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1.  The Genotypic Characterization of Cronobacter spp. Isolated in China 
PLoS ONE  2014;9(7):e102179.
Cronobacter spp. (Enterobacter sakazakii) is an important pathogen contaminating powdered infant formula (PIF). To describe the genotypic diversity of Cronobacter isolated in China, we identified the isolates using fusA allele sequencing, and subtyped all of the isolates using pulsed-field gel electrophoresis (PFGE), multi-locus sequence typing (MLST), and multiple-locus variable-number tandem-repeat analysis (MLVA). A total of 105 isolates were identified, which included C. sakazakii (58 isolates), C. malonaticus (30 isolates), C. dublinensis (11 isolates), C. turicensis (5 isolates), and C. muytjensii (1 isolate). These isolates were showed to have 85 PFGE-patterns, 71 sequence types (STs), and 55 MLVA-patterns. Comparisons among the three molecular subtyping methods revealed that the PFGE method was the most distinguishable tool in identifying clusters of Cronobacter spp. through DNA fingerprinting, and MLST method came second. However, ESTR-1, ESTR-2, ESTR-3, and ESTR-4 were not effective loci for subtyping Cronobacter spp. such that the MLVA method requires further improvement.
doi:10.1371/journal.pone.0102179
PMCID: PMC4100892  PMID: 25029018
3.  Successful percutaneous coronary intervention in a patient with combined deficiency of FV and FVIII due to novel compound heterozygous mutations in LMAN1 
Introduction
Percutaneous coronary intervention (PCI) in patients with congenital coagulation factor deficiencies presents a unique challenge. They are not only at increased risk of perioperative bleeding but can also suffer thrombosis of the stent since preventive anticoagulation and antiplatelet therapy is difficult. Several cases of successful PCI have been described in patients with hemophilias A and B, but there are no reports in patients with combined coagulation factor deficiencies.
Aim
We used PCI to treat the coronary artery disease in a patient with the combined deficiency of factor V and factor VIII (F5F8D) and analyzed the molecular basis of the disorder for this patient.
Methods
A 68 year old patient was admitted for urgent PCI with bare metal stent placement after the diagnosis of the combined deficiency of F5F8D. Peripheral blood DNA was extracted for the sequence analysis of LMAN1 and MCFD2 genes. Mutation in LMAN1 was confirmed by molecular cloning of the PCR product and resequencing of the resulting clones.
Results
The patient underwent successful PCI with good long-term outcome. He tolerated well anticoagulation therapy with unfractionated heparin and double antiplatelet therapy while he was initially supported with fresh frozen plama and recombinant FVIII. Molecular analysis revealed that the patient carries unusual compound heterozygous frameshift mutations on the same microsatellite repeat region in exon 8 of LMAN1, one of which is a novel mutation (c.912delA).
Conclusion
Our results suggest that patients with F5F8D can safely undergo PCI for coronary artery disease, with the treatment individualized to the specific patient.
doi:10.1111/hae.12128
PMCID: PMC3688640  PMID: 23557496
4.  Enantioselective Metabolism of Quizalofop-Ethyl in Rat 
PLoS ONE  2014;9(6):e101052.
The pharmacokinetic and distribution of the enantiomers of quizalofop-ethyl and its metabolite quizalofop-acid were studied in Sprague-Dawley male rats. The two pairs of enantiomers were determined using a validated chiral high-performance liquid chromatography method. Animals were administered quizalofop-ethyl at 10 mg kg−1 orally and intravenously. It was found high concentration of quizalofop-acid in the blood and tissues by both intragastric and intravenous administration, and quizalofop-ethyl could not be detected through the whole study which indicated a quick metabolism of quizalofop-ethyl to quizalofop-acid in vivo. In almost all the samples, the concentrations of (+)-quizalofop-acid exceeded those of (−)-quizalofop-acid. Quizalofop-acid could still be detected in the samples even at 120 h except in brain due to the function of blood-brain barrier. Based on a rough calculation, about 8.77% and 2.16% of quizalofop-acid were excreted through urine and feces after intragastric administration. The oral bioavailability of (+)-quizalofop-acid and (−)-quizalofop-acid were 72.8% and 83.6%.
doi:10.1371/journal.pone.0101052
PMCID: PMC4071037  PMID: 24964043
5.  Metabolites produced by commensal bacteria promote peripheral regulatory T cell generation 
Nature  2013;504(7480):10.1038/nature12726.
Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T (Treg) cells expressing transcription factor Foxp3 play a key role in limiting inflammatory responses in the intestine1. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory Th17 cells2-6, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we hypothesized that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We found that a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg cell numbers upon provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells as the observed phenomenon was dependent upon intronic enhancer CNS1, essential for extrathymic, but dispensable for thymic Treg cell differentiation1, 7. In addition to butyrate, de novo Treg cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of HDAC inhibition, but not acetate, lacking this activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
doi:10.1038/nature12726
PMCID: PMC3869884  PMID: 24226773
6.  Construction and Analysis of High-Density Linkage Map Using High-Throughput Sequencing Data 
PLoS ONE  2014;9(6):e98855.
Linkage maps enable the study of important biological questions. The construction of high-density linkage maps appears more feasible since the advent of next-generation sequencing (NGS), which eases SNP discovery and high-throughput genotyping of large population. However, the marker number explosion and genotyping errors from NGS data challenge the computational efficiency and linkage map quality of linkage study methods. Here we report the HighMap method for constructing high-density linkage maps from NGS data. HighMap employs an iterative ordering and error correction strategy based on a k-nearest neighbor algorithm and a Monte Carlo multipoint maximum likelihood algorithm. Simulation study shows HighMap can create a linkage map with three times as many markers as ordering-only methods while offering more accurate marker orders and stable genetic distances. Using HighMap, we constructed a common carp linkage map with 10,004 markers. The singleton rate was less than one-ninth of that generated by JoinMap4.1. Its total map distance was 5,908 cM, consistent with reports on low-density maps. HighMap is an efficient method for constructing high-density, high-quality linkage maps from high-throughput population NGS data. It will facilitate genome assembling, comparative genomic analysis, and QTL studies. HighMap is available at http://highmap.biomarker.com.cn/.
doi:10.1371/journal.pone.0098855
PMCID: PMC4048240  PMID: 24905985
7.  Single-incision versus conventional laparoscopic appendectomy in 688 patients: a retrospective comparative analysis 
Canadian Journal of Surgery  2014;57(3):E89-E97.
Background
Laparoscopic surgery has become the standard for treating appendicitis. The cosmetic benefits of using single-incision laparoscopy are well known, but its duration, complications and time to recovery have not been well documented. We compared 2 laparoscopic approaches for treating appendicitis and evaluated postoperative pain, complications and time to full recovery.
Methods
We retrospectively reviewed the cases of consecutive patients with appendicitis and compared those who underwent conventional laparoscopic appendectomy (CLA) performed using 3 incisions and those who underwent single-incision laparoscopic appendectomy (SILA). During SILA, the single port was prepared to increase visibility of the operative site.
Results
Our analysis included 688 consecutive patients: 618 who underwent CLA and 70 who underwent SILA. Postsurgical complications occurred more frequently in the CLA than the SILA group (18.1% v. 7.1%, p = 0.018). Patients who underwent SILA returned to oral feeding sooner than those who underwent CLA (median 12 h v. 22 h, p < 0.001). These between-group differences remained significant after controlling for other factors. Direct comparison of only nonperforated cases, which was determined by pathological examination, revealed that SILA was significantly longer than CLA (60 min v. 50 min, p < 0.001). Patients who underwent SILA had longer in-hospital stays than those who underwent CLA (72 v. 55 h, p < 0.001); however, they had significantly fewer complications (3.0% v. 14.4%, p = 0.006).
Conclusion
In addition to its cosmetic advantages, SILA led to rapid recovery and no increase in postsurgical pain or complications.
doi:10.1503/cjs.023812
PMCID: PMC4035411  PMID: 24869622
8.  Screening to Identify Commonly Used Chinese Herbs That Affect ERBB2 and ESR1 Gene Expression Using the Human Breast Cancer MCF-7 Cell Line 
Aim. Our aim the was to screen the commonly used Chinese herbs in order to detect changes in ERBB2 and ESR1 gene expression using MCF-7 cells. Methods. Using the MCF-7 human breast cancer cell line, cell cytotoxicity and proliferation were evaluated by MTT and trypan blue exclusion assays, respectively. A luciferase reporter assay was established by transient transfecting MCF-7 cells with plasmids containing either the ERBB2 or the ESR1 promoter region linked to the luciferase gene. Chinese herbal extracts were used to treat the cells at 24 h after transfection, followed by measurement of their luciferase activity. The screening results were verified by Western blotting to measure HER2 and ERα protein expression. Results. At concentrations that induced little cytotoxicity, thirteen single herbal extracts and five compound recipes were found to increase either ERBB2 or ESR1 luciferase activity. By Western blotting, Si-Wu-Tang, Kuan-Shin-Yin, and Suan-Tsao-Ren-Tang were found to increase either HER2 or ERα protein expression. In addition, Ligusticum chuanxiong was shown to have a great effect on ERBB2 gene expression and synergistically with estrogen to stimulate MCF-7 cell growth. Conclusion. Our results provide important information that should affect clinical treatment strategies among breast cancer patients who are receiving hormonal or targeted therapies.
