only one cell type with two-dimensional (2D) monolayer cell cultures, which do not accurately reflect the complexity of inflammation in vivo. Here, a three-dimensional (3D) cell co-culture collagen gel model was employed, containing human lung adenocarcinoma cells (HCC), human lung fibroblast cells (MRC-5), and macrophages. Cell culture media and cell images were collected, and matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor (VEGF) production was monitored under different cell culture conditions. We found that simulating hypoxia and/or serum starvation conditions induced elevated secretion of VEGF in the 3D co-culture model in vitro, but not MMP-1; the morphology of HCC in the 2D versus the 3D co-culture system was extremely different. MMP-1 and VEGF were secreted at higher levels in mixed cell groups rather than mono-culture groups. Therefore, incorporating lung cancer cells, fibroblasts, and macrophages may better reflect physiological metastasis mechanisms compared to mono-culture systems. Tumour stromal cells, macrophages, and fibroblast cells may promote invasion and metastasis, which also provides a new direction for the design of therapies targeted at destroying the stroma of tumor tissues.
PMCID: PMC4883750  PMID: 27232698
9.  Filtering genetic variants and placing informative priors based on putative biological function 
BMC Genetics  2016;17(Suppl 2):8.
High-density genetic marker data, especially sequence data, imply an immense multiple testing burden. This can be ameliorated by filtering genetic variants, exploiting or accounting for correlations between variants, jointly testing variants, and by incorporating informative priors. Priors can be based on biological knowledge or predicted variant function, or even be used to integrate gene expression or other omics data. Based on Genetic Analysis Workshop (GAW) 19 data, this article discusses diversity and usefulness of functional variant scores provided, for example, by PolyPhen2, SIFT, or RegulomeDB annotations. Incorporating functional scores into variant filters or weights and adjusting the significance level for correlations between variants yielded significant associations with blood pressure traits in a large family study of Mexican Americans (GAW19 data set). Marker rs218966 in gene PHF14 and rs9836027 in MAP4 significantly associated with hypertension; additionally, rare variants in SNUPN significantly associated with systolic blood pressure. Variant weights strongly influenced the power of kernel methods and burden tests. Apart from variant weights in test statistics, prior weights may also be used when combining test statistics or to informatively weight p values while controlling false discovery rate (FDR). Indeed, power improved when gene expression data for FDR-controlled informative weighting of association test p values of genes was used. Finally, approaches exploiting variant correlations included identity-by-descent mapping and the optimal strategy for joint testing rare and common variants, which was observed to depend on linkage disequilibrium structure.
PMCID: PMC4895695  PMID: 26866982
10.  Ginsenoside Rg1 protects against neurodegeneration by inducing neurite outgrowth in cultured hippocampal neurons 
Neural Regeneration Research  2016;11(2):319-325.
Ginsenoside Rg1 (Rg1) has anti-aging and anti-neurodegenerative effects. However, the mechanisms underlying these actions remain unclear. The aim of the present study was to determine whether Rg1 affects hippocampal survival and neurite outgrowth in vitro after exposure to amyloid-beta peptide fragment 25–35 (Aβ25–35), and to explore whether the extracellular signal-regulated kinase (ERK) and Akt signaling pathways are involved in these biological processes. We cultured hippocampal neurons from newborn rats for 24 hours, then added Rg1 to the medium for another 24 hours, with or without pharmacological inhibitors of the mitogen-activated protein kinase (MAPK) family or Akt signaling pathways for a further 24 hours. We then immunostained the neurons for growth associated protein-43, and measured neurite length. In a separate experiment, we exposed cultured hippocampal neurons to Aβ25–35 for 30 minutes, before adding Rg1 for 48 hours, with or without Akt or MAPK inhibitors, and assessed neuronal survival using Hoechst 33258 staining, and phosphorylation of ERK1/2 and Akt by western blot analysis. Rg1 induced neurite outgrowth, and this effect was blocked by API-2 (Akt inhibitor) and PD98059 (MAPK/ERK kinase inhibitor), but not by SP600125 or SB203580 (inhibitors of c-Jun N-terminal kinase and p38 MAPK, respectively). Consistent with this effect, Rg1 upregulated the phosphorylation of Akt and ERK1/2; these effects were reversed by API-2 and PD98059, respectively. In addition, Rg1 significantly reversed Aβ25–35-induced apoptosis; this effect was blocked by API-2 and PD98059, but not by SP600125 or SB203580. Finally, Rg1 significantly reversed the Aβ25–35-induced decrease in Akt and ERK1/2 phosphorylation, but API-2 prevented this reversal. Our results indicate that Rg1 enhances neurite outgrowth and protects against Aβ25–35-induced damage, and that its mechanism may involve the activation of Akt and ERK1/2 signaling.
