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1.  The Cytokine and Chemokine Profiles in Patients with Hand, Foot and Mouth Disease of Different Severities in Shanghai, China, 2010 
Background and purpose
Systemic upregulation of inflammatory cytokines is characteristic of critical severe hand, foot, and mouth disease (HFMD) with pulmonary edema. Thus, immunomodulatory medicines such as steroids, including methylprednisolone, have been proposed to treat patients with severe HFMD in China, because it is postulated that inflammatory cytokines play a role in the development of severe complications. This study is to further investigate the inflammatory response in the relatively mild HFMD patients, and whether steroid treatment has a beneficial effect on the suppression of inflammation in HFMD patients.
We measured the levels of 50 kinds of chemokines, cytokines, growth factors and soluble receptors in serum samples from control patients without HFMD and the HFMD patients with or without prior treatment of intravenous methylprednisolone.
Our present study found that even relatively mild HFMD patients without central nervous system (CNS) complications had elevated serum levels of inflammatory cytokines, including interleukin (IL)-3, IL-6, IL-12p40, and tumor necrosis factor (TNF)-α, which suggested systemic inflammation. In contrast, these patients also have decreased levels of other serum biomarkers, including IL-1Ra, IL-8, IL-16, soluble ICAM-1, CXCL-1, and CCL27. The dysregulation of cytokine and chemokine expression may be involved in CNS complications and unbalanced circulating leukocytes in HFMD patients. Surprisingly, patients treated with methylprednisolone had no difference in the expression levels of HFMD-associated biomarkers instead had slightly increased levels of IL-17A, which was not associated with the occurrence of HFMD.
Whether steroid treatment has any beneficial effect on the prognosis of HFMD patients requires to be further investigated.
Author Summary
Systemic inflammation is characteristic of severe hand, foot, and mouth disease (HFMD). Steroids are considered immunomodulators and have been officially recommended to treat the severe HFMD patients with CNS complications in China. So far, it is uncertain whether steroid treatment has an immunomodulatory role in inflammation in HFMD patients and has a real beneficial effect on their prognosis. This study revealed that even relatively mild HFMD patients without CNS complications had elevated inflammation. Unexpectedly, the inflammatory cytokine levels in patients treated with methylprednisolone, one kind of steroid, were not significantly different from those in patients without the treatment. Rather, the treated patients tended to have elevated levels of IL-17A, whose expression levels were actually not significantly associated with the presence of HFMD. IL-17A is known to play a role in the pathogenesis of CNS-related inflammatory diseases. Altogether, our study does not support the presumption that steroids have beneficial effect on the prognosis of HFMD patients by inhibiting systemic inflammation.
PMCID: PMC3868519  PMID: 24367714
2.  3D Echo-Based Patient-Specific Computational Left Ventricle Models to Quantify Material Properties and Stress/Strain Differences between Ventricles with and without Infarct 
Identifying ventricle material properties and its infarct area after heart attack noninvasively is of great important in clinical applications. An echo-based computational modeling approach was proposed to investigate left ventricle (LV) mechanical properties and stress conditions using patient-specific data. Echo data was acquired from one healthy volunteer (male, age: 58) and a male patient (age: 60) who had an acute inferior myocardial infarction one week before echo image acquisition. Standard echocardiograms were obtained using an ultrasound machine (E9, GE Mechanical Systems, Milwaukee, Wisconsin) with a 3V probe and data were segmented for model construction. Finite element models were constructed to obtain ventricle stress and strain conditions. A pre-shrink process was applied so that the model ventricle geometries under end-of-systole pressure matched in vivo data. Our results indicated that the modeling approach has the potential to be used to determine ventricle material properties. The equivalent Young’s modulus value from the healthy LV (LV1) was about 30% softer than that of the infarct LV (LV2) at end of diastole, but was about 100% stiffer than that of LV2 at end of systole. This can be explained as LV1 has more active contraction reflected by stiffness variations. Using averaged values, at end-systole, longitudinal curvature from LV2 was 164% higher than that from LV1. LV stress from LV2 was 82% higher than that from LV1. At end-diastole, L-curvature from LV2 was still 132% higher than that from LV1, while LV stress from LV2 was only 9% higher than that from LV1. Longitudinal curvature and stress showed the largest differences between the two ventricles, with the LV with infarct having higher longitudinal curvature and stress values. Large scale studies are needed to further confirm our findings.
PMCID: PMC4319570  PMID: 25663830
Heart attack; infarct, ventricle model; ventricle mechanics; left ventricle
3.  Genetic polymorphism analyses of 30 InDels in Chinese Xibe ethnic group and its population genetic differentiations with other groups 
Scientific Reports  2015;5:8260.
In the present study, we obtained population genetic data and forensic parameters of 30 InDel loci in Chinese Xibe ethnic group from northwestern China and studied the genetic relationships between the studied Xibe group and other reference groups. The observed heterozygosities ranged from 0.1704 at HLD118 locus to 0.5247 at HLD92 locus while the expected heterozygosities ranged from 0.1559 at HLD118 locus to 0.4997 at HLD101 locus. The cumulative power of exclusion and total probability of discrimination power in the studied group were 0.9867 and 0.9999999999902 for the 30 loci, respectively. Analyses of structure, PCA, interpopulation differentiations and phylogenetic tree revealed that the Xibe group had close genetic relationships with South Korean, Beijing Han and Guangdong Han groups. The results indicated that these 30 loci should only be used as a complement for autosomal STRs in paternity cases but could provide an acceptable level of discrimination in forensic identification cases in the studied Xibe group. Further studies should be conducted for better understanding of the Xibe genetic background.
PMCID: PMC4317707  PMID: 25651970
4.  TLR3 Signaling in Macrophages Is Indispensable for the Protective Immunity of Invariant Natural Killer T Cells against Enterovirus 71 Infection 
PLoS Pathogens  2015;11(1):e1004613.
Enterovirus 71 (EV71) is the most virulent pathogen among enteroviruses that cause hand, foot and mouth disease in children but rarely in adults. The mechanisms that determine the age-dependent susceptibility remain largely unclear. Here, we found that the paucity of invariant natural killer T (iNKT) cells together with immaturity of the immune system was related to the susceptibility of neonatal mice to EV71 infection. iNKT cells were crucial antiviral effector cells to protect young mice from EV71 infection before their adaptive immune systems were fully mature. EV71 infection led to activation of iNKT cells depending on signaling through TLR3 but not other TLRs. Surprisingly, iNKT cell activation during EV71 infection required TLR3 signaling in macrophages, but not in dendritic cells (DCs). Mechanistically, interleukin (IL)-12 and endogenous CD1d-restricted antigens were both required for full activation of iNKT cells. Furthermore, CD1d-deficiency led to dramatically increased viral loads in central nervous system and more severe disease in EV71-infected mice. Altogether, our results suggest that iNKT cells may be involved in controlling EV71 infection in children when their adaptive immune systems are not fully developed, and also imply that iNKT cells might be an intervention target for treating EV71-infected patients.
Author Summary
Enterovirus 71 (EV71) is a major causative pathogen of hand, foot and mouth disease. EV71 infection occurs mainly in children but rarely in adults. The factors that determine the susceptibility of children to EV71 infection remain elusive. Here, we found that the paucity of invariant natural killer T (iNKT) cells in new-born mice was associated with their susceptibility to EV71 infection. Furthermore, iNKT cells played a critical role in protecting older young mice from EV71 infection before their adaptive immune systems were fully developed. Mechanistically, TLR3 signaling in macrophages, but not in dendritic cells, was essentially required for iNKT cell activation during EV71 infection. Both interleukin (IL)-12 production and endogenous lipid antigens presented by macrophages were required for full iNKT cell activation. iNKT cells tended to prevent the dissemination of EV71 into central nervous system. Taken together, our findings provide a new insight into the susceptibility of children to EV71 infection, and imply that the manipulation of iNKT cells might represent a potential therapeutic strategy for HFMD and other viral infectious diseases in children.
PMCID: PMC4304831  PMID: 25615690
5.  Higher critical plaque wall stress in patients who died of coronary artery disease compared with those who died of other causes: a 3D FSI study based on ex vivo MRI of coronary plaques 
Journal of biomechanics  2013;47(2):432-437.
Mechanical forces play an important role in the rupture of vulnerable plaques. This process is often associated with cardiovascular syndromes, such as heart attack and stroke. In this study, magnetic resonance imaging (MRI)-based models were used to investigate the association between plaque wall stress (PWS) and coronary artery disease (CAD).
Ex vivo MRI data of coronary plaques from 12 patients were used to construct 12 three-dimensional (3D) fluid-structure interaction (FSI) computational models. Six of the patients had died from CAD and six had died from non-CAD causes. PWS was assessed using all nodal points on the lumen surface of each plaque. The maximum PWS from all possible vulnerable sites of each plaque was defined as the 3D critical plaque wall stress (CPWS).
Mean 3D CPWS in the CAD group was 94.3% higher than that in the non-CAD group (265.6 vs. 136.7 kPa, P=0.0029). There was no statistically significant difference in global maximum plaque wall stress (GMPWS) between the two groups (P=0.347). There was also no statistically significant difference in plaque burden between the CAD group (84.4 ± 5%) and the non-CAD group (82.0 ± 8%, P=0.552). The results indicate that plaques from patients who died from CAD were associated with higher CPWS compared with those from patients who died from non-CAD causes. With further validation, analysis of CPWS may prove to be an important component in assessment of plaque vulnerability.
PMCID: PMC3988129  PMID: 24345380
coronary artery disease; fluid structure interactions; magnetic resonance imaging; vulnerable plaque; stress
6.  Activation of Akt Signaling in Prostate Induces a TGFβ Mediated Restraint on Cancer Progression and Metastasis 
Oncogene  2013;33(28):3660-3667.
Mutations in the PTEN tumor suppressor gene are found in a high proportion of human prostate cancers, and in mice, Pten deletion induces high-grade prostate intra-epithelial neoplasia (HGPIN). However, progression from HGPIN to invasive cancer occurs slowly, suggesting that tumorigenesis is subject to restraint. We show that Pten deletion, or constitutive activation of the downstream kinase AKT, activates the transforming growth factor (TGF) β pathway in prostate epithelial cells. TGFβ signaling is known to play a tumor suppressive role in many cancer types, and reduced expression of TGFβ receptors correlates with advanced human prostate cancer. We demonstrate that in combination either with loss of Pten, or expression of constitutively active AKT1, inactivation of TGFβ signaling by deletion of the TGFβ type II receptor gene relieves a restraint on tumorigenesis. This results in rapid progession to lethal prostate cancer, including metastasis to lymph node and lung. In prostate epithelium, inactivation of TGFβ signaling alone is insufficient to initiate tumorigenesis, but greatly accelerates cancer progression. The activation of TGFβ signaling by Pten loss or AKT activation suggests that the same signaling events that play key roles in tumor initiation also induce the activity of a pathway that restrains disease progression.
PMCID: PMC3939071  PMID: 23995785
TGFβ; Akt; Pten; prostate cancer; signaling
7.  The Thellungiella salsuginea Tonoplast Aquaporin TsTIP1;2 Functions in Protection Against Multiple Abiotic Stresses 
Plant and Cell Physiology  2013;55(1):148-161.
Examination of aquaporin (AQP) membrane channels in extremophile plants may increase our understanding of plant tolerance to high salt, drought or other conditions. Here, we cloned a tonoplast AQP gene (TsTIP1;2) from the halophyte Thellungiella salsuginea and characterized its biological functions. TsTIP1;2 transcripts accumulate to high levels in several organs, increasing in response to multiple external stimuli. Ectopic overexpression of TsTIP1;2 in Arabidopsis significantly increased plant tolerance to drought, salt and oxidative stresses. TsTIP1;2 had water channel activity when expressed in Xenopus oocytes. TsTIP1;2 was also able to conduct H2O2 molecules into yeast cells in response to oxidative stress. TsTIP1;2 was not permeable to Na+ in Xenopus oocytes, but it could facilitate the entry of Na+ ions into plant cell vacuoles by an indirect process under high-salinity conditions. Collectively, these data showed that TsTIP1;2 could mediate the conduction of both H2O and H2O2 across membranes, and may act as a multifunctional contributor to survival of T. salsuginea in highly stressful habitats.
PMCID: PMC3894706  PMID: 24214268
Aquaporin; Channeling activity; Stress tolerance; Thellungiella salsuginea
9.  Risk Assessment of Adverse Birth Outcomes in Relation to Maternal Age 
PLoS ONE  2014;9(12):e114843.
Although a number of studies have investigated correlations of maternal age with birth outcomes, an extensive assessment using age as a continuous variable is lacking. In the current study, we estimated age-specific risks of adverse birth outcomes in childbearing women.
National population-based data containing maternal and neonatal information were derived from the Health Promotion Administration, Taiwan. A composite adverse birth outcome was defined as at least anyone of stillbirth, preterm birth, low birth weight, macrosomia, neonatal death, congenital anomaly, and small for gestational age (SGA). Singletons were further analyzed for outcomes of live birth in relation to each year of maternal age. A log-binomial model was used to adjust for possible confounders of maternal and neonatal factors.
In total, 2,123,751 births between 2001 and 2010 were utilized in the analysis. The risk of a composite adverse birth outcome was significantly higher at extreme maternal ages. In specific, risks of stillbirth, neonatal death, preterm birth, congenital anomaly, and low birth weight were higher at the extremes of maternal age. Furthermore, risk of macrosomia rose proportionally with an increasing maternal age. In contrast, risk of SGA declined proportionally with an increasing maternal age. The log-binomial model showed greater risks at the maternal ages of <26 and > 30 years for a composite adverse birth outcome.
Infants born to teenagers and women at advanced age possess greater risks for stillbirth, preterm birth, neonatal death, congenital anomaly, and low birth weight. Pregnancies at advanced age carry an additional risk for macrosomia, while teenage pregnancies carry an additional risk for SGA. The data suggest that the optimal maternal ages to minimize adverse birth outcomes are 26∼30 years.
PMCID: PMC4262474  PMID: 25494176
10.  Chemicals having estrogenic activity can be released from some bisphenol a-free, hard and clear, thermoplastic resins 
Environmental Health  2014;13(1):103.
Chemicals that have estrogenic activity (EA) can potentially cause adverse health effects in mammals including humans, sometimes at low doses in fetal through juvenile stages with effects detected in adults. Polycarbonate (PC) thermoplastic resins made from bisphenol A (BPA), a chemical that has EA, are now often avoided in products used by babies. Other BPA-free thermoplastic resins, some hypothesized or advertised to be EA-free, are replacing PC resins used to make reusable hard and clear thermoplastic products such as baby bottles.
We used two very sensitive and accurate in vitro assays (MCF-7 and BG1Luc human cell lines) to quantify the EA of chemicals leached into ethanol or water/saline extracts of fourteen unstressed or stressed (autoclaving, microwaving, UV radiation) thermoplastic resins. Estrogen receptor (ER)-dependent agonist responses were confirmed by their inhibition with the ER antagonist ICI 182,780.
Our data showed that some (4/14) unstressed and stressed BPA-free thermoplastic resins leached chemicals having significant levels of EA, including one polystyrene (PS), and three Tritan™ resins, the latter reportedly EA-free. Exposure to UV radiation in natural sunlight resulted in an increased release of EA from Tritan™ resins. Triphenyl-phosphate (TPP), an additive used to manufacture some thermoplastic resins such as Tritan™, exhibited EA in both MCF-7 and BG1Luc assays. Ten unstressed or stressed glycol-modified polyethylene terephthalate (PETG), cyclic olefin polymer (COP) or copolymer (COC) thermoplastic resins did not release chemicals with detectable EA under any test condition.
This hazard survey study assessed the release of chemicals exhibiting EA as detected by two sensitive, widely used and accepted, human cell line in vitro assays. Four PC replacement resins (Tritan™ and PS) released chemicals having EA. However, ten other PC-replacement resins did not leach chemicals having EA (EA-free-resins). These results indicate that PC-replacement plastic products could be made from EA-free resins (if appropriate EA-free additives are chosen) that maintain advantages of re-usable plastic items (price, weight, shatter resistance) without releasing chemicals having EA that potentially produce adverse health effects on current or future generations.
PMCID: PMC4298073  PMID: 25477047
BG1Luc; Bisphenol A; Tritan; Estrogenic activity; MCF-7; Thermoplastic resins
11.  Pollination in a patchily distributed lousewort is facilitated by presence of a co-flowering plant due to enhancement of quantity and quality of pollinator visits 
Annals of Botany  2013;112(9):1751-1758.
Background and Aims
Plants surrounded by individuals of other co-flowering species may suffer a reproductive cost from interspecific pollen transfer (IPT). However, differences in floral architecture may reduce or eliminate IPT.
A study was made of Pedicularis densispica (lousewort) and its common co-flowering species, Astragalus pastorius, to compare reproductive and pollination success of lousewort plants from pure and mixed patches. Floral architecture and pollinator behaviour on flowers of the two plants were compared along with the composition of stigmatic pollen load of the louseworts. The extent of pollen limitation of plants from pure and mixed patches was also explored through supplemental pollination with self- and outcross pollen (PLs and PLx).
Key Results
Mixed patches attracted many more nectar-searching individuals of Bombus richardsi. These bumble-bees moved frequently between flowers of the two species. However, they pollinated P. densispica with their dorsum and A. pastorius with their abdomen. This difference in handling almost completely eliminated IPT. Lousewort plants from mixed patches yielded more seeds, and seeds of higher mass and germinability, than those from pure patches. Moreover, louseworts from mixed patches had lower PLs and PLx compared with those from pure patches.
Differences in floral architecture induced differences in pollinator behaviour that minimized IPT, such that co-flowering plants significantly enhanced quantity and quality of pollinator visits for the lousewort plants in patchy habitat. These findings add to our understanding of the mechanisms of pollination facilitation.
PMCID: PMC3838553  PMID: 24131615
Astragalus pastorius; bumble-bee; geitonogamous mating; interspecific pollen transfer; lousewort; mechanical isolation; Pedicularis densispica; pollen limitation; pollination; pollinator behaviour
12.  Mechanical memory and dosing influence stem cell fate 
Nature materials  2014;13(6):645-652.
We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young’s modulus E ~ 2 kPa) depended on prior culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). Additionally, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible - or above a threshold mechanical dose, irreversible - activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs toward osteogenic differentiation. We conclude that stem cells possess mechanical memory - with YAP/TAZ acting as an intracellular mechanical rheostat - that stores information from past physical environments and influences the cells’ fate.
PMCID: PMC4031270  PMID: 24633344
13.  Acceptability and Correlates of Primary and Secondary Prevention of Cervical Cancer among Medical Students in Southwest China: Implications for Cancer Education 
PLoS ONE  2014;9(10):e110353.
To understand knowledge about, and acceptability of, cervical cancer screening and HPV vaccines among medical students; and to explore potential factors that influence their acceptability in China.
We conducted a survey among medical students at six universities across southwest China using a 58-item questionnaire regarding knowledge and perceptions of HPV, cervical cancer, and HPV vaccines.
We surveyed 1878 medical students with a mean age of 20.8 years (standard deviation: 1.3 years). Of these, 48.8% and 80.1% believed cervical cancer can be prevented by HPV vaccines and screening respectively, while 60.2% and 71.2% would like to receive or recommend HPV vaccines and screening. 35.4% thought HPV vaccines ought to be given to adolescents aged 13–18 years. 32% stated that women should start to undergo screening from the age of 25. 49.2% felt that women should receive screening every year. Concern about side effects (38.3% and 39.8%), and inadequate information (42.4% and 35.0%) were the most cited barriers to receiving or recommending HPV vaccination and cervical cancer screening. Females were more likely to accept HPV vaccines (OR, 1.86; 95% CI: 1.47–2.35) or cervical cancer screening (OR, 3.69; 95% CI: 2.88–4.74). Students with a higher level of related knowledge were much more willing to receive or recommend vaccines (P<0.001) or screening (P<0.001). Students who showed negative or uncertain attitudes towards premarital sex were less likely to accept either HPV vaccines (OR, 0.67; 95% CI: 0.47–0.96), or screening (OR, 0.68; 0.47–0.10). Non-clinical students showed lower acceptability of cervical screening compared to students in clinical medicine (OR, 0.74; 95% CI: 0.56–0.96).
The acceptability of HPV vaccines and cervical cancer screening is relatively low among medical students in southwest China. Measures should be taken to improve knowledge about cervical cancer and awareness of HPV vaccines and screening among medical students at university.
PMCID: PMC4215919  PMID: 25360743
14.  Regulatory role of tetR gene in a novel gene cluster of Acidovorax avenae subsp. avenae RS-1 under oxidative stress 
Acidovorax avenae subsp. avenae is the causal agent of bacterial brown stripe disease in rice. In this study, we characterized a novel horizontal transfer of a gene cluster, including tetR, on the chromosome of A. avenae subsp. avenae RS-1 by genome-wide analysis. TetR acted as a repressor in this gene cluster and the oxidative stress resistance was enhanced in tetR-deletion mutant strain. Electrophoretic mobility shift assay demonstrated that TetR regulator bound directly to the promoter of this gene cluster. Consistently, the results of quantitative real-time PCR also showed alterations in expression of associated genes. Moreover, the proteins affected by TetR under oxidative stress were revealed by comparing proteomic profiles of wild-type and mutant strains via 1D SDS-PAGE and LC-MS/MS analyses. Taken together, our results demonstrated that tetR gene in this novel gene cluster contributed to cell survival under oxidative stress, and TetR protein played an important regulatory role in growth kinetics, biofilm-forming capability, superoxide dismutase and catalase activity, and oxide detoxicating ability.
PMCID: PMC4204640  PMID: 25374564
horizontal gene transfer; tetR; repressor; oxidative stress; EMSA; proteome profiling
15.  3-methyladenine, an autophagic inhibitor, attenuates therapeutic effects of sirolimus on scopolamine-induced cognitive dysfunction in a rat model 
Previous studies have demonstrated that sirolimus has therapeutic effects for Alzheimer’s disease which characterized by cognitive dysfunction. However, its underlying mechanisms have not been fully elucidated. In the present study, we aimed to investigate the mechanisms of therapeutic effects of sirolimus for cognitive dysfunction rat model which induced by chronic administration of scopolamine. Forty Wistar rats were randomly divided into 4 groups (n=10 each): saline group and scopolamine group, sirolimus plus scopolamine group and 3-methyladenine pretreatment group. Morris water maze test was applied to measure the cognitive function of rat. After behavioral test, rats were sacrificed and prefrontal cortex and hippocampus were harvested for measuring amyloid-β (Aβ), Beclin-1 and mammalian target of rapamycin (mTOR). Compared with saline group, scopolamine administered significantly decreased the cognitive performance of rats during the Morris water maze test and changed Aβ, Beclin-1 and mTOR levels in rat prefrontal cortex and hippocampus (P<0.05); In addition, rats in sirolimus plus scopolamine group significantly reversed scopolamine-induced effects (P<0.05). Most importantly, 3-methyladenine abrogated the effects of sirolimus on scopolamine-induced cognitive dysfunction (P<0.05). In conclusion, the mechanism of sirolimus exerting therapeutic effects for scopolamine-induced cognitive dysfunction is likely related to the activation of autophagy.
PMCID: PMC4238551  PMID: 25419365
3-methyladenine; autophagy; sirolimus; scopolamine; cognitive dysfunction
16.  Genetic and Dietary Determinants of Insulin-Like Growth Factor (IGF)-1 and IGF Binding Protein (BP)-3 Levels among Chinese Women 
PLoS ONE  2014;9(10):e108934.
Higher insulin-like growth factor (IGF)-1 and lower IGF binding protein (BP)-3 levels have been associated with higher commoncancer risk, including breast cancer. Dietary factors, genetic polymorphisms, and the combination of both may influence circulating IGF-1 and IGFBP-3 serum concentrations.
From September 2011 to July 2012, we collected demographic, reproductive and dietary data on 143 women (≥40 years). We genotyped IGF-1 rs1520220 and IGFBP-3 rs2854744 and measured circulating IGF-1 and IGFBP-3 levels in serum. Covariance analyses were used to estimate the associations of serum levels of IGF-1 and IGFBP-3, and the molar ratio of IGF-1to IGFBP-3 with IGF-1 rs1520220 and IGFBP-3 rs2854744 genotypes. We subsequently assessed the combined influence of genetics and diet (daily intake of protein, fat and soy isoflavones) on IGF-1 and IGFBP-3 levels.
Among women aged less than 50 years, circulating IGF-1 serum levels were significantly lower for those with CC genotype for IGF-1 rs1520220 than levels for those with the GC or GG genotypes (in recessive model: P = 0.007).In gene-diet analyses among these women, we found carrying CC genotype for IGF-1 rs1520220 and high soy isoflavone intake tend to be associated with lower circulating IGF-1 levels synthetically (P = 0.002). Women with GG or GC genotypes for IGF-1 rs1520220 and with low intake of soy isoflavones had the highest levels of circulating IGF-1 (geometric mean [95% CI]: 195 [37, 1021] µg/L). Comparatively, women with both the CC genotype and high soy intake had the lowest levels of circulating IGF-1 (geometric mean [95% CI]: 120 [38,378] µg/L).
IGF-1 serum levels are significantly lower among women with the CC genotype for IGF-1-rs1520220. High soy isoflavone intake may interact with carrying CC genotype for IGF-1-rs1520220 to lower women's serum IGF-1 levels more.
PMCID: PMC4186782  PMID: 25285521
17.  Diagnostic Value of Surfactant Protein-A in Severe Acute Pancreatitis-Induced Acute Respiratory Distress Syndrome 
The complexity of multiple-item criteria in acute respiratory distress syndrome (ARDS) often causes inconvenience for physicians in the management of patients with severe acute pancreatitis (SAP). We evaluated whether serum SP-A levels in the presence of diffuse alveolar damage (DAD) can be qualitatively assessed for diagnosis of SAP-induced ARDS.
Eighty rats were randomly divided into 2 groups (n=40 each) – the sham-operated (SO) group and the SAP group – and then randomly subdivided into 4 subgroups in a time-course manner. Furthermore, rats in the SAP group were subdivided into the SAP induced-ARDS group (ARDS group) and the SAP without ARDS group (non-ARDS group) according to the diagnostic standard of ARDS. The diagnostic cut-off values of SP-A for SAP-induced ARDS were determined by the receiver operating characteristic curve (ROC).
Serum SP-A levels in Baseline, SO group, SAP group, ARDS group, and non-ARDS group were 43.15±14.29, 51.91±16.99, 193.4±35.37, 198.0+29.73, and 185.7±43.21 ug/ml, respectively. The best cut-off value for the serum SP-A level for the diagnosis of SAP-induced ARDS was 150 ug/ml and the area under the ROC curve of SP-A was 0.88. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of SP-A in the diagnosis of SAP-induced ARDS were 100.0%, 81.8%, 71.4%, 100.0%, and 87.5%, respectively.
Serum SP-A levels may allow the detection of SAP-induced ARDS and may help to support the clinical diagnosis of ARDS. The optimal serum SP-A cut-off value to discriminate SAP-induced ARDS and other groups (SO group and non-ARDS group) is around 150 ug/ml.
PMCID: PMC4186216  PMID: 25256693
Acute Respiratory Distress Syndrome; Pancreatitis; Pulmonary Surfactant-Associated Proteins
18.  Visit-to-visit variability of fasting plasma glucose as predictor of ischemic stroke: competing risk analysis in a national cohort of Taiwan Diabetes Study 
BMC Medicine  2014;12(1):165.
Glycemic variation as an independent predictor of ischemic stroke in type 2 diabetic patients remains unclear. This study examined visit-to-visit variations in fasting plasma glucose (FPG), as represented by the coefficient of variation (CV), for predicting ischemic stroke independently, regardless of glycated hemoglobin (HbA1c) and other conventional risk factors in such patients.
Type 2 diabetic patients enrolled in the National Diabetes Care Management Program, ≥30 years old and free of ischemic stroke (n = 28,354) in 2002 to 2004 were included, and related factors were analyzed with extended Cox proportional hazards regression models of competing risk data on stroke incidence.
After an average 7.5 years of follow-up, there were 2,250 incident cases of ischemic stroke, giving a crude incidence rate of 10.56/1,000 person-years (11.64 for men, 9.63 for women). After multivariate adjustment, hazard ratios for the second, third and fourth versus first FPG-CV quartile were 1.11 (0.98, 1.25), 1.22 (1.08, 1.38) and 1.27 (1.12, 1.43), respectively, without considering HbA1c, and 1.09 (0.96, 1.23), 1.16 (1.03, 1.31) and 1.17 (1.03, 1.32), respectively, after considering HbA1c.
Besides HbA1c, FPG-CV was a potent predictor of ischemic stroke in type 2 diabetic patients, suggesting that different therapeutic strategies now in use be rated for their potential to (1) minimize glucose fluctuations and (2) reduce HbA1c level in type 2 diabetic patients to prevent ischemic stroke.
PMCID: PMC4182812  PMID: 25255837
Glucose variation; Ischemic stroke; Type 2 diabetes
19.  Leptin deficiency is involved in the cognitive impairment of streptozocin-induced diabetic rats undergoing cardiopulmonary bypass 
Several lines of evidence have demonstrated that leptin is probably involved in the cognitive impairment which induced by a single injection of streptozocin (STZ). However, there is little literature reporting the relationship between cognitive impairment and cardiopulmonary bypass (CPB). This study aimed to investigate the role of leptin in the cognitive impairment of STZ-induced diabetic rats undergoing CPB. Wistar rats received 2 h of CPB exposure 1 month after a single intraperitoneal injection of 60 mg/kg of STZ or the vehicle. Behavioral results of rats in Morris water maze were recorded. After that, rat hippocampi were harvested for measuring leptin, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Besides, we observed intracerebroventricular injection of leptin on the cognitive impairment of diabetic-rats undergoing CPB and measured behavioral performance and hippocampal TNF-α and IL-1β levels. Rats undergoing CPB significantly aggravates STZ-induced an increase of the latency to the platform and a decrease of the proportion of time spent in the target quadrant of rats in Morris water maze test. Additionally, the expression of leptin significantly decreased, while TNF-α and IL-1β levels significantly increased. Moreover, intracerebroventricular injection of leptin has a therapeutic effect for cognitive impairment of diabetic rats undergoing CPB. Leptin deficiency in hippocampus is probably involved in the cognitive impairment of streptozocin-induced diabetic rats undergoing cardiopulmonary bypass.
PMCID: PMC4211761  PMID: 25356111
Leptin; cognitive impairment; streptozocin; cardiopulmonary bypass
20.  The surgical learning curve for robotic-assisted laparoscopic radical prostatectomy: experience of a single surgeon with 500 cases in Taiwan, China 
Asian Journal of Andrology  2014;16(5):728-734.
To analyze the learning curve for cancer control from an initial 250 cases (Group I) and subsequent 250 cases (Group II) of robotic-assisted laparoscopic radical prostatectomy (RALP) performed by a single surgeon. Five hundred consecutive patients with clinically localized prostate cancer received RALP and were evaluated. Surgical parameters and perioperative complications were compared between the groups. Positive surgical margin (PSM) and biochemical recurrence (BCR) were assessed as cancer control outcomes. Patients in Group II had significantly more advanced prostate cancer than those in Group I (22.2% vs 14.2%, respectively, with Gleason score 8–10, P= 0.033; 12.8% vs 5.6%, respectively, with clinical stage T3, P= 0.017). The incidence of PSM in pT3 was decreased significantly from 49% in Group I to 32.6% in Group II. A meaningful trend was noted for a decreasing PSM rate with each consecutive group of 50 cases, including pT3 and high-risk patients. Neurovascular bundle (NVB) preservation was significantly influenced by the PSM in high-risk patients (84.1% in the preservation group vs 43.9% in the nonpreservation group). The 3-year, 5-year, and 7-year BCR-free survival rates were 79.2%, 75.3%, and 70.2%, respectively. In conclusion, the incidence of PSM in pT3 was decreased significantly after 250 cases. There was a trend in the surgical learning curve for decreasing PSM with each group of 50 cases. NVB preservation during RALP for the high-risk group is not suggested due to increasing PSM.
PMCID: PMC4215670  PMID: 24830691
cancer control; learning curve; prostate cancer; prostatectomy; robotics; surgical margin
21.  Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica 
Neurology  2013;81(8):710-713.
To determine the effect of a lower dose of rituximab in depleting B lymphocytes, maintaining low B-cell counts, and relapse in patients with neuromyelitis optica (NMO) and NMO spectrum disorders.
We treated 5 Chinese patients with deteriorating NMO and NMO spectrum disorders with a 100-mg IV infusion of rituximab once a week for 3 consecutive weeks, followed by additional infusion of the same dosage depending on circulating B-cell repopulation.
This reduced dosage of rituximab was sufficient to deplete B cells and maintain low B-cell counts. None of the treated patients experienced relapse, and all patients exhibited stabilized or improved neurologic function during the 1-year follow-up period. MRI revealed the absence of new lesions, no enhancement in spinal cord and brain, a significant shrinkage of spinal cord segments, and a reduction/disappearance of previous brain lesions.
A lower dosage of rituximab may be sufficient in depleting B cells, maintaining low B-cell counts, and preventing disease progression in Chinese patients with NMO.
PMCID: PMC3776460  PMID: 23884041
22.  Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons 
The Journal of Neuroscience  2014;34(8):2832-2844.
The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically projecting GABAergic/PV neurons.
PMCID: PMC3931499  PMID: 24553925
brain slices; optostimulation; patch-clamp; transgenic mice
23.  Cloning and characterization of Clp protease proteolytic subunit 2 and its implication in clinical diagnosis of tuberculosis 
Objective: To clone, express, and characterize Mycobacterium tuberculosis (Mtb) ClpP2, and evaluated the potential usage of ClpP2 in clinical diagnosis of tuberculosis. Methods: Mtb ClpP2 was cloned into recombinant plasmid pET32a (+) and transformed into E. coli BL21 (DE3). SDS-PAGE and Western blot analysis were performed to detect the expression of the recombinant protein. The immunogenicity of Mtb ClpP2 was assessed with epitope prediction and antibody titer assay. Quantitative real-time PCR was performed to detect the influence of stress conditions on ClpP2 expression. ClpP2 antigen and antibody in patients with pulmonary diseases were detected by indirect ELISA. ROC curve was constructed to assess the diagnostic accuracy of Mtb ClpP2 for tuberculosis. Results: We had cloned and expressed recombinant Mtb ClpP2 in E. coli. Our results showed that Mtb ClpP2 had potent immunogenicity, and our own prepared polyclonal antibody could be used in detection and diagnostic tests. Results from Western blot showed that ClpP2 was mainly located in M. bovis BCG cytoplasm, and real-time PCR indicated that stress conditions could enhance the mRNA expression of ClpP2. Indirect ELISA suggested that, in tuberculosis patients, both the levels of ClpP2 antigen and antibody were increased, and the positive rates of ClpP2 were elevated. ROC curve had demonstrated satisfactory sensitivity and specificity of ClpP2-based diagnosis for tuberculosis. Conclusion: Our results suggest that Mtb ClpP2 antigens would be used as a biomarker in tuberculosis pathogenesis. These findings highlight the feasibility of the application of Mtb ClpP2 in the clinical diagnosis of tuberculosis.
PMCID: PMC4203179  PMID: 25337208
Clp protease proteolytic subunit 2 (ClpP2); Mycobacterium tuberculosis (Mtb); tuberculosis; serological diagnosis
24.  Fabrication of mAb G250-SPIO Molecular Magnetic Resonance Imaging Nanoprobe for the Specific Detection of Renal Cell Carcinoma In Vitro 
PLoS ONE  2014;9(7):e101898.
Molecular magnetic resonance imaging (mMRI) has been paid more and more attention for early diagnosis of cancer. A sensitive and specific mMRI probe plays the most important role in this technique. In this study, superparamagnetic iron oxide (SPIO) nanoparticles and mAb G250 were conjugated as mMRI probe for the detection of clear cell renal cell carcinoma (ccRCC) using 3.0-Tesla MRI in vitro. mAb G250 could specifically recognize carbonic anhydrase IX (CAIX) antigen overexpressed in ccRCC and the SPIO nanoparticles as MRI contrast agent presented excellent MRI response and good biocompatibility. The successful assembly of this nanoprobe was confirmed by UV-vis spectrum, FT-IR spectroscopy and DLS analysis. In vitro MRI study on ccRCC cells and control cells indicated that our fabricated mAb G250-SPIO nanoprobe could be used in the specific labeling of clear cell renal carcinoma cells successfully.
PMCID: PMC4084989  PMID: 24999987
25.  Quality of life in women with cervical precursor lesions and cancer: a prospective, 6-month, hospital-based study in China 
Chinese Journal of Cancer  2014;33(7):339-345.
The overall survival of patients with cervical cancer has improved due to detection at an early stage and availability of comprehensive treatments in China. As patients' lives prolonged, it is important to understand their health-related quality of life (QoL) during and after treatment. We used the EQ-5D questionnaire to assess QoL of 194 patients with cervical lesions at Sichuan University West China Second Hospital between May 2010 and January 2011. Patients were surveyed before primary treatment and at 1, 3, and 6 months after primary treatment. Results showed a consistent decline in EQ-5D scores in the spectrum of cervical lesions at each time point after treatment (all P < 0.05). For patients with precursor lesions, there was an increasing trend along the timeline of treatment (P < 0.01). For patients with early-stage cervical cancer, EQ-5D scores declined in the first month (P = 0.01) and gradually increased to higher levels at 6 months post-treatment than those before treatment (P < 0.01). EQ-5D scores followed a similar trend in patients with advanced cervical cancer (P = 0.04), though they did not statistically rebound after 6 months (0.84 ± 0.19 vs. 0.86 ± 0.11, P = 0.62). Regarding advanced cervical cancer, EQ-5D scores for women above 40 years of age appeared to recover more rapidly and reached higher levels than those for women below 40 years (P = 0.03). Caution and extra care are recommended in the early period of cervical cancer treatment given the slight deterioration in the QoL, and in particular, for younger cervical cancer patients. Our study implies that health care providers may need to improve the health-related QoL of cervical cancer patients.
PMCID: PMC4110466  PMID: 24698497
Cervical cancer; cervical precursor lesion; quality of life; EQ-5D; prospective study; Chinese women

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