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1.  Incidence and psychological-behavioral characteristics of refractory functional dyspepsia: A large, multi-center, prospective investigation from China 
AIM: To explore the incidence and psychological and behavioral characteristics of refractory functional dyspepsia (RFD) in China.
METHODS: The subjects of this study were 1341 new outpatients with functional dyspepsia (FD) who were diagnosed according to the Rome III criteria at four hospitals in Guangdong Province between June and September 2012, and 100 healthy volunteers. All subjects completed questionnaires and scales administered.
RESULTS: Three-hundred and twenty-seven of the 1341 patients with FD had RFD (24.4%). Patients with RFD had a longer disease duration and a more severe form of the disease than patients with non-refractory FD (NRFD). The prevalence of depression and anxiety symptoms was higher in patients with RFD than in patients with NRFD. The prevalence of unhealthy eating behaviors, lack of physical activity, and sleeping disorders was higher in patients with RFD than in patients with NRFD. Patients with RFD sought medical advice on more occasions and spent more money on treatment than patients with NRFD. Finally, patients with RFD had poorer quality of life than patients with NRFD.
CONCLUSION: RFD is not rare in clinical practice and should get attention by patients and doctors because of its long duration, severe symptoms, and associations with abnormal psychology and poor quality of life.
doi:10.3748/wjg.v21.i6.1932
PMCID: PMC4323473
Refractory functional dyspepsia; Psychological-behavioral characteristics; Depression; Anxiety; Behavior; Quality of life
2.  Optimization of 4-(N-Cycloamino)phenylquinazolines as a Novel Class of Tubulin-Polymerization Inhibitors Targeting the Colchicine Site 
Journal of Medicinal Chemistry  2014;57(4):1390-1402.
The 6-methoxy-1,2,3,4-tetrahydroquinoline moiety in prior leads 2-chloro- and 2-methyl-4-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)quinazoline (1a and 1b) was modified to produce 4-(N-cycloamino)quinazolines (4a–c and 5a–m). The new compounds were evaluated in cytotoxicity and tubulin inhibition assays, resulting in the discovery of new tubulin-polymerization inhibitors. 7-Methoxy-4-(2-methylquinazolin-4-yl)-3,4-dihydroquinoxalin- 2(1H)-one (5f), the most potent compound, exhibited high in vitro cytotoxic activity (GI50 1.9–3.2 nM), significant potency against tubulin assembly (IC50 0.77 μM), and substantial inhibition of colchicine binding (99% at 5 μM). In mechanism studies, 5f caused cell arrest in G2/M phase, disrupted microtubule formation, and competed mostly at the colchicine site on tubulin. Compound 5f and N-methylated analogue 5g were evaluated in nude mouse MCF7 xenograft models to validate their antitumor activity. Compound 5g displayed significant in vivo activity (tumor inhibitory rate 51%) at a dose of 4 mg/kg without obvious toxicity, whereas 5f unexpectedly resulted in toxicity and death at the same dose.
doi:10.1021/jm4016526
PMCID: PMC3983391  PMID: 24502232
3.  Antrodin C Inhibits Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer Cells via Suppression of Smad2/3 and β-Catenin Signaling Pathways 
PLoS ONE  2015;10(2):e0117111.
Epithelial-to-mesenchymal transition (EMT) is a crucial event involved metastasis of certain tumors. Thus, identifying chemical agents that can block EMT is highly warranted for the development of anti-cancer chemoprevention/chemotherapies. In this study, we found that Antrodin C (ADC), a maleimide derivative isolated from Antrodia cinnamomea health food product inhibits TGF-β1-induced EMT and breast cancer cell metastasis in vitro. Pretreatment of MCF-7 cells with ADC significantly blocked TGF-β1-induced phenotypic changes and actin cytoskeleton remodeling. In addition, ADC was able to up-regulate epithelial markers such as E-cadherin and occludin, whereas mesenchymal markers including N-cadherin and vimentin were significantly inhibited, possibly through the modulation of transcriptional regulators Smad/Smad3. ADC blocked TGF-β1-induced migration and invasion of MCF-7 cells through the down-regulation of matrix-metalloproteinases (MMP-2, -9) and urokinase plasminogen activator (uPA). The inhibition of MMPs and uPA activity by ADC was reasoned by suppression of its corresponding transcription factor β-catenin. Taken together, our data suggested that ADC attenuates the TGF-β1-induced EMT, migration and invasion of human breast carcinoma through the suppression of Smad2/3 and β-catenin signaling pathways.
doi:10.1371/journal.pone.0117111
PMCID: PMC4319743  PMID: 25658913
4.  Discovery of Novel Antitumor Dibenzocyclooctatetraene Derivatives and Related Biphenyls as Potent Inhibitors of NF-κB Signaling Pathway 
Bioorganic & medicinal chemistry  2013;22(1):325-333.
Several dibenzocyclooctatetraene derivatives (5-7) and related biphenyls (8-11) were designed, synthesized, and evaluated for inhibition of cancer cell growth and the NF-κB signaling pathway. Compound 5a, a dibenzocyclooctatetraene succinimide, was discovered as a potent inhibitor of the NF-κB signaling pathway with significant antitumor activity against several human tumor cell lines (GI50 1.38–1.45 μM) and was more potent than paclitaxel against the drug-resistant KBvin cell line. Compound 5a also inhibited LPS-induced NF-κB activation in RAW264.7 cells with an IC50 value of 0.52 μM, prevented IκB-α degradation and p65 nuclear translocation, and suppressed LPS-induced NO production in a dose-dependent manner. The antitumor data in cellular assays indicated that relative positions and types of substituents on the dibenzocyclooctatetraene or acyclic biphenyl as well as torsional angles between the two phenyls are of primary importance to antitumor activity.
doi:10.1016/j.bmc.2013.11.018
PMCID: PMC3899348  PMID: 24315191
dibenzocyclooctatetraene derivatives; unsymmetrical biphenyls; anticancer agents; NF-κB inhibitor
5.  Identification of causative pathogens in mouse eyes with bacterial keratitis by sequence analysis of 16S rDNA libraries 
Experimental Animals  2014;64(1):49-56.
The clone library method using PCR amplification of the 16S ribosomal RNA (rRNA) gene was used to identify pathogens from corneal scrapings of C57BL/6-corneal opacity (B6-Co) mice with bacterial keratitis. All 10 samples from the eyes with bacterial keratitis showed positive PCR results. All 10 samples from the normal cornea showed negative PCR results. In all 10 PCR-positive samples, the predominant and second most predominant species accounted for 20.9 to 40.6% and 14.7 to 26.1%, respectively, of each clone library. The predominant species were Staphylococcus lentus, Pseudomonas aeruginosa, and Staphylococcus epidermidis. The microbiota analysis detected a diverse group of microbiota in the eyes of B6-Co mice with bacterial keratitis and showed that the causative pathogens could be determined based on percentages of bacterial species in the clone libraries. The bacterial species detected in this study were mostly in accordance with results of studies on clinical bacterial keratitis in human eyes. Based on the results of our previous studies and this study, the B6-Co mouse should be considered a favorable model for studying bacterial keratitis.
doi:10.1538/expanim.14-0046
PMCID: PMC4329515
bacteria; keratitis; mice; 16S rDNA
6.  Influence of three coccidiostats on the pharmacokinetics of florfenicol in rabbits 
Experimental Animals  2014;64(1):73-79.
In-feed Medication has been used for a long time to prevent coccidiosis, a worldwide protozoal disease in rabbits. Florfenicol (FFC) has been widely used in veterinary clinics for bacterial diseases treatment. Therefore, the use of combinations of coccidiostats with FFC in rabbits is common. In the present study, we aimed to evaluate the effect of three coccidiostats, sulfaquinoxaline (SUL), robenidine (ROB), and toltrazuril (TOL), as feed additives on the pharmacokinetic profile of FFC in rabbits. The disposition kinetics of FFC in rabbits were investigated after a single intravenous injection (25 mg/kg) in rabbits fed anticoccidial-free diets or feeds containing SUL (250 ppm), ROB (66 ppm), or TOL (2 ppm), respectively, for 20 days. Plasma FFC concentrations were determined by the high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters of FFC were analyzed using a non-compartmental analysis based on the statistical moment theory. The results demonstrated that ROB feeding resulted in an obvious decrease in plasma FFC level as compared with anticoccidial-free feeding. The terminal elimination half-life (t1/2z), area under the concentration–time curve (AUC), area under the first moment curve (AUMC), and mean residence time (MRT) significantly decreased, whereas the elimination rate constant (λz) and total body clearance (CLz) obviously increased in rabbits pretreated with ROB. However, we did not find that SUL or TOL feeding had any effect on the pharmacokinetic profile of FFC. Our findings suggested that more attention should be paid to the use of FFC in rabbits supplemented with ROB.
doi:10.1538/expanim.14-0064
PMCID: PMC4329518
coccidiostats; drug-drug interactions; florfenicol; pharmacokinetics
7.  Proteomic approaches for site-specific O-GlcNAcylation analysis 
Bioanalysis  2014;6(19):2571-2580.
O -GlcNAcylation is a dynamic protein post-translational modification of serine or threonine residues by an O-linked monosaccharide N-acetylglucosamine (O-GlcNAc). O-GlcNAcylation was discovered three decades ago and its significance has been implicated in several disease states, such as metabolic diseases, cancer and neurological diseases. Yet it remains technically challenging to characterize comprehensively and quantitatively because of its low abundance, low stoichiometry and extremely labile nature under conventional collision-induced dissociation tandem MS conditions. Herein, we review the recent advances addressing these challenges in developing proteomic approaches for site-specific O-GlcNAcylation analysis, including specific enrichment of O-GlcNAc peptides/proteins, unambiguous site-determination of O-GlcNAc modification and quantitative analysis of O-GlcNAcylation.
doi:10.4155/bio.14.239
PMCID: PMC4275047  PMID: 25411699
8.  Emergence of disassortative mixing from pruning nodes in growing scale-free networks 
Scientific Reports  2014;4:7536.
Disassortative mixing is ubiquitously found in technological and biological networks, while the corresponding interpretation of its origin remains almost virgin. We here give evidence that pruning the largest-degree nodes of a growing scale-free network has the effect of decreasing the degree correlation coefficient in a controllable and tunable way, while keeping both the trait of a power-law degree distribution and the main properties of network's resilience and robustness under failures or attacks. The essence of these observations can be attributed to the fact the deletion of large-degree nodes affects the delicate balance of positive and negative contributions to degree correlation in growing scale-free networks, eventually leading to the emergence of disassortativity. Moreover, these theoretical prediction will get further validation in the empirical networks. We support our claims via numerical results and mathematical analysis, and we propose a generative model for disassortative growing scale-free networks.
doi:10.1038/srep07536
PMCID: PMC4269889  PMID: 25520244
9.  An Integrative Computational Approach for Prioritization of Genomic Variants 
PLoS ONE  2014;9(12):e114903.
An essential step in the discovery of molecular mechanisms contributing to disease phenotypes and efficient experimental planning is the development of weighted hypotheses that estimate the functional effects of sequence variants discovered by high-throughput genomics. With the increasing specialization of the bioinformatics resources, creating analytical workflows that seamlessly integrate data and bioinformatics tools developed by multiple groups becomes inevitable. Here we present a case study of a use of the distributed analytical environment integrating four complementary specialized resources, namely the Lynx platform, VISTA RViewer, the Developmental Brain Disorders Database (DBDB), and the RaptorX server, for the identification of high-confidence candidate genes contributing to pathogenesis of spina bifida. The analysis resulted in prediction and validation of deleterious mutations in the SLC19A placental transporter in mothers of the affected children that causes narrowing of the outlet channel and therefore leads to the reduced folate permeation rate. The described approach also enabled correct identification of several genes, previously shown to contribute to pathogenesis of spina bifida, and suggestion of additional genes for experimental validations. The study demonstrates that the seamless integration of bioinformatics resources enables fast and efficient prioritization and characterization of genomic factors and molecular networks contributing to the phenotypes of interest.
doi:10.1371/journal.pone.0114903
PMCID: PMC4266634  PMID: 25506935
10.  Patients Infected with CRF07_BC Have Significantly Lower Viral Loads than Patients with HIV-1 Subtype B: Mechanism and Impact on Disease Progression 
PLoS ONE  2014;9(12):e114441.
The circulating recombinant form (CRF) 07_BC is the most prevalent HIV-1 strain among injection drug users (IDUs) in Taiwan. It contains a 7 amino-acid deletion in its p6gag. We conducted a cohort study to compare viral loads and CD4 cell count changes between patients infected with subtype B and CRF07_BC and to elucidate its mechanism. Twenty-one patients infected with CRF07_BC and 59 patients with subtype B were selected from a cohort of 667 HIV-1/AIDS patients whom have been followed up for 3 years. Generalized estimated equation was used to analyze their clinical data and the results showed that patients infected with CRF07_BC had significantly lower viral loads (about 58,000 copies per ml less) than patients with subtype B infection (p = 0.002). The replicative capacity of nine CRF07_BC and four subtype B isolates were compared and the results showed that the former had significantly lower replicative capacity than the latter although all of them were CCR5- tropic and non-syncytium inducing viruses. An HIV-1-NL4-3 mutant virus which contains a 7 amino-acid deletion in p6gag (designated as 7d virus) was generated and its live cycle was investigated. The results showed that 7d virus had significantly lower replication capacity, poorer protease-mediated processing and viral proteins production. Electron microscopic examination of cells infected with wild-type or 7d virus demonstrated that the 7d virus had poorer and slower viral maturation processes: more viruses attached to the cell membrane and higher proportion of immature virions outside the cells. The interaction between p6gag and Alix protein was less efficient in cells infected with 7d virus. In conclusion, patients infected with CRF07_BC had significantly lower viral loads than patients infected with subtype B and it may due to the deletion of 7 amino acids which overlaps with Alix protein-binding domain of the p6gag.
doi:10.1371/journal.pone.0114441
PMCID: PMC4263662  PMID: 25502811
11.  Concordance between Patient Self-Reports and Claims Data on Clinical Diagnoses, Medication Use, and Health System Utilization in Taiwan 
PLoS ONE  2014;9(12):e112257.
Purpose
The aim of this study was to evaluate the concordance between claims records in the National Health Insurance Research Database and patient self-reports on clinical diagnoses, medication use, and health system utilization.
Methods
In this study, we used the data of 15,574 participants collected from the 2005 Taiwan National Health Interview Survey. We assessed positive agreement, negative agreement, and Cohen's kappa statistics to examine the concordance between claims records and patient self-reports.
Results
Kappa values were 0.43, 0.64, and 0.61 for clinical diagnoses, medication use, and health system utilization, respectively. Using a strict algorithm to identify the clinical diagnoses recorded in claims records could improve the negative agreement; however, the effect on positive agreement and kappa was diverse across various conditions.
Conclusion
We found that the overall concordance between claims records in the National Health Insurance Research Database and patient self-reports in the Taiwan National Health Interview Survey was moderate for clinical diagnosis and substantial for both medication use and health system utilization.
doi:10.1371/journal.pone.0112257
PMCID: PMC4251897  PMID: 25464005
12.  Video-assisted thoracic surgery right sleeve lobectomy 
Journal of Thoracic Disease  2014;6(12):1831-1833.
A 50-year-old active male with a smoking history of 30 years (20 cigarettes per day) was admitted to hospital because of more than one month’s cough without sputum. No comorbidity was present. The preoperative examination showed: blood test normal, ECG normal, cardio-pulmonary function normal, chest computed tomography (CT) display right upper lobe (RUL) mass of 5 cm diameter. Bronchoscopy examination and biopsy indicated large cell neuroendocrine carcinoma (LCNEC) in the take-off of RUL bronchus. No metastatic focus was found after emission computed tomography (ECT) scan of whole body bone, abdominal US scanning and brain MR. After initial evaluation, the clinical stage before operation was cT2bN0M0 (IIA stage). A selective video-assisted thoracic surgery (VATS) operation was arranged after 9 days of smoking cessation. Lateral position, one 10 mm trocar for camera in the 7th intercostals space in the mid-auxiliary line, 4 cm trocar for operation in the 4th intercostal space in the anterior axillary line, 15 mm trocar for auxiliary operation in the 8th intercostal space in the scapula line, the patient received VATS RUL lobectomy, plus systemic mediastinal lymph nodes dissection. The procedure of 200 minutes operation was smooth with blood loss of about 150 mL. Chest tube was removed 6 days after operation, and the patient discharged 11 days after the operation; The post-operation pathological examination showed RUL LCNEC, and the pathological stage was pT2bN0M0R0 (IIA stage). The patient has received four cycles of EP adjuvant chemotherapy per 21 days and is still alive without disease recurrence and metastasis after re-examination.
doi:10.3978/j.issn.2072-1439.2014.12.03
PMCID: PMC4283298  PMID: 25589983
Carcinoma; non-small-cell lung; thoracic surgery; video-assisted; pneumonectomy; thoracic surgical procedures
13.  Good neurological recovery after rescue thrombolysis of presumed pulmonary embolism despite prior 100 minutes CPR 
Journal of Thoracic Disease  2014;6(12):E289-E293.
We reported the case of a 70-year-old man who was admitted to neurologic wards for recurrent syncope for 3 years. Unfortunately, just 2 hours after his admission, he suddenly collapsed and failed to return of spontaneous circulation (ROSC) after a 100-minute standard cardiopulmonary resuscitation (CPR). Fortunately, he was timely suspected to have pulmonary embolism (PE) based on his sedentary lifestyle, elevated D-dimer and markedly enlarged right ventricle chamber on bedside echocardiography. After a rescue thrombolytic alteplase therapy, he was successfully resuscitated and good neurological recovery was achieved.
doi:10.3978/j.issn.2072-1439.2014.12.23
PMCID: PMC4283306  PMID: 25590010
Cardiac arrest; pulmonary embolism (PE); thrombolysis
14.  Lipoprotein Lipase, Tissue Expression and Effects on Genes Related to Fatty Acid Synthesis in Goat Mammary Epithelial Cells 
Lipoprotein lipase (LPL) serves as a central factor in hydrolysis of triacylglycerol and uptake of free fatty acids from the plasma. However, there are limited data concerning the action of LPL on the regulation of milk fat synthesis in goat mammary gland. In this investigation, we describe the cloning and sequencing of the LPL gene from Xinong Saanen dairy goat mammary gland, along with a study of its phylogenetic relationships. Sequence analysis showed that goat LPL shares similarities with other species including sheep, bovine, human and mouse. LPL mRNA expression in various tissues determined by RT-qPCR revealed the highest expression in white adipose tissue, with lower expression in heart, lung, spleen, rumen, small intestine, mammary gland, and kidney. Expression was almost undetectable in liver and muscle. The expression profiles of LPL gene in mammary gland at early, peak, mid, late lactation, and the dry period were also measured. Compared with the dry period, LPL mRNA expression was markedly greater at early lactation. However, compared with early lactation, the expression was lower at peak lactation and mid lactation. Despite those differences, LPL mRNA expression was still greater at peak, mid, and late lactation compared with the dry period. Using goat mammary epithelial cells (GMEC), the in vitro knockdown of LPL via shRNA or with Orlistat resulted in a similar degree of down-regulation of LPL (respectively). Furthermore, knockdown of LPL was associated with reduced mRNA expression of SREBF1, FASN, LIPE and PPARG but greater expression of FFAR3. There was no effect on ACACA expression. Orlistat decreased expression of LIPE, FASN, ACACA, and PPARG, and increased FFAR3 and SREBF1 expression. The pattern of LPL expression was similar to the changes in milk fat percentage in lactating goats. Taken together, results suggest that LPL may play a crucial role in fatty acid synthesis.
doi:10.3390/ijms151222757
PMCID: PMC4284735  PMID: 25501331
LPL gene; lactation; goat mammary epithelial cells; Orlistat
15.  Assessing the effects of an educational program for the prevention of work-related musculoskeletal disorders among school teachers 
BMC Public Health  2014;14(1):1211.
Background
Musculoskeletal disorders represent one of the most common and most costly occupational health problems in both developed and developing countries. The aim of this study was to assess the effect of occupational health education and ergonomic training on awareness, attitude and behavior of work-related musculoskeletal disorders among teachers.
Methods
A self-controlled longitudinal study with pre/post design was used to evaluate the effects of intervention among school teachers from the 21st of June, 2010 to the 21st of August, 2011. Choosing a cluster random sampling method, 350 (70.0% response rate (350/500)) teachers from four schools were assigned to receive eight weeks of intervention (participatory ergonomic training and occupational health education). Evaluations focused on teachers who participated in both pre- and post-questionnaires. Two post-tests were then administered to the participants to identify changes at six and 12 months after intervention.
Results
The follow-up rate was 93.7% (328/350) at six months after intervention, and 90.9% (319/350) at 12 months after intervention. After the intervention, the awareness rate, attitude and health behavior improved. The self-reported prevalence of work-related musculoskeletal disorders for neck, shoulder, upper and lower back pain, or discomfort were lower than before intervention (P < 0.05).
Conclusion
Interventions based on occupational health education lectures, on-site ergonomics training, publicity brochures and posters showed a positive effect on prevention and control of the occurrence of work-related musculoskeletal disorders in teachers. Improvement in awareness, behavior and attitude changes, and prevalence were found at both six and 12 months post-intervention, confirming that the effectiveness of the program can be sustained.
doi:10.1186/1471-2458-14-1211
PMCID: PMC4256741  PMID: 25422067
Teachers; Work-related Musculoskeletal Disorders; Intervention
16.  Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function 
Cell reports  2014;7(1):180-193.
SUMMARY
Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes with p53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.
doi:10.1016/j.celrep.2014.02.042
PMCID: PMC4219651  PMID: 24685134
17.  Postzygotic single-nucleotide mosaicisms in whole-genome sequences of clinically unremarkable individuals 
Cell Research  2014;24(11):1311-1327.
Postzygotic single-nucleotide mutations (pSNMs) have been studied in cancer and a few other overgrowth human disorders at whole-genome scale and found to play critical roles. However, in clinically unremarkable individuals, pSNMs have never been identified at whole-genome scale largely due to technical difficulties and lack of matched control tissue samples, and thus the genome-wide characteristics of pSNMs remain unknown. We developed a new Bayesian-based mosaic genotyper and a series of effective error filters, using which we were able to identify 17 SNM sites from ∼80× whole-genome sequencing of peripheral blood DNAs from three clinically unremarkable adults. The pSNMs were thoroughly validated using pyrosequencing, Sanger sequencing of individual cloned fragments, and multiplex ligation-dependent probe amplification. The mutant allele fraction ranged from 5%-31%. We found that C→T and C→A were the predominant types of postzygotic mutations, similar to the somatic mutation profile in tumor tissues. Simulation data showed that the overall mutation rate was an order of magnitude lower than that in cancer. We detected varied allele fractions of the pSNMs among multiple samples obtained from the same individuals, including blood, saliva, hair follicle, buccal mucosa, urine, and semen samples, indicating that pSNMs could affect multiple sources of somatic cells as well as germ cells. Two of the adults have children who were diagnosed with Dravet syndrome. We identified two non-synonymous pSNMs in SCN1A, a causal gene for Dravet syndrome, from these two unrelated adults and found that the mutant alleles were transmitted to their children, highlighting the clinical importance of detecting pSNMs in genetic counseling.
doi:10.1038/cr.2014.131
PMCID: PMC4220156  PMID: 25312340
single-nucleotide mutation; postzygotic mosaicism; Dravet syndrome; next-generation sequencing; Bayesian model
18.  Improving the accuracy of genomic prediction in Chinese Holstein cattle by using one-step blending 
Background
The one-step blending approach has been suggested for genomic prediction in dairy cattle. The core of this approach is to incorporate pedigree and phenotypic information of non-genotyped animals. The objective of this study was to investigate the improvement of the accuracy of genomic prediction using the one-step blending method in Chinese Holstein cattle.
Findings
Three methods, GBLUP (genomic best linear unbiased prediction), original one-step blending with a genomic relationship matrix, and adjusted one-step blending with an adjusted genomic relationship matrix, were compared with respect to the accuracy of genomic prediction for five milk production traits in Chinese Holstein. For the two one-step blending methods, de-regressed proofs of 17 509 non-genotyped cows, including 424 dams and 17 085 half-sisters of the validation cows, were incorporated in the prediction model. The results showed that, averaged over the five milk production traits, the one-step blending increased the accuracy of genomic prediction by about 0.12 compared to GBLUP. No further improvement in accuracies was obtained from the adjusted one-step blending over the original one-step blending in our situation. Improvements in accuracies obtained with both one-step blending methods were almost completely contributed by the non-genotyped dams.
Conclusions
Compared with GBLUP, the one-step blending approach can significantly improve the accuracy of genomic prediction for milk production traits in Chinese Holstein cattle. Thus, the one-step blending is a promising approach for practical genomic selection in Chinese Holstein cattle, where the reference population mainly consists of cows.
doi:10.1186/s12711-014-0066-4
PMCID: PMC4196050  PMID: 25315995
19.  Air pollution exposure and lung function in highly exposed subjects in Beijing, China: a repeated-measure study 
Background
Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China.
Methods
The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase.
Results
The two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 μg/m3 (IQR: 48.5-126.6) in office workers and 126.8 μg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; -0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers.
Conclusion
Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone.
Electronic supplementary material
The online version of this article (doi:10.1186/s12989-014-0051-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12989-014-0051-7
PMCID: PMC4192276  PMID: 25272992
Lung function; Metals; Particulate matter; Traffic exposure; FEV1; FVC
20.  Functional Genetic Polymorphisms in CYP2C19 Gene in Relation to Cardiac Side Effects and Treatment Dose in a Methadone Maintenance Cohort 
Abstract
Methadone maintenance therapy is an established treatment for heroin dependence. This study tested the influence of functional genetic polymorphisms in CYP2C19 gene encoding a CYP450 enzyme that contributes to methadone metabolism on treatment dose, plasma concentration, and side effects of methadone. Two single nucleotide polymorphisms (SNPs), rs4986893 (exon 4) and rs4244285 (exon 5), were selected and genotyped in 366 patients receiving methadone maintenance therapy in Taiwan. The steady-state plasma concentrations of both methadone and its EDDP metabolite enantiomers were measured. SNP rs4244285 allele was significantly associated with the corrected QT interval (QTc) change in the electrocardiogram (p=0.021), and the Treatment Emergent Symptom Scale (TESS) total score (p=0.021) in patients who continued using heroin, as demonstrated with a positive urine opiate test. Using the gene dose (GD) models where the CYP2C19 SNPs were clustered into poor (0 GD) versus intermediate (1 GD) and extensive (2 GD) metabolizers, we found that the extensive metabolizers required a higher dose of methadone (p=0.035), and showed a lower plasma R-methadone/methadone dose ratio (p=0.007) in urine opiate test negative patients, as well as a greater QTc change (p=0.008) and higher total scores of TESS (p=0.018) in urine opiate test positive patients, than poor metabolizers. These results in a large study sample from Taiwan suggest that the gene dose of CYP2C19 may potentially serve as an indicator for the plasma R-methadone/methadone dose ratio and cardiac side effect in patients receiving methadone maintenance therapy. Further studies of pharmacogenetic variation in methadone pharmacokinetics and pharmacodynamics are warranted in different world populations.
doi:10.1089/omi.2012.0068
PMCID: PMC3783925  PMID: 24016178
21.  Caution for acute submassive pulmonary embolism with syncope as initial symptom: a case report 
Journal of Thoracic Disease  2014;6(10):E212-E216.
Pulmonary embolism (PE) may escape prompt diagnosis since clinical symptoms and signs are nonspecific. The occurrence of syncope as the sole initial symptom in a previously healthy patient with no predisposing factors to embolism and no hemodynamic instability is extremely rare, which may have been a factor in the delayed diagnosis. We describe a case of acute submassive PE with syncope as the initial symptom. A 62-year-old previously healthy female was admitted to our hospital for transitory episode of syncope. Following admission, chest computed tomography demonstrated embolism in the right main pulmonary and left inferior pulmonary arteries. Following the final diagnosis, the patient was successfully treated with thrombolytic therapy with systemic urokinase. We consider that raised awareness and early diagnosis and treatment were key factors in ensuring a satisfactory prognosis.
doi:10.3978/j.issn.2072-1439.2014.08.11
PMCID: PMC4215133  PMID: 25364533
Pulmonary embolism (PE); syncope; thrombolysis
22.  Depression and Somatic Symptoms May Influence on Chronic Prostatitis/Chronic Pelvic Pain Syndrome: A Preliminary Study 
Psychiatry Investigation  2014;11(4):495-498.
The present study is the first one to investigate the impacts of depression and somatization on the disease severity and quality of life (QoL) in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The Korean version of National Institutes of Health (NIH)- Chronic Prostatitis Symptom Index (CPSI) for severity of CP/CPPS. Korean version of Patient Health Questionnaire-9 (PHQ-9) for depression, Korean version of Patient Health Questionnaire-15 (PHQ-15) for somatization, and Korean version of EuroQol Questionnaire-5 Dimensions (EQ-5D)- [(EQ-5D utility index and visual analog scale (EQ-5D VAS)] for QoL, were administered. Eighty patients were enrolled. The NIH-CPSI total scores were significantly higher in those with depression (25.3%, p=0.01) or somatization (23.2%, p=0.03) than in those without. These trends toward significantly negative influence of depression and somatic symptoms on QoL were also observed. Our preliminary results indicate that depression and somatization may have negative influence on the symptom severity and QoL in patients with CP/CPPS. However, adequately-powered and more well-designed studies are mandatory to prove our results.
doi:10.4306/pi.2014.11.4.495
PMCID: PMC4225217  PMID: 25395984
Chronic prostatitis/chronic pelvic pain syndrome; Depression; Somatization
23.  Pharmacogenomics study in a Taiwan methadone maintenance cohort 
Journal of food and drug analysis  2013;21(4):S62-S68.
Pharmacogenomics is research to study the drug treatment responses in subgroups of patients according to their genetic variants or genetic expression information. Methadone maintenance treatment, which is usually prescribed for patients with heroin dependence, was launched in Taiwan by the government in 2006. In this study, 366 patients who had taken methadone continually in the previous 7 days were examined. Data from administration of the Treatment Outcomes Profile (TOP), Severity of Dependence Scale (SDS), Clinical Opioid Withdrawal Scale (COWS), and Treatment Emergent Symptoms Scale (TESS) were obtained from patients' report records. Genes encoding the liver cytochrome P-450 (CYP) enzymes that are involved with the metabolism of methadone (CYP2B6, 3A4 and 2C19) were selected and genotyped in this cohort. We found that the SNPs on CYP2B6 were associated with plasma S-methadone concentration; SNPs on CYP3A4 were associated with withdrawal symptoms and side effects; and SNPs on CYP2C19 were associated with methadone dose. SNPs in the genes encoding the morphine phase II metabolic enzyme, UGT2B7, were associated with withdrawal symptom scores. In pharmacodynamic genes, the SNPs on OPRM1 were associated with insomnia and change in libido side effects. We conclude that SNP markers may be useful for future methadone dosage adjustment and to reduce adverse reactions.
doi:10.1016/j.jfda.2013.09.036
PMCID: PMC4179242  PMID: 25278738
COWS; CYP2B6; methadone; opioid receptors; pharmacogenomics; TESS
24.  EUS assisted transmural cholecystogastrostomy fistula creation as a bridge for endoscopic internal gallbladder therapy using a novel fully covered metal stent 
BMC Gastroenterology  2014;14(1):164.
Background
Laparoscopic cholecystectomy (LC) has become the “gold standard” for treating symptomatic gallstones. Innovative methods, such as a scarless therapeutic procedure through a natural orifice are being introduced, and include transgastric or transcolonic endoscopic cholecystectomy. However, before clinical implementation, instruments still need modification, and a more convenient treatment is still needed. The aim of this study was to evaluate the feasibility of endoscopic internal gallbladder therapy such as cholecystolithotomy in an animal survival model.
Methods
Four pigs underwent endoscopic-ultrasound (EUS)-guided cholecystogastrostomy and the placement of a novel covered mental stent. Four weeks later the stents were removed and an endoscope was advanced into the gallbladder via the fistula, and cholecystolithotomy was performed. Two weeks later the pigs were sacrificed, and the healing of the fistulas was assessed.
Results
EUS-guided cholecystogastrostomy with mental stent deployment was successfully performed in all the animals. Four weeks after the procedure, the fistulas had formed and all the stents were removed. Endoscopic cholecystolithotomy was performed through each fistula. All the animals survived until they were sacrificed 2 weeks later. The fistulas were found to be completely healed.
Conclusions
This study reports the first endoscopic transmural cholecystolithotomy after placement of a novel mental stent in an animal survival model.
doi:10.1186/1471-230X-14-164
PMCID: PMC4189557  PMID: 25249425
Endoscopic-ultrasound; Cholecystectomy; Mental stent
25.  7-Ketocholesterol induces P-glycoprotein through PI3K/mTOR signaling in hepatoma cells 
Biochemical pharmacology  2013;86(4):548-560.
7-Ketocholesterol (7-KC) is found at an elevated level in patients with cancer and chronic liver disease. The up-regulation of an efflux pump, P-glycoprotein (P-gp) leads to drug resistance. To elucidate the effect of 7-KC on P-gp, P-gp function and expression were investigated in hepatoma cell lines Huh-7 and HepG2 and in primary hepatocyte-derived HuS-E/2 cells. At a subtoxic concentration, 48-h exposure to 7-KC reduced the intracellular accumulation and cytotoxicity of P-gp substrate doxorubicin in hepatoma cells, but not in HuS-E/2 cells. In Huh-7 cells, 7-KC elevated efflux function through the activation of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway. 7-KC activated the downstream protein synthesis initiation factor 4E-BP1 and induced P-gp expression post-transcriptionally. The stimulation of efflux was reversible and could not be prevented by N-acetyl cysteine. Total cellular ATP content remained the same, whereas the lactate production was increased and fluorescence lifetime of protein-bound NADH was shortened. These changes suggested a metabolic shift to glycolysis, but glycolytic inhibitors did not eliminate 7-KC-mediated P-gp induction. These results demonstrate that 7-KC induces P-gp through PI3K/mTOR signaling and decreased the cell-killing efficacy of doxorubicin in hepatoma cells.
doi:10.1016/j.bcp.2013.06.006
PMCID: PMC4164904  PMID: 23792120
7-ketocholesterol; P-glycoprotein; PI3K/mTOR; glycolysis; hepatoma

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