PMCID: PMC4810998  PMID: 27073387
nerve regeneration; ginsenoside Rg1; neurite outgrowth; Aβ25–35; hippocampal neurons; Akt; MAPK; apoptosis; growth associated protein-43; Hoechst 33258 staining; PD98059; API-2; neural regeneration
12.  Clinical, Virological and Immunological Features from Patients Infected with Re-Emergent Avian-Origin Human H7N9 Influenza Disease of Varying Severity in Guangdong Province 
PLoS ONE  2015;10(2):e0117846.
The second wave of avian influenza H7N9 virus outbreak in humans spread to the Guangdong province of China by August of 2013 and this virus is now endemic in poultry in this region.
Five patients with H7N9 virus infection admitted to our hospital during August 2013 to February 2014 were intensively investigated. Viral load in the respiratory tract was determined by quantitative polymerase chain reaction (Q-PCR) and cytokine levels were measured by bead-based flow cytometery.
Four patients survived and one died. Viral load in different clinical specimens was correlated with cytokine levels in plasma and broncho-alveolar fluid (BALF), therapeutic modalities used and clinical outcome. Intravenous zanamivir appeared to be better than peramivir as salvage therapy in patients who failed to respond to oseltamivir. Higher and more prolonged viral load was found in the sputum or endotracheal aspirates compared to throat swabs. Upregulation of proinflammatory cytokines IP-10, MCP-1, MIG, MIP-1α/β, IL-1β and IL-8 was found in the plasma and BALF samples. The levels of cytokines in the plasma and viral load were correlated with disease severity. Reactivation of herpes simplex virus type 1(HSV-1) was found in three out of five patients (60%).
Expectorated sputum or endotracheal aspirate specimens are preferable to throat swabs for detecting and monitoring H7N9 virus. Severity of the disease was correlated to the viral load in the respiratory tract as well as the extents of cytokinemia. Reactivation of HSV-1 may contribute to clinical outcome.
PMCID: PMC4344233  PMID: 25723593
13.  Compliance with severe sepsis bundles and its effect on patient outcomes of severe community-acquired pneumonia in a limited resources country 
Archives of Medical Science : AMS  2014;10(5):970-978.
Validation of compliance with severe sepsis bundles is still needed. The purpose of this study was to determine compliance and its outcomes in severe community-acquired pneumonia (CAP) patients in a limited resources country.
Material and methods
A prospective cohort study of 212 severe CAP patients was carried out. The implementation programme was organized into two continuous phases. The primary outcomes were compliance and hospital mortality.
Compliance with administration of antibiotics and vasopressors as well as plateau pressure on average < 30 cm H2O was high in both groups. In the bundles group, patients received more serum lactate monitoring (62.3% vs. 11.3%), more blood cultures (47.1% vs. 24.5%), more fluid resuscitation (63.2% vs. 26.4%) and volumes infused (1319.8 ±1107.4 ml vs. 461.9 ±799.3 ml), more inotropic dobutamine and/or packed red blood cells (21.7% vs. 10.0%), more low-dose steroids (56.5% vs. 15.0%), and more glucose control (51.9% vs. 6.6%) compared with such patients in the control group. The rates of total compliance with 6-hour, 24-hour, and 6/24-hour bundles in the prospective period were 47.1%, 51.9%, and 42.5%, respectively. Hospital mortality was reduced from 44.3% to 29.2% (p = 0.023) in the bundles group, and the compliant subgroup had a more than twofold decrease in mortality (17.8% vs. 37.7%, p = 0.003). Serum lactate measured, blood cultures, and fluid resuscitation showed independent relationships with decreased mortality.
Total compliance was relatively low, but the implementation of severe sepsis bundles could clearly reduce mortality from severe CAP.
PMCID: PMC4223141  PMID: 25395949
severe sepsis bundles; severe community-acquired pneumonia; severe sepsis; septic shock; compliance; mortality
14.  Correction: Genome-Wide Sequence Characterization and Expression Analysis of Major Intrinsic Proteins in Soybean (Glycine max L.) 
PLoS ONE  2014;9(1):10.1371/annotation/e3307d0c-bb59-4f75-89b4-8e0d5af087d5.
PMCID: PMC3894297
15.  Identification of genetic loci underlying the phenotypic constructs of autism spectrum disorders Running head: Genetic loci for latent factors in ASD 
To investigate the underlying phenotypic constructs in autism spectrum disorders (ASD) and to identify genetic loci that are linked to these empirically derived factors.
Exploratory factor analysis was applied to two datasets with 28 selected Autism Diagnostic Interview-Revised (ADI-R) algorithm items. The first dataset was from the Autism Genome Project (AGP) phase I (1,236 ASD subjects from 618 families); the second was from the AGP phase II (804 unrelated ASD subjects). Variables derived from the factor analysis were then used as quantitative traits in genome-wide variance components linkage analyses.
Six factors, joint attention, social interaction and communication, non-verbal communication, repetitive sensory-motor behaviour, peer interaction, and compulsion/restricted interests, were retained for both datasets. There was good agreement between the factor loading patterns from the two datasets. All factors showed familial aggregation. Suggestive evidence for linkage was obtained for the joint attention factor on 11q23. Genome-wide significant evidence for linkage was obtained for the repetitive sensory-motor behaviour factor on 19q13.3.
This study demonstrates that the underlying phenotypic constructs based on the ADI-R algorithm items are replicable in independent datasets; and the empirically derived factors are suitable and informative in genetic studies of ASD.
PMCID: PMC3593812  PMID: 21703496
autism; ADI-R; factor analysis; linkage analysis; quantitative trait
16.  Genome-Wide Sequence Characterization and Expression Analysis of Major Intrinsic Proteins in Soybean (Glycine max L.) 
PLoS ONE  2013;8(2):e56312.
Water is essential for all living organisms. Aquaporin proteins are the major facilitator of water transport activity through cell membranes of plants including soybean. These proteins are diverse in plants and belong to a large major intrinsic (MIP) protein family. In higher plants, MIPs are classified into five subfamilies including plasma membrane intrinsic proteins (PIP), tonoplast intrinsic proteins (TIP), NOD26-like intrinsic proteins (NIP), small basic intrinsic proteins (SIP), and the recently discovered X intrinsic proteins (XIP). This paper reports genome wide assembly of soybean MIPs, their functional prediction and expression analysis. Using a bioinformatic homology search, 66 GmMIPs were identified in the soybean genome. Phylogenetic analysis of amino acid sequences of GmMIPs divided the large and highly similar multi-gene family into 5 subfamilies: GmPIPs, GmTIPs, GmNIPs, GmSIPs and GmXIPs. GmPIPs consisted of 22 genes and GmTIPs 23, which showed high sequence similarity within subfamilies. GmNIPs contained 13 and GmSIPs 6 members which were diverse. In addition, we also identified a two member GmXIP, a distinct 5th subfamily. GmMIPs were further classified into twelve subgroups based on substrate selectivity filter analysis. Expression analyses were performed for a selected set of GmMIPs using semi-quantitative reverse transcription (semi-RT-qPCR) and qPCR. Our results suggested that many GmMIPs have high sequence similarity but diverse roles as evidenced by analysis of sequences and their expression. It can be speculated that GmMIPs contains true aquaporins, glyceroporins, aquaglyceroporins and mixed transport facilitators.
PMCID: PMC3577755  PMID: 23437113
17.  Uncovering the Salt Response of Soybean by Unraveling Its Wild and Cultivated Functional Genomes Using Tag Sequencing 
PLoS ONE  2012;7(11):e48819.
Soil salinity has very adverse effects on growth and yield of crop plants. Several salt tolerant wild accessions and cultivars are reported in soybean. Functional genomes of salt tolerant Glycine soja and a salt sensitive genotype of Glycine max were investigated to understand the mechanism of salt tolerance in soybean. For this purpose, four libraries were constructed for Tag sequencing on Illumina platform. We identify around 490 salt responsive genes which included a number of transcription factors, signaling proteins, translation factors and structural genes like transporters, multidrug resistance proteins, antiporters, chaperons, aquaporins etc. The gene expression levels and ratio of up/down-regulated genes was greater in tolerant plants. Translation related genes remained stable or showed slightly higher expression in tolerant plants under salinity stress. Further analyses of sequenced data and the annotations for gene ontology and pathways indicated that soybean adapts to salt stress through ABA biosynthesis and regulation of translation and signal transduction of structural genes. Manipulation of these pathways may mitigate the effect of salt stress thus enhancing salt tolerance.
PMCID: PMC3509101  PMID: 23209559
18.  Effects of total dissolved gas supersaturated water on lethality and catalase activity of Chinese sucker (Myxocyprinus asiaticus Bleeker)*  
Total dissolved gas (TDG) supersaturation caused by dam sluicing can result in gas bubble trauma (GBT) in fish and threaten their survival. In the present study, Chinese suckers (Myxocyprinus asiaticus Bleeker) were exposed to TDG supersaturated water at levels ranging from 120% to 145% for 48 h. The median lethal concentration (LC50) and the median lethal time (LT50) were determined to evaluate acute lethal effects on Chinese suckers. The results showed that the LC50 values of 4, 6, 8, and 10 h were 142%, 137%, 135%, and 130%, respectively. The LT50 values were 3.2, 4.7, 7.8, 9.2, and 43.4 h, respectively, when TDG supersaturated levels were 145%, 140%, 135%, 130%, and 125%. Furthermore, the biological responses in Chinese suckers were studied by assaying the catalase (CAT) activities in gills and muscles at the supersaturation level of 140% within LT50. The CAT activities in the gills and muscle tissues exhibited a regularity of a decrease after an increase. CAT activities in the muscles were increased significantly at 3/5LT50 (P<0.05) and then came back to the normal level. However, there were no significant differences between the treatment group (TDG level of 140%) and the control group (TDG level of 100%) on CAT activities in the gills before 3/5LT50 (P>0.05), but the activities were significantly lower than the normal level at 4/5LT50 and LT50 (P<0.05).
PMCID: PMC3468822  PMID: 23024046
Total dissolved gas supersaturation; Median lethal time (LT50); Median lethal concentration (LC50); Chinese sucker; Catalase
19.  Individual common variants exert weak effects on the risk for autism spectrum disorders 
Anney, Richard | Klei, Lambertus | Pinto, Dalila | Almeida, Joana | Bacchelli, Elena | Baird, Gillian | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Casey, Jillian | Conroy, Judith | Correia, Catarina | Corsello, Christina | Crawford, Emily L. | de Jonge, Maretha | Delorme, Richard | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Folstein, Susan E. | Fombonne, Eric | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Heron, Elizabeth A. | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Jacob, Suma | Kenny, Graham P. | Kim, Cecilia | Kolevzon, Alexander | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Law-Smith, Miriam | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Liu, Xiao-Qing | Lombard, Frances | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Magalhaes, Tiago R. | Mantoulan, Carine | McDougle, Christopher J. | Melhem, Nadine M. | Merikangas, Alison | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Noakes, Carolyn | Nygren, Gudrun | Papanikolaou, Katerina | Pagnamenta, Alistair T. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Posey, David J. | Poustka, Fritz | Ragoussis, Jiannis | Regan, Regina | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Schlitt, Sabine | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stoppioni, Vera | Sykes, Nuala | Tancredi, Raffaella | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Vorstman, JAS | Wallace, Simon | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Bailey, Anthony J. | Battaglia, Agatino | Cantor, Rita M. | Coon, Hilary | Cuccaro, Michael L. | Dawson, Geraldine | Ennis, Sean | Freitag, Christine M. | Geschwind, Daniel H. | Haines, Jonathan L. | Klauck, Sabine M. | McMahon, William M. | Maestrini, Elena | Miller, Judith | Monaco, Anthony P. | Nelson, Stanley F. | Nurnberger, John I. | Oliveira, Guiomar | Parr, Jeremy R. | Pericak-Vance, Margaret A. | Piven, Joseph | Schellenberg, Gerard D. | Scherer, Stephen W. | Vicente, Astrid M. | Wassink, Thomas H. | Wijsman, Ellen M. | Betancur, Catalina | Buxbaum, Joseph D. | Cook, Edwin H. | Gallagher, Louise | Gill, Michael | Hallmayer, Joachim | Paterson, Andrew D. | Sutcliffe, James S. | Szatmari, Peter | Vieland, Veronica J. | Hakonarson, Hakon | Devlin, Bernie
Human Molecular Genetics  2012;21(21):4781-4792.
While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
PMCID: PMC3471395  PMID: 22843504
20.  Tris(1,10-phenanthrolin-1-ium) hexa­cyanidoferrate(III) ethanol monosolvate trihydrate 
The asymmetric unit of the title complex, (C12H9N2)3[Fe(CN)6]·C2H5OH·3H2O, consists of two half [Fe(CN)6]3− anions located on inversion centers, three 1,10-phenanthrolin-1-ium cations, [Hphen]+, an ethanol and three water solvent mol­ecules. The average Fe—C and C—N bond lengths are 1.942 (6) and 1.154 (3) Å, respectively, while the Fe—C—N angles deviate slightly from linearity with values ranging from 177.8 (2) to 179.7 (2)°. The FeIII atoms adopt a distorted octa­hedral geometry. All the species are linked through O—H⋯N, N—H⋯O and O—H⋯O hydrogen-bonding inter­actions, resulting in a three-dimensional supra­molecular network.
PMCID: PMC3344416  PMID: 22590178
21.  Poly[[diaqua­hexa-μ-cyanido-cerium(III)ferrate(III)] dihydrate] 
In the structure of the title complex, {[CeFe(CN)6(H2O)2]·2H2O}n, the CeIII and FeIII atoms exhibit square anti­prismatic [CeN6(H2O)2] (site symmetry m2m) and octahedral [FeC6] (site symmetry 2/m) coordination geometries, respectively. The metal atoms are linked alternately through the cyanide groups, forming a three-dimensional framework in which the {Ce2Fe2(CN)4} puckered square unit is the basic building block. The crystal packing is enforced by O—H⋯O and O—H⋯N hydrogen bonds, including the uncoordinated water molecule which is located on a mirror plane.
PMCID: PMC3344291  PMID: 22590057
22.  A comparison of ARMS and direct sequencing for EGFR mutation analysis and Tyrosine Kinase Inhibitors treatment prediction in body fluid samples of Non-Small-Cell Lung Cancer patients 
Epidermal growth factor receptor (EGFR) mutation is strongly associated with the therapeutic effect of tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC). Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable. Body fluid was considered to be a feasible substitute for the analysis, but arising problems in clinical practice such as relatively lower mutation rate and poor clinical correlation are not yet fully resolved.
In this study, 50 patients (32 pleural fluids and 18 plasmas) with TKIs therapy experience and with direct sequencing results were selected from 220 patients for further analysis. The EGFR mutation status was re-evaluated by Amplification Refractory Mutation System (ARMS), and the clinical outcomes of TKIs were analyzed retrospectively.
As compared with direct sequencing, 16 positive and 23 negative patients were confirmed by ARMS, and the other 11 former negative patients (6 pleural fluids and 5 plasmas) were redefined as positive, with a fairly well clinical outcome (7 PR, 3 SD, and 1 PD). The objective response rate (ORR) of positive patients was significant, 81.3% (direct sequencing) and 72.7% (ARMS) for pleural fluids, and 80% (ARMS) for plasma. Notably, even reclassified by ARMS, the ORR for negative patients was still relatively high, 60% for pleural fluids and 46.2% for plasma.
When using body fluids for EGFR mutation analysis, positive result is consistently a good indicator for TKIs therapy, and the predictive effect was no less than that of tumor tissue, no matter what method was employed. However, even reclassified by ARMS, the correlation between negative results and clinical outcome of TKIs was still unsatisfied. The results indicated that false negative mutation still existed, which may be settled by using method with sensitivity to single DNA molecule or by optimizing the extraction procedure with RNA or CTC to ensure adequate amount of tumor-derived nucleic acid for the test.
PMCID: PMC3287118  PMID: 22142557
Body Fluids; EGFR Mutation; Direct Sequencing; ARMS; TKIs; NSCLC
23.  Growth rate, catalase and superoxide dismutase activities in rock carp (Procypris rabaudi Tchang) exposed to supersaturated total dissolved gas*  
Total dissolved gas supersaturation (TDGS) appears when the pressures of gases in a solution exceed the barometric pressures. TDGS is often caused by flood discharge at dams. It may lead to gas bubble disease (GBD) for fish and biochemical responses of selected fish and other aquatic organisms. The purpose of this study was to determine the impact of long-term TDGS levels on the growth and biochemical responses of rock carp (Procypris rabaudi Tchang) dwelling in the upper reaches of the Yangtze River. Three-year-old rock carp were exposed to TDGS levels at 100%, 104%, 108%, 112%, and 116% for 42 d. Samples were taken every 7 d after the start of the trial in order to determine catalase (CAT) and superoxide dismutase (SOD) activities in gill and muscle tissues. Samples were taken at Days 0 and 42 of exposure to determine growth rate. Little effect was found on growth rate in all treatment groups. SOD and CAT activities varied in different tissues, according to time of exposure and TDGS levels. The biochemical response of fish exposed to TDGS was more obvious in gill tissue than in muscle tissue. Surveys of SOD and CAT activities in different tissues offer important information about the effect of TDGS on the rare fish in the Yangtze River, and may help evaluate the risk to the aquatic eco-environment and aquatic ecosystem in the downstream of the Yangtze River.
PMCID: PMC3208170  PMID: 22042655
Total dissolved gas supersaturation (TDGS); Rock carp (Procypris rabaudi Tchang); Growth rate; Catalase; Superoxide dismutase
24.  Subclinical atherosclerosis in northern and southern China: the Chinese paradox 
The incidence of coronary heart disease (CHD) is higher in Northern than that in Southern China, however differences in traditional CHD risk factors do not fully explain this. No study has examined the differences in subclinical atherosclerosis that may help explain the differences in incidence. This study examined these differences in subclinical atherosclerosis using coronary computed tomography (CT) for calcification between the Northern and Southern China.
We selected a random sample of participants in a large multi-center ongoing epidemiologic study for coronary calcium scanning in one northern city (North) (Beijing, n = 49) and in two southern cities (South) (Shanghai, n = 50, and Guangzhou, n = 50). Participants from the three field centers (mean age 67 years) underwent coronary risk factor evaluation and cardiac CT scanning for coronary calcium measurement using the Multi-Ethnic Study of Atherosclerosis scanning protocol.
Adjusted log-transformed coronary artery calcium score in North China (Beijing) was 3.1 ± 0.4 and in South China (Shanghai and Guangzhou) was 2.2 ± 0.3 (P = 0.04). Mean calcium score for the northern city of Beijing was three times higher than that of the southern city of Guangzhou (P = 0.01) and 2.5 times higher than for the southern city of Shanghai (P = 0.03).
The extent of subclinical atherosclerosis is significantly higher in the northern city of Beijing than that in the two southern cities of Guangzhou and Shanghai, even after adjusting for standard cardiac risk factors. This finding suggests that standard risk factors do not fully explain north south differences in clinical CHD incidence.
PMCID: PMC3390074  PMID: 22783288
coronary calcium; CT scanning; atherosclerosis; epidemiology; China
25.  Functional Impact of Global Rare Copy Number Variation in Autism Spectrum Disorder 
Pinto, Dalila | Pagnamenta, Alistair T. | Klei, Lambertus | Anney, Richard | Merico, Daniele | Regan, Regina | Conroy, Judith | Magalhaes, Tiago R. | Correia, Catarina | Abrahams, Brett S. | Almeida, Joana | Bacchelli, Elena | Bader, Gary D. | Bailey, Anthony J. | Baird, Gillian | Battaglia, Agatino | Berney, Tom | Bolshakova, Nadia | Bölte, Sven | Bolton, Patrick F. | Bourgeron, Thomas | Brennan, Sean | Brian, Jessica | Bryson, Susan E. | Carson, Andrew R. | Casallo, Guillermo | Casey, Jillian | Cochrane, Lynne | Corsello, Christina | Crawford, Emily L. | Crossett, Andrew | Dawson, Geraldine | de Jonge, Maretha | Delorme, Richard | Drmic, Irene | Duketis, Eftichia | Duque, Frederico | Estes, Annette | Farrar, Penny | Fernandez, Bridget A. | Filipa, Ana | Folstein, Susan E. | Fombonne, Eric | Freitag, Christine M. | Gilbert, John | Gillberg, Christopher | Glessner, Joseph T. | Goldberg, Jeremy | Green, Andrew | Green, Jonathan | Guter, Stephen J. | Hakonarson, Hakon | Heron, Elizabeth A. | Hill, Matthew | Holt, Richard | Howe, Jennifer L. | Hughes, Gillian | Hus, Vanessa | Igliozzi, Roberta | Kim, Cecilia | Klauck, Sabine M. | Kolevzon, Alexander | Korvatska, Olena | Kustanovich, Vlad | Lajonchere, Clara M. | Lamb, Janine A. | Laskawiec, Magdalena | Leboyer, Marion | Le Couteur, Ann | Leventhal, Bennett L. | Lionel, Anath C. | Liu, Xiao-Qing | Lord, Catherine | Lotspeich, Linda | Lund, Sabata C. | Maestrini, Elena | Mahoney, William | Mantoulan, Carine | Marshall, Christian R. | McConachie, Helen | McDougle, Christopher J. | McGrath, Jane | McMahon, William M. | Merikangas, Alison | Migita, Ohsuke | Minshew, Nancy J. | Mirza, Ghazala K. | Munson, Jeff | Nelson, Stanley F. | Noakes, Carolyn | Noor, Abdul | Nygren, Gudrun | Oliveira, Guiomar | Papanikolaou, Katerina | Parr, Jeremy R. | Parrini, Barbara | Paton, Tara | Pickles, Andrew | Pilorge, Marion | Piven, Joseph | Ponting, Chris P. | Posey, David J. | Poustka, Annemarie | Poustka, Fritz | Prasad, Aparna | Ragoussis, Jiannis | Renshaw, Katy | Rickaby, Jessica | Roberts, Wendy | Roeder, Kathryn | Roge, Bernadette | Rutter, Michael L. | Bierut, Laura J. | Rice, John P. | Consortium, SAGE | Salt, Jeff | Sansom, Katherine | Sato, Daisuke | Segurado, Ricardo | Senman, Lili | Shah, Naisha | Sheffield, Val C. | Soorya, Latha | Sousa, Inês | Stein, Olaf | Stoppioni, Vera | Strawbridge, Christina | Tancredi, Raffaella | Tansey, Katherine | Thiruvahindrapduram, Bhooma | Thompson, Ann P. | Thomson, Susanne | Tryfon, Ana | Tsiantis, John | Van Engeland, Herman | Vincent, John B. | Volkmar, Fred | Wallace, Simon | Wang, Kai | Wang, Zhouzhi | Wassink, Thomas H. | Webber, Caleb | Wing, Kirsty | Wittemeyer, Kerstin | Wood, Shawn | Wu, Jing | Yaspan, Brian L. | Zurawiecki, Danielle | Zwaigenbaum, Lonnie | Buxbaum, Joseph D. | Cantor, Rita M. | Cook, Edwin H. | Coon, Hilary | Cuccaro, Michael L. | Devlin, Bernie | Ennis, Sean | Gallagher, Louise | Geschwind, Daniel H. | Gill, Michael | Haines, Jonathan L. | Hallmayer, Joachim | Miller, Judith | Monaco, Anthony P. | Nurnberger, John I. | Paterson, Andrew D. | Pericak-Vance, Margaret A. | Schellenberg, Gerard D. | Szatmari, Peter | Vicente, Astrid M. | Vieland, Veronica J. | Wijsman, Ellen M. | Scherer, Stephen W. | Sutcliffe, James S. | Betancur, Catalina
Nature  2010;466(7304):368-372.
The autism spectrum disorders (ASDs) are a group of conditions characterized by impairments in reciprocal social interaction and communication, and the presence of restricted and repetitive behaviors1. Individuals with an ASD vary greatly in cognitive development, which can range from above average to intellectual disability (ID)2. While ASDs are known to be highly heritable (~90%)3, the underlying genetic determinants are still largely unknown. Here, we analyzed the genome-wide characteristics of rare (<1% frequency) copy number variation (CNV) in ASD using dense genotyping arrays. When comparing 996 ASD individuals of European ancestry to 1,287 matched controls, cases were found to carry a higher global burden of rare, genic CNVs (1.19 fold, P= 0.012), especially so for loci previously implicated in either ASD and/or intellectual disability (1.69 fold, P= 3.4×10−4). Among the CNVs, there were numerous de novo and inherited events, sometimes in combination in a given family, implicating many novel ASD genes like SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53-PTCHD1 locus. We also discovered an enrichment of CNVs disrupting functional gene-sets involved in cellular proliferation, projection and motility, and GTPase/Ras signaling. Our results reveal many new genetic and functional targets in ASD that may lead to final connected pathways.
PMCID: PMC3021798  PMID: 20531469

Results 1-25 (35)