doi:10.1155/2014/965486
PMCID: PMC4058453  PMID: 24987437
9.  Yiqihuoxuejiedu Formula Inhibits Vascular Remodeling by Reducing Proliferation and Secretion of Adventitial Fibroblast after Balloon Injury 
Vascular remodeling occurs in atherosclerosis, hypertension, and restenosis after percutaneous coronary intervention. Adventitial remodeling may be a potential therapeutic target. Yiqihuoxuejiedu formula uses therapeutic principles from Chinese medicine to supplement Qi, activate blood circulation, and resolve toxin and it has been shown to inhibit vascular stenosis. To investigate effects and mechanisms of the formula on inhibiting vascular remodeling, especially adventitial remodeling, rats with a balloon injury to their common carotid artery were used and were treated for 7 or 28 days after injury. The adventitial area and α-SMA expression increased at 7 days after injury, which indicated activation and proliferation of adventitial fibroblasts. Yiqihuoxuejiedu formula reduced the adventitial areas at 7 days, attenuated the neointima and vessel wall area, stenosis percent, and α-SMA expression in the neointima, and reduced collagen content and type I/III collagen ratio in the adventitia at 28 days. Yiqihuoxuejiedu formula had more positive effects than Captopril in reducing intimal proliferation and diminishing stenosis, although Captopril lowered neointimal α-SMA expression and reduced the collagen content at 28 days. Yiqihuoxuejiedu formula has inhibitory effects on positive and negative remodeling by reducing adventitial and neointimal proliferation, reducing content, and elevating adventitial compliance.
doi:10.1155/2014/849167
PMCID: PMC4058465  PMID: 24987435
10.  Self-similar erbium-doped fiber laser with large normal dispersion 
Optics letters  2014;39(4):1019-1021.
We report a large normal dispersion erbium-doped fiber laser with self-similar pulse evolution in the gain fiber. The cavity is stabilized by the local nonlinear attractor in the gain fiber through the use of a narrow filter. Experimental results are accounted for by numerical simulations. This laser produces 3.5 nJ pulses, which can be dechirped to 70 fs with an external grating pair.
PMCID: PMC4006903  PMID: 24562267
11.  Effusion cytology: an effective method for the diagnosis of pulmonary lymphangioleiomyomatosis 
Journal of Thoracic Disease  2014;6(5):E54-E57.
Lymphangioleiomyomatosis (LAM) is a rare progressive lung disease. Chylous effusion is one of the most common clinical manifestations of LAM. Herein we present a 39-year-old female who presented progressive dyspnea on exertion and chylothorax. The chest computed tomography showed multiple thin-walled cysts in both lungs which suggesting LAM. The pleural effusion cytology plus with further immunocytochemistry confirmed the computed tomography diagnosis. Therefore, the LAM can be diagnosed by cytologic examination combined with conventional chest computed tomography and clinical manifestations, which can help some patients to avoid an invasive biopsy.
doi:10.3978/j.issn.2072-1439.2014.03.12
PMCID: PMC4015018  PMID: 24822126
Lymphangioleiomyomatosis (LAM); immunocytochemistry; cytology; diagnosis
12.  Detection and identification of huwentoxin-IV interacting proteins by biotin-avidin chemistry combined with mass spectrometry 
Background
Numerous spider toxins are of interest as tools for neurophysiological research or as lead molecules for the development of pharmaceuticals and insecticides. Direct detection and identification of the interacting proteins of a spider toxin are helpful for its action-mechanism analysis and practical application. The present study employed a combinative strategy for the analysis of interacting proteins of huwentoxin-IV (HWTX-IV), a peptidic neurotoxin from the venom of the spider Selenocosmia huwena.
Results
HWTX-IV was first lightly labeled with biotin under the optimized mild experimental conditions and the toxin labeled with a single biotin group (monobiotinylated HWTX-IV) was demonstrated by electrophysiological experiments to retain its original bioactivity and was used in combination with far-western blotting to detect its interacting proteins. Comparative experiments indicated that some membrane proteins from rat neuromuscular junction preparations bind to monobiotinylated HWTX-IV after being transferred onto a PVDF membrane from the SDS-gel. With capillary high performance liquid chromatography-tandem mass spectrometry, several membrane proteins with which HWTX-IV potentially interacted were identified from the preparations and then bioinformatically analyzed.
Conclusions
This work has provided not only a new insight into the action mechanism of HWTX-IV but also a reference technology for the relevant researches.
doi:10.1186/1678-9199-20-18
PMCID: PMC4011514  PMID: 24803923
Biotin labeling; Huwentoxin-IV; Far-western blotting; Interacting protein; Mass spectrometry
13.  Clotrimazole induces a late G1 cell cycle arrest and sensitizes glioblastoma cells to radiation in vitro 
Anti-cancer drugs  2010;21(9):841-849.
Tumor cells are characterized by their high rate of glycolysis and clotrimazole has been shown to disrupt the glycolysis pathway thereby arresting the cells in the G1 cell cycle phase. Herein, we present data to support our hypothesis that clotrimazole arrests tumor cells in a radiosensitizing, late G1 phase. The effects of clotrimazole were studied using the glioblastoma cell line, U-87 MG. Flow cytometry was used to analyze cell cycle redistribution and induction of apoptosis. Immunoblots were probed to characterize a late G1 cell cycle arrest. Nuclear and cytoplasmic fractions were collected to follow the clotrimazole-induced translocation of hexokinase II. Clonogenic assays were designed to determine the radiosensitizing effect by clotrimazole. Our studies have shown a dose-dependent and time-dependent clotrimazole arrest in a late G1 cell cycle phase. Concurrent with the late G1 arrest, we observed an overexpression of p27Kip along with a decreased expression of p21Cip, cyclin-dependent kinase 1, cyclin-dependent kinase 4, and cyclin D. Clotrimazole induced the translocation of mitochondrial-bound hexokinase II to the cytoplasm and the release of cytochrome c into the cytoplasm. Clotrimazole-induced apoptosis was enhanced when combined with radiation. Clotrimazole was shown to sensitize tumor cells to radiation when the cells were irradiated for 18 h post-clotrimazole treatment. The disruption of the glycolysis pathway by clotrimazole leads to cell cycle arrest of U-87 MG cells in the radiosensitizing late G1 phase. The use of clotrimazole as a radiosensitizing agent for cancer treatment is novel and may have broad therapeutic applications.
doi:10.1097/CAD.0b013e32833e8022
PMCID: PMC3996651  PMID: 20724915
antitumor; clotrimazole; glioblastoma; hexokinase II; radiosensitizing
14.  Identification of Gene Expression Changes from Colitis to CRC in the Mouse CAC Model 
PLoS ONE  2014;9(4):e95347.
A connection between colorectal carcinogenesis and inflammation is well known, but the underlying molecular mechanisms have not been elucidated. Chemically induced colitis-associated cancer (CAC) is an outstanding mouse model for studying the link between inflammation and cancer. Additionally, the CAC model is used for examining novel diagnostic, prognostic, and predictive markers for use in clinical practice. Here, a CAC model was established in less than 100 days using azoxymethane (AOM) with dextran sulfate sodium salt (DSS) in BALB/c mice. We examined the mRNA expression profiles of three groups: control untreated mice (K), DSS-induced chronic colitis mice (D), and AOM/DSS-induced CAC (AD) mice. We identified 6301 differentially expressed genes (DEGs) among the three groups, including 93 persistently upregulated genes and 139 persistently downregulated genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the most persistent DEGs were significantly enriched in metabolic or inflammatory components in the tumor microenvironment. Furthermore, several associated DEGs were identified as potential DEGs by protein-protein interaction (PPI) network analysis. We selected 14 key genes from the DEGs and potential DEGs for further quantitative real-time PCR (qPCR) verification. Six persistently upregulated, 3 persistently downregulated DEGs, and the other 3 genes showed results consistent with the microarray data. We demonstrated the regulation of 12 key genes specifically involved in Wnt signaling, cytokine and cytokine receptor interactions, homeostasis, and tumor-associated metabolism during colitis-associated CRC. Our results suggest that a close relationship between metabolic and inflammatory mediators of the tumor microenvironment is present in CAC.
doi:10.1371/journal.pone.0095347
PMCID: PMC3990644  PMID: 24743346
15.  Erythroblastic Islands in the Bone Marrow of Patients with Immune-Related Pancytopenia 
PLoS ONE  2014;9(4):e95143.
Background
Immune-related pancytopenia (IRP) is characterized by pancytopenia caