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author:("Li, xiyanping")
1.  The Association between Insomnia Symptoms and Mortality: A Prospective Study of US Men 
Circulation  2013;129(7):737-746.
Background
Insomnia complaints are common in older adults and may be associated with mortality risk. However, evidence regarding this association is mixed. We thus prospectively examined whether men with insomnia symptoms had an increased risk of mortality during 6 years of follow-up.
Methods and Results
A prospective cohort study of 23,447 US men participating in the Health Professionals Follow-up Study and free of cancer, reported on insomnia symptoms in 2004 were followed through 2010. Deaths were identified from state vital statistic records, the National Death Index, family reports, and the postal system. We documented 2025 deaths during 6 years of follow-up (2004-2010). The multivariable-adjusted hazard ratios (HRs) of total mortality were 1.25 (95% confidence interval (CI):1.04-1.50) for difficulty initiating sleep, 1.09 (95%CI:0.97-1.24) for difficulty maintaining sleep, 1.04 (95%CI:0.88-1.22) for early-morning awakenings, and 1.24 (95%CI:1.05-1.46) for non-restorative sleep, comparing men with those symptoms most of the time to men without those symptoms, after adjusting for age, lifestyle factors and presence of common chronic conditions. Men with difficulty initiating sleep and non-restorative sleep most of the time had a 55% (HR:1.55; 95% CI:1.19-2.04; P-trend= 0.01) and 32% (HR:1.32; 95% CI:1.02-1.72; P-trend=0.002) increased risk of CVD mortality, respectively, relative to men without those symptoms.
Conclusion
Some insomnia symptoms, especially difficulty initiating asleep and non-restorative sleep, are associated with a modestly higher risk of mortality.
doi:10.1161/CIRCULATIONAHA.113.004500
PMCID: PMC3987964  PMID: 24226807
Mortality; Sleep Disorders; Cardiovascular Outcomes; Insomnia
2.  Circulating adiponectin and cardiovascular mortality in patients with type 2 diabetes mellitus: evidence of sexual dimorphism 
Cardiovascular Diabetology  2014;13(1):130.
Background
The pathogenesis of cardiovascular (CV) mortality, whose rate is increased in type 2 diabetes, is poorly understood.
While high serum adiponectin is associated with increased CV mortality in the general population, no data are available in type 2 diabetes.
We here investigated whether this counterintuitive association was observable also in diabetic patients and whether it was sex-specific.
Methods
Three prospective cohorts were analyzed: 1) Gargano Heart Study (GHS; 359 patients, 58 events/1,934 person-years; py); 2) Health Professional Follow-up Study (HPFS; 833 men, 146 events/10,024 py); 3) Nurses’ Health Study (NHS; 902 women, 144 events/15,074 py).
Results
In GHS serum adiponectin predicted CV mortality in men (hazard ratio, HR, and 95% CI per standard deviation, SD, increment = 1.54, 1.19-2.01), but not women (HR = 0.98, 0.48-2.01).
Circulating adiponectin predicted CV mortality in men from HPFS (HR = 1.44, 1.21-1.72), but not in women from NHS (HR = 1.08, 0.86-1.35), used as replication samples. In a pooled analysis, HRs were 1.47 (1.27-1.70) in 1,075 men and 1.07 (0.86-1.33) in 1,019 women (p for HRs heterogeneity across sexes = 0.018).
Conclusions
This is the first report showing that high circulating adiponectin predicts increased CV mortality in men, but not in women with type 2 diabetes. Further studies are necessary to unravel the mechanisms through which adiponectin influences CV mortality in a sex-specific manner.
Electronic supplementary material
The online version of this article (doi:10.1186/s12933-014-0130-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12933-014-0130-y
PMCID: PMC4172916  PMID: 25200659
Adipokines; Prospective studies; Paradoxical effect; Sex-linked genes
4.  Paclitaxel- and/or cisplatin-induced ocular neurotoxicity: a case report and literature review 
OncoTargets and therapy  2014;7:1361-1366.
Paclitaxel (PTX) and/or cisplatin (CDDP), as important cytotoxic anti-cancer agents, are widely used to treat various solid tumors. Both may cause moderate or severe neurotoxicity, but ocular neurotoxicity is also occasionally reported. A patient diagnosed with nasopharyngeal cancer suffering acute ocular neurotoxicity 10 days after paclitaxel and CDDP administration at the recommended dose is described in the present case report, and PTX- and/or CDDP-induced ocular neurotoxicity are summarized according to previous reports. Possible mechanisms and the potential diagnostic, therapeutic and predictive strategies of PTX- and/or CDDP-induced ocular neurotoxicity are reviewed, to help the oncologist to take the infrequent toxicity of cytotoxic drugs into account and improve patient safety during anti-cancer therapy.
doi:10.2147/OTT.S65774
PMCID: PMC4125372  PMID: 25114574
cytotoxic drugs; PTX; CDDP; oncology; chemotherapy
5.  Prospective study of restless legs syndrome and mortality among men 
Neurology  2013;81(1):52-59.
Objective:
To prospectively examine whether men with restless legs syndrome (RLS) had an increased risk of mortality.
Method:
This was a prospective cohort study of 18,425 US men free of diabetes, arthritis, and renal failure in the Health Professionals Follow-up Study (HPFS). In 2002, RLS was assessed using a set of standardized questions. Deaths were identified from state vital statistics records, the National Death Index, family reports, and the postal system.
Results:
During 8 years of follow-up (2002–2010), we documented 2,765 deaths. In an age-adjusted model, RLS was associated with a 39% increased risk of mortality (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.19–1.62; p < 0.0001). The association between RLS and mortality was slightly attenuated after further adjustment for body mass index, lifestyle factors, chronic conditions, sleep duration, and other sleep-related disorders (adjusted HR = 1.30; 95% CI 1.11–1.52; p = 0.003). When we further excluded those with major chronic conditions (e.g., cancer, high blood pressure, cardiovascular disease, and other comorbidities), the adjusted HR was 1.92 (95% CI 1.03–3.56; p = 0.04). The interactions between RLS and other risk factors (older age, overweight, short sleep duration, smoking, low physical activity, and unhealthy diet) in relation to total mortality risk were not significant (p for interaction >0.2 for all).
Conclusion:
We observed that men with RLS had a higher overall mortality and this association was independent of known risk factors. The increased mortality in RLS was more frequently associated with respiratory disease, endocrine disease, nutritional/metabolic disease, and immunologic disorders. Future research exploring the pathophysiologic relationship between these disorders and RLS is warranted.
doi:10.1212/WNL.0b013e318297eee0
PMCID: PMC3770202  PMID: 23761622
6.  Prospective Study of Restless Legs Syndrome and Risk of Erectile Dysfunction 
American Journal of Epidemiology  2013;177(10):1097-1105.
In our previous cross-sectional study, we found that restless legs syndrome (RLS) was associated with erectile dysfunction (ED). Thus, we conducted a prospective study to examine whether RLS was associated with a higher risk of developing ED based on 6 years of follow-up among 10,394 men (mean age = 63.4 years) in the Health Professionals Follow-up Study. RLS was assessed in 2002 using a set of standardized questions recommended by the International RLS Study Group. Erectile function was assessed by means of questionnaires in 2000, 2004, and 2008. We identified 1,633 incident ED cases. Men with RLS were more likely to develop ED (relative risk = 1.38, 95% confidence interval: 1.14, 1.68; P = 0.001) than were those without the syndrome, after adjustment for potential confounders, such as age, body mass index, smoking, physical activity, other sleep disorders, and snoring status. A higher frequency of RLS symptoms was also associated with an increased risk of ED (Ptrend = 0.001). In conclusion, men with RLS had a higher risk of ED, and the magnitude of the risk increased with a higher frequency of RLS symptoms. Combinations of other sleep disorders with RLS further increased the risk of ED.
doi:10.1093/aje/kws364
PMCID: PMC3649636  PMID: 23608708
erectile dysfunction; prospective studies; restless legs syndrome; sleep disorders
7.  B-Raf is required for positive selection and survival of DP cells, but not for negative selection of SP cells 
International Immunology  2013;25(4):259-269.
B-Raf affects ERK and controls thymocyte positive but not negative selection.
The duration of signaling through the MAP kinase (or ERK pathway) cascade has been implicated in thymic development, particularly positive and negative selection. In T cells, two isoforms of the MAP kinase kinase kinase Raf function to transmit signals from the T-cell receptor to ERK: C-Raf and B-Raf. In this study, we conditionally ablated B-Raf expression within thymocytes to assess the effects on ERK activation and thymocyte development. The complete loss of B-Raf is accompanied by a dramatic loss of ERK activation in both the double positive (DP) and single positive (SP) thymocytes, as well as peripheral splenocytes. There was a significant decrease in the cellularity of KO thymi, largely due to a loss of pre-selected DP cells, a decrease in DP cells undergoing positive selection, and a defect in SP maturation. B-Raf plays significant roles in survival of DP thymocytes and function of SP cells in the periphery. Surprisingly, we saw no effect of B-Raf deficiency on negative selection of autoreactive SP thymocytes, despite the greatly reduced ERK activation in these cells.
doi:10.1093/intimm/dxs104
PMCID: PMC3597848  PMID: 23334952
B-Raf; ERK; MAPK; positive selection; thymic development
8.  Electroacupuncture attenuates cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive rats 
Cerebral ischemia induces injury, not only in the ischemic core and surrounding penumbra tissues, but also in remote areas such as the cervical spinal cord. The aim of the present study was to determine the effects of electroacupuncture (EA) on cervical spinal cord injury following cerebral ischemia/reperfusion in stroke-prone renovascular hypertensive (RHRSP) rats. The results demonstrated that neuronal loss, which was assayed by Nissl staining in the cervical spinal cords of RHRSP rats subjected to transient middle cerebral artery occlusion (MCAO), was markedly decreased by EA stimulation at the GV20 (Baihui) and GV14 (Dazhui) acupoints compared with that in rats undergoing sham stimulation. Quantitative polymerase chain reaction and western blot analysis demonstrated that EA stimulation blocked the MCAO-induced elevated protein expression levels of glial fibrillary acidic protein and amyloid precursor protein in the cervical spinal cord at days 24 and 48. To further investigate the mechanism underlying the neuroprotective role of EA stimulation, the protein expression levels of Nogo-A and Nogo-66 receptor-1 (NgR1), two key regulatory molecules for neurite growth, were recorded in each group. The results revealed that EA stimulation reduced the MCAO-induced elevation of Nogo-A and NgR1 protein levels at day 14 and 28 in RHRSP rats. Therefore, the results demonstrated that EA reduced cervical spinal cord injury following cerebral ischemia in RHRSP rats, indicating that EA has the potential to be developed as a therapeutic treatment agent for cervical spinal cord injury following stroke.
doi:10.3892/etm.2014.1619
PMCID: PMC4043606  PMID: 24926338
cerebral ischemia; cervical spinal cord; neuron; stroke-prone renovascular hypertensive rats
9.  CK2 Phosphorylates SSRP1 and Inhibits Its DNA-binding Activity* 
The Journal of biological chemistry  2005;280(12):11869-11875.
We have previously shown that CK2 associates with the human high-mobility group protein SSRP1 and that this association increases in response to UV irradiation. CK2 also phosphorylates SSRP1 in vitro. Here we extend this work by investigating CK2 regulation of SSRP1 function through phosphorylation. Phosphorylation of SSRP1 by CK2 inhibited the nonspecific DNA-binding activity of SSRP1 and FACT (facilitating chromatin-mediated transcription) complex in vitro. Using a serine/threonine-scanning Auto-spot peptide array coupled with a filter-based kinase assay with synthetic peptides as substrates, we identified serines 510, 657, and 688 as phosphorylation targets of CK2 in vitro. Mutagenesis of the three serines revealed that serine 510 was more important for the regulation of SSRP1 DNA-binding activity. Furthermore, we found that SSRP1 was phosphorylated in cells in response to UV (but not γ) irradiation. These results suggest that CK2 regulates the DNA-binding ability of SSRP1 and that this regulation may be responsive to specific cell stresses.
doi:10.1074/jbc.M413944200
PMCID: PMC3923407  PMID: 15659405
10.  Genome-Wide Gene Expression Profiles in Lung Tissues of Pig Breeds Differing in Resistance to Porcine Reproductive and Respiratory Syndrome Virus 
PLoS ONE  2014;9(1):e86101.
Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is an infectious disease characterized by severe reproductive deficiency in pregnant sows, typical respiratory symptoms in piglets, and high mortality rate of piglets. In this study, we employed an Affymetrix microarray chip to compare the gene expression profiles of lung tissue samples from Dapulian (DPL) pigs (a Chinese indigenous pig breed) and Duroc×Landrace×Yorkshire (DLY) pigs after infection with PRRSV. During infection with PRRSV, the DLY pigs exhibited a range of clinical features that typify the disease, whereas the DPL pigs showed only mild signs of the disease. Overall, the DPL group had a lower percentage of CD4+ cells and lower CD4+/CD8+ratios than the DLY group (p<0.05). For both IL-10 and TNF-α, the DLY pigs had significantly higher levels than the DPL pigs (p<0.01). The DLY pigs have lower serum IFN-γ levels than the DPL pigs (p<0.01). The serum IgG levels increased slightly from 0 dpi to 7 dpi, and peaked at 14 dpi (p<0.0001). Microarray data analysis revealed 16 differentially expressed (DE) genes in the lung tissue samples from the DLY and DPL pigs (q≤5%), of which LOC100516029 and LOC100523005 were up-regulated in the PRRSV-infected DPL pigs, while the other 14 genes were down-regulated in the PRRSV-infected DPL pigs compared with the PRRSV-infected DLY pigs. The mRNA expression levels of 10 out of the 16 DE genes were validated by real-time quantitative RT-PCR and their fold change was consistent with the result of microarray data analysis. We further analyzed the mRNA expression level of 8 differentially expressed genes between the DPL and DLY pigs for both uninfected and infected groups, and found that TF and USP18 genes were important in underlying porcine resistance or susceptibility to PRRSV.
doi:10.1371/journal.pone.0086101
PMCID: PMC3900479  PMID: 24465897
11.  Reversal Effect of ST6GAL 1 on Multidrug Resistance in Human Leukemia by Regulating the PI3K/Akt Pathway and the Expression of P-gp and MRP1 
PLoS ONE  2014;9(1):e85113.
β-galactoside α2, 6-sialyltransferse gene (ST6GAL) family has two members, which encode corresponding enzymes ST6Gal I and ST6Gal II. The present atudy was to investigate whether and how ST6GAL family involved in multidrug resistance (MDR) in human leukemia cell lines and bone marrow mononuclear cells (BMMC) of leukemia patients. Real-time PCR showed a high expression level of ST6GAL1 gene in both MDR cells and BMMCs (*P<0.05). Alternation of ST6GAL1 levels had a significant impact on drug-resistant phenotype changing of K562 and K562/ADR cells both in vitro and in vivo. However, no significant changes were observed of ST6GAL2 gene. Further data revealed that manipulation of ST6GAL1 modulated the activity of phosphoinositide 3 kinase (PI3K)/Akt signaling and consequently regulated the expression of P-glycoprotein (P-gp, *P<0.05) and multidrug resistance related protein 1 (MRP1, *P<0.05), which are both known to be associated with MDR. Therefore we postulate that ST6GAL1 is responsible for the development of MDR in human leukemia cells probably through medicating the activity of PI3K/Akt signaling and the expression of P-gp and MRP1.
doi:10.1371/journal.pone.0085113
PMCID: PMC3894187  PMID: 24454800
12.  Use of Granulocyte Colony-Stimulating Factor for the Treatment of Thin Endometrium in Experimental Rats 
PLoS ONE  2013;8(12):e82375.
Granulocyte colony-stimulating factor (G-CSF) induces stem cells to mobilize to the injury site, which have beneficial effect on tissue repair. The aim of this study was to investigate the effect of G-CSF on the thin endometrium in rat models. In the present study, rats with thin endometrium were divided into 4 groups (experimental group I: administrated with G-CSF (40 µg/kg/d) 4–6 hours post-modeling; control group I: administrated with saline 4–6 hours post-modeling; experimental group II: administrated with G-CSF (40 µg/kg/d) 12 days post-modeling; control group II: administrated with saline 12 days post-modeling. The agentia was given once daily and last for 5 days. Endometrial morphology was analyzed by Hematoxylin-Eosin staining, and the regeneration of endometrial cells was evaluated by immunohistochemistry and western-blot with cytokeratin and vimentin. We found that endometrial thickness and morphology presented a significant difference between experimental groups and control groups. No matter when we start with G-CSF, there was a significantly thicker endometrium and stronger expression of cytokeratin/vimintin in the experimental groups compared with the control groups (P<0.01). There were significant thicker endometrial lining and stronger expression of cytokeratin/vimintin in experimental group I than that of experimental group II (P<0.05), but there was no difference in the endometrial lining and the expression of cytokeratin/vimintin between the two control groups (P>0.05). In conclusion, G-CSF can promote the regeneration of endometrial cells in animal research, especially when the G-CSF was administrated earlier.
doi:10.1371/journal.pone.0082375
PMCID: PMC3871160  PMID: 24376532
13.  Birth Weight, Genetic Susceptibility, and Adulthood Risk of Type 2 Diabetes 
Diabetes Care  2012;35(12):2479-2484.
OBJECTIVE
Both stressful intrauterine milieus and genetic susceptibility have been linked to later-life diabetes risk. The current study aims to examine the interaction between low birth weight, a surrogate measure of stressful intrauterine milieus, and genetic susceptibility in relation to risk of type 2 diabetes in adulthood.
RESEARCH DESIGN AND METHODS
The analysis included two independent, nested case-control studies of 2,591 type 2 diabetic case subjects and 3,052 healthy control subjects. We developed two genotype scores: an obesity genotype score based on 32 BMI-predisposing variants and a diabetes genotype score based on 35 diabetes-predisposing variants.
RESULTS
Obesity genotype scores showed a stronger association with type 2 diabetes risk in individuals with low birth weight. In low–birth weight individuals, the multivariable-adjusted odds ratio (OR) was 2.55 (95% CI 1.34–4.84) by comparing extreme quartiles of the obesity genotype score, while the OR was 1.27 (1.04–1.55) among individuals with birth weight >2.5 kg (P for interaction = 0.017). We did not observe significant interaction between diabetes genotype scores and birth weight with regard to risk of type 2 diabetes. In a comparison of extreme quartiles of the diabetes gene score, the multivariable-adjusted OR was 3.80 (1.76–8.24) among individuals with low birth weight and 2.27 (1.82–2.83) among those with high birth weight (P for interaction = 0.16).
CONCLUSIONS
Our data suggest that low birth weight and genetic susceptibility to obesity may synergistically affect adulthood risk of type 2 diabetes.
doi:10.2337/dc12-0168
PMCID: PMC3507591  PMID: 22923665
14.  Target volume and position variations during intensity-modulated radiotherapy for patients with nasopharyngeal carcinoma 
OncoTargets and therapy  2013;6:1719-1728.
Purpose
Considerable anatomical changes occur during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC). This study aimed to quantify volumetric and positional variations of the target volume during IMRT.
Materials and methods
Twenty patients with locally advanced NPC who received concurrent (13 patients) or sequential (seven patients) chemoradiotherapy were prospectively recruited and underwent planning computed tomography (CT) and six repeat CTs (every five fractions). Each repeat CT was rigidly registered to the planning CT. Gross tumor volume (GTV) and elective clinical target volume (CTV) were manually delineated on each axial CT image. CTVs of the primary tumor and lymph nodes were expanded with 5 mm margins to corresponding GTVs, with necessary modifications. Volume loss, system and random errors, and the mean and three-dimensional vector displacements were calculated and compared statistically.
Results
Volumes of the primary tumor and small (>1 cm, ≤3 cm) and large (>3 cm) positive neck lymph nodes decreased at a rate of 2.6%, 3.7%, and 3.9% per treatment day, respectively. CTVs of the primary tumor, lymph nodes, and elective region decreased 1.5%, 2.3%, and 0.3% per treatment day, respectively. Average displacements of the GTVs and CTVs were <1.3 mm in all directions. GTVs and CTVs of the large and small lymph nodes shifted medially by 0.8–1.3 and 0.6–1.2 mm, respectively, on average. Average three-dimensional displacements of the GTVs and CTVs were 3.4–4.3 mm and 2.5–3.7 mm, respectively. Volume loss and displacements in most directions were significantly larger in patients receiving concurrent chemoradiotherapy than in those receiving sequential therapy. Volume loss and displacements of the GTV of large nodes and elective CTV were significantly larger in male than in female patients.
Conclusion
Volumetric and positional changes of the target volume were considerable, and volume loss increased as treatment time elapsed during IMRT for NPC.
doi:10.2147/OTT.S53639
PMCID: PMC3839809  PMID: 24311943
nasopharyngeal carcinoma; adaptive radiotherapy; radiation response; anatomical changes; organ motion
15.  The Cross-Neutralizing Activity of Enterovirus 71 Subgenotype C4 Vaccines in Healthy Chinese Infants and Children 
PLoS ONE  2013;8(11):e79599.
Background
EV71 is one of major etiologic causes of hand-foot-mouth disease (HFMD) and leads to severe neurological complications in young children and infants. Recently inactivated EV71 vaccines have been developed by five manufactures and clinically show good safety and immunogenicity. However, the cross-neutralizing activity of these vaccines remains unclear, and is of particular interest because RNA recombination is seen more frequently in EV71 epidemics.
Methodology/Principal Findings
In this post-hoc study, sera from a subset of 119 infants and children in two clinical trials of EV71 subgenotype C4 vaccines (ClinicalTrials.gov Identifier: NCT01313715 and NCT01273246), were detected for neutralizing antibody (NTAb) titres with sera from infected patients as controls. Cytopathogenic effect method was employed to test NTAb against EV71 subgenotype B4, B5, C2, C4 and C5, which were prominent epidemic strains worldwide over the past decade. To validate the accuracy of the results, ELISpot assay was employed in parallel to detect NTAb in all the post-vaccine sera. After two-dose vaccination, 49 out of 53 participants in initially seronegative group and 52 out of 53 participants in initially seropositive group showed less than 4-fold differences in NTAb titers against five EV71 strains, whereas corresponding values among sera from pediatric patients recovering from EV71-induced HFMD and subclinically infected participants were 8/8 and 41/43, respectively. The geometric mean titers of participants against five subgenotypes EV71 all grew significantly after vaccinations, irrespective of the baseline NTAb titer. The relative fold increase in antibody titers (NTAb-FI) against B4, B5, C2, and C5 displayed a positive correlation to the NTAb-FI against C4.
Conclusions/Significance
The results demonstrated broad cross-neutralizing activity induced by two C4 EV71 vaccines in healthy Chinese infants and children. However, the degree of induced cross-protective immunity, and the potential escape evolution for EV71 still need to be monitored and researched in future for these new vaccines.
doi:10.1371/journal.pone.0079599
PMCID: PMC3834186  PMID: 24260259
16.  Association of Follicle-Stimulating Hormone Receptor Polymorphisms with Ovarian Response in Chinese Women: A Prospective Clinical Study 
PLoS ONE  2013;8(10):e78138.
Background
Follicular stimulating hormone (FSH) is a glycoprotein and widely used for the treatment of infertility; FSH action is mediated by FSH receptor (FSHR), SNPs of which determine the ovarian response. Two polymorphisms of the FSHR gene were identified, which caused a change of threonine (T) to alanine (A) at position 307 and asparagine (N) to serine(S) at position 680. Both polymorphic sites give rise to three discrete variants of the FSHR: TT, TA, and AA for position 307; NN, NS, and SS for position 680.
Methodology/Principal Findings
450 Chinese women were recruited in an assisted reproductive technology program from October 2011 to March 2012. FSHR polymorphisms at the positions 307 and 680 were examined by PCR-RFLP. Serum FSH and estradiol level, FSH amount, ovarian response and pregnancy rate were recorded during treatment. The basal FSH levels were higher in AA [7.38 ± 2.07 vs 6.34 ± 1.75, 6.63 ± 1.94, P<0.05, 95% CI (6.75, 8.01)] and SS [7.51 ± 2.01 vs 6.31 ± 1.75, 6.66 ± 1.96, P<0.05, 95% CI (6.88, 8.15)] compared to other genotypes respectively; the days for ovulation induction was slightly longer in AA and SS. Women with AA and SS have higher rates of poor response compared to carriers of other genotypes (P<0.05). Furthermore, there is a nearly complete linkage between these two polymorphisms in Chinese women (D’=0.95, r2=0.84).
Conclusions/Significance
In Chinese women receiving ART, the subjects with AA and SS genotypes have higher basal FSH levels, and these genotypes are associated with an increased risk of poor response. Our data suggested that the personalized FSH therapy may be applied according to patient’s genetic background in clinical settings. The linkage suggested that the polymorphisms of Thr307Ala and Asn680Ser may be used as TAG-SNP markers for analysis of potential genotyping in ART.
doi:10.1371/journal.pone.0078138
PMCID: PMC3805513  PMID: 24167601
17.  Identification and Characterization of a Novel Trehalose Synthase Gene Derived from Saline-Alkali Soil Metagenomes 
PLoS ONE  2013;8(10):e77437.
A novel trehalose synthase (TreS) gene was identified from a metagenomic library of saline-alkali soil by a simple activity-based screening system. Sequence analysis revealed that TreS encodes a protein of 552 amino acids, with a deduced molecular weight of 63.3 kDa. After being overexpressed in Escherichia coli and purified, the enzymatic properties of TreS were investigated. The recombinant TreS displayed its optimal activity at pH 9.0 and 45 °C, and the addition of most common metal ions (1 or 30 mM) had no inhibition effect on the enzymatic activity evidently, except for the divalent metal ions Zn2+ and Hg2+. Kinetic analysis showed that the recombinant TreS had a 4.1-fold higher catalytic efficientcy (Kcat/Km) for maltose than for trehalose. The maximum conversion rate of maltose into trehalose by the TreS was reached more than 78% at a relatively high maltose concentration (30%), making it a good candidate in the large-scale production of trehalsoe after further study. In addition, five amino acid residues, His172, Asp201, Glu251, His318 and Asp319, were shown to be conserved in the TreS, which were also important for glycosyl hydrolase family 13 enzyme catalysis.
doi:10.1371/journal.pone.0077437
PMCID: PMC3797794  PMID: 24146994
18.  Television Watching, Leisure-Time Physical Activity and the Genetic Predisposition in Relation to Body Mass Index in Women and Men 
Circulation  2012;126(15):1821-1827.
Background
Previous studies on gene-lifestyle interaction and obesity have mostly focused on the FTO gene and physical activity, while little attention has been paid to sedentary behavior as indicated by television (TV) watching.
Methods and Results
We analyzed interactions between TV watching, leisure-time physical activity and genetic predisposition in relation to body mass index (BMI) in 7740 women and 4564 men from 2 prospective cohorts: the Nurses’ Health Study and Health Professionals Follow-up Study. Data on physical activity and TV watching were collected 2 years prior to assessment of BMI. A weighted genetic risk score (GRS) was calculated on the basis of 32 established BMI-associated variants. In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted GRS was associated with 0.8 [SE 0.4], 0.8 [0.2], 1.4 [0.2], 1.5 [0.2] and 3.4 [1.0] kg/m2 higher BMI across the 5 categories of TV watching (0-1, 2-5, 6-20, 21-40, and >40h/wk) (P for interaction=0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted GRS was associated with 1.5 [0.2], 1.3 [0.2], 1.2 [0.2], 1.2 [0.2] and 0.8 [0.2] kg/m2 higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other.
Conclusions
Sedentary lifestyle indicated by prolonged TV watching may accentuate predisposition to elevated adiposity, whereas greater leisure-time physical activity may attenuate the genetic association.
doi:10.1161/CIRCULATIONAHA.112.098061
PMCID: PMC3667660  PMID: 22949498
Body mass index; Genetics; Gene-lifestyle interaction; Television watching; Physical activity
19.  Prospective Study of Restless Legs Syndrome and Coronary Heart Disease Among Women 
Circulation  2012;126(14):1689-1694.
Background
Previous cross-sectional studies suggested a positive association between restless legs syndrome (RLS) and coronary heart disease (CHD). This observation was not confirmed by subsequent prospective studies. However, these prospective studies did not take into account the duration of RLS symptoms. We thus prospectively examined whether RLS was associated with an increased risk of CHD in women who participated in the Nurses’ Health Study taking into account the duration of RLS symptoms.
Methods and Results
A total of 70, 694 women (mean age 67 years) who were free of CHD and stroke at baseline (2002) were followed until 2008. Physician-diagnosed RLS was collected via questionnaire. CHD was defined as nonfatal myocardial infarction or fatal CHD. Women with RLS at baseline had a marginally higher risk of developing CHD (multivariable-adjusted hazard ratio (HR), 1.46; 95% confidence interval (CI), 0.97–2.18) as compared with women without RLS. The risk was dependent on duration of symptoms-0.98 (95% CI, 0.44–2.19) for women with RLS less than three years and 1.72 (95% CI, 1.09–2.73) for women with RLS for three years or longer (P trend=0.03). The multivariable-adjusted HRs of women with RLS for three years or longer were 1.80 (95%CI, 1.07–3.01) for nonfatal myocardial infarction and 1.49 (95%CI, 0.55–4.04) for fatal CHD, relative to women without RLS.
Conclusions
We observed that women with RLS for at least three years had an elevated risk of CHD. These results suggest that RLS or RLS associated conditions may contribute to the etiology of cardiovascular disease.
doi:10.1161/CIRCULATIONAHA.112.112698
PMCID: PMC3493117  PMID: 22967852
Restless legs syndrome (Willis Ekbom Disease); coronary heart disease; sleep; prospective cohort study
20.  Prospective Study of Restless Legs Syndrome and Risk of Depression in Women 
American Journal of Epidemiology  2012;176(4):279-288.
Most research on the association between restless legs syndrome (RLS) and depression has involved cross-sectional data. The objective of the present study was to evaluate this issue prospectively among Nurses' Health Study participants. A total of 56,399 women (mean age = 68 years) who were free of depression symptoms at baseline (2002) were followed until 2008. Physician-diagnosed RLS was self-reported. During 300,155 person-years of follow-up, the authors identified 1,268 incident cases of clinical depression (regular use of antidepressant medication and physician-diagnosed depression). Women with RLS at baseline were more likely to develop clinical depression (multivariate-adjusted relative risk (RR) = 1.5, 95% confidence interval (CI): 1.1, 2.1; P = 0.02) than those without RLS. The presence of RLS at baseline was also associated with higher scores on the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the 15-item Geriatric Depression Scale (GDS-15) thereafter. Multivariable-adjusted mean differences were 1.00 (standard error, 0.12) for CESD-10 score and 0.47 (standard error, 0.07) for GDS-15 score between women with RLS and those without RLS (P < 0.0001). In conclusion, women with physician-diagnosed RLS had an increased risk of developing clinical depression and clinically relevant depression symptoms. Further prospective studies using refined approaches to ascertainment of RLS and depression are warranted.
doi:10.1093/aje/kws016
PMCID: PMC3491969  PMID: 22805376
depression; meta-analysis; prospective studies; restless legs syndrome
21.  Joint Association of Dietary Pattern and Physical Activity Level with Cardiovascular Disease Risk Factors among Chinese Men: A Cross-Sectional Study 
PLoS ONE  2013;8(6):e66210.
The purpose of this cross-sectional study was to investigate the joint associations of physical activity level (PAL) and dietary patterns in relation to cardiovascular disease (CVD) risk factors among Chinese men. The study population consisted of 13 511 Chinese males aged 18–59 years from the 2002 China National Nutrition and Health Survey. Based on dietary data collected by a food frequency questionnaire, four dietary patterns were identified and labeled as “Green Water” (high consumption of rice, vegetables, seafood, pork, and poultry), “Yellow Earth” (high consumption of wheat flour products and starchy tubers), “New Affluent” (high consumption of animal sourced foods and soybean products), and “Western Adopter” (high consumption of animal sourced foods, cakes, and soft drinks). From the information collected by a 1-year physical activity questionnaire, PAL was calculated and classified into 4 categories: sedentary, low active, active, and very active. As compared with their counterparts from the New Affluent pattern, participants who followed the Green Water pattern had a lower likelihood of abdominal obesity (AO; 50.2%), hypertension (HT; 37.9%), hyperglycemia (HG; 41.5%), elevated triglyceride (ETG; 14.5%), low HDL (LHDL; 39.8%), and metabolic syndrome (MS; 51.9%). When compared to sedentary participants, the odds ratio of participants with very active PAL was 0.62 for AO, 0.85 for HT, 0.71 for HG, 0.76 for ETG, 0.74 for LHDL, and 0.58 for MS. Individuals who followed both very active PAL and the Green Water pattern had a lower likelihood of CVD risk factors (AO: 65.8%, HT: 39.1%, HG: 57.4%, ETG: 35.4%, LHDL: 56.1%, and MS: 75.0%), compared to their counterparts who followed both sedentary PAL and the New Affluent pattern. In addition, adherence to both healthy dietary pattern and very active PAL presented a remarkable potential for CVD risk factor prevention.
doi:10.1371/journal.pone.0066210
PMCID: PMC3686814  PMID: 23840426
22.  Genome Sequence of Clostridium tyrobutyricum ATCC 25755, a Butyric Acid-Overproducing Strain 
Genome Announcements  2013;1(3):e00308-13.
Clostridium tyrobutyricum ATCC 25755 is an efficient producer of butyric acid. Here we report a 3.01-Mb assembly of its genome sequence and other useful information, including the coding sequences (CDSs) responsible for an alternative pathway leading to acetate synthesis as well as a series of membrane transport systems.
doi:10.1128/genomeA.00308-13
PMCID: PMC3668012  PMID: 23723404
23.  Synergistic Effects of Serum Uric Acid and Cardiometabolic Risk Factors on Early Stage Atherosclerosis: The Cardiometabolic Risk in Chinese Study 
PLoS ONE  2012;7(12):e51101.
Objective
To comprehensively examine the associations of serum uric acid (SUA) with central and peripheral arterial stiffness in Chinese adults, and particularly assess the interactions between SUA and other cardiometabolic risk factors.
Methods
The study included 3,772 Chinese men and women with carotid radial pulse wave velocity (crPWV), carotid femoral PWV (cfPWV), carotid artery dorsalis pedis PWV (cdPWV) and SUA measured.
Results
After adjustment for age, sex, and BMI, the levels of SUA were significantly associated with increasing trend of cfPWV, crPWV and cdPWV (P for trend <0.0001). Further adjustment for heart rate (HR), blood pressure (BP) and lipids attenuated the associations with crPWV and cdPWV to be non-significant (P = 0.1, P = 0.099 respectively), but the association between SUV and cfPWV remained significant (P = 0.004). We found significant interactions between SUA and HR or BP in relation to cfPWV (P for interaction = 0.03, 0.003 respectively). The associations between SUA and cfPWV were more evident among individuals with higher HR or normal BP than those with lower HR or hypertension.
Conclusions
SUA was associated with elevated aortic arterial stiffness in Chinese adults, independent of conventional cardiovascular risk factors. BP and HR might modify the deleterious effects of SUA.
doi:10.1371/journal.pone.0051101
PMCID: PMC3524235  PMID: 23284659
24.  The effect of endometrial thickness and pattern measured by ultrasonography on pregnancy outcomes during IVF-ET cycles 
Background
To study the effect of endometrial thickness and pattern measured using ultrasound upon pregnancy outcomes in patients undergoing IVF-ET.
Method
One thousand nine hundred thirty-three women undergoing IVF treatment participated in the study. We assessed and recorded endometrial patterns and thickness on the day of human chorionic gonadotropin (hCG) administration. Receiver operator curves (ROC) were used to determine the predictive accuracy of endometrial thickness. Cycles were divided into 3 groups depending on the thickness (group 1: ≤ 7 mm; group 2: > 7 mm to ≤ 14 mm; group 3: > 14 mm). Each group was subdivided into three groups according to the endometrial pattern as follows: pattern A (a triple-line pattern consisting of a central hyperechoic line surround by two hypoechoic layers); pattern B (an intermediate isoechogenic pattern with the same reflectivity as the surrounding myometrium and a poorly defined central echogenic line); and pattern C (homogenous, hyperechogenic endometrium). Clinical outcomes such as implantation and clinical pregnancy rates were analyzed.
Results
The endometrial thickness predicts pregnancy outcome with high sensitivity and specificity. The cutoff value was 9 mm. The implantation rate and clinical pregnancy rate in group 3 were 39.1% and 63.5%, respectively, which were significantly higher than those in group 2 (33.8% and 52.1%, respectively) and group 1 (13% and 25.5%, respectively). Among those with Pattern A, the implantation rate and clinical pregnancy rate were 35.3% and 55.2%, respectively, which were significantly higher than among women with Pattern B (32.1% and 50.9%, respectively) and Pattern C (23.4% and 37.4%, respectively). In groups 1 and 3, clinical pregnancy and implantation rates did not show any significant differences between different endometrial patterns (P > 0.05), whereas in group 2, the clinical pregnancy rate and implantation rate in women with pattern A were significantly higher than those with pattern B or C (P < 0.05).
Conclusions
Endometrial thickness and pattern independently affect pregnant outcomes. Combined endometrial thickness and pattern could not predict the outcome of IVF-ET when endometrial thickness was < 7 mm or >14 mm, while a triple-line pattern with a moderate endometrial thickness appeared to be associated with a good clinical outcome.
doi:10.1186/1477-7827-10-100
PMCID: PMC3551825  PMID: 23190428
Endometrial thickness; Endometrial pattern; IVF-ET; Implantation; Pregnancy
25.  RESTLESS LEGS SYNDROME AND HYPERTENSION IN MIDDLE-AGE WOMEN 
Hypertension  2011;58(5):791-796.
Limited research suggests a relationship between Restless Legs Syndrome and hypertension. We, therefore, assessed the relationship between restless legs syndrome and hypertension among middle-aged women.
This is a cross-sectional study including 65,544 women (aged 41-58 years) participating in Nurses Health Study II. The participants with diabetes and arthritis were excluded as these conditions can mimic restless legs syndrome. Restless legs syndrome was assessed by a self-administered questionnaire based on the International Restless Legs Study Group criteria. Information on diagnosis of hypertension and blood pressure values were collected via questionnaires. Multivariable logistic regression models were used to analyze the relation between restless legs syndrome and hypertension, with adjustment for age, race, body mass index, physical activity, menopausal status, smoking, use of analgesics, and intake of alcohol, caffeine, folate, and iron.
Compared to women with no restless legs symptoms, the multiple adjusted odds of having hypertension were 1.20 (95% CI: 1.10-1.30; P<0.0001) times higher among women with restless legs symptoms. The adjusted odds ratios for women who reported restless legs symptoms 5-14 times/month and ≥15 times/month were 1.06 (95% CI 0.94-1.18) and 1.41 (95% CI 1.24-1.61) respectively, compared to those without the symptoms (P trend <0.0001). Greater frequency of restless legs symptoms was associated with higher concurrent systolic and diastolic blood pressures (P trend<0.0001 for both).
Women with restless legs syndrome have a higher prevalence of hypertension, and this prevalence increases with more frequent restless legs symptoms.
doi:10.1161/HYPERTENSIONAHA.111.174037
PMCID: PMC3221559  PMID: 21986505
Restless legs syndrome; Hypertension; Sleep; Cardiovascular disease; Women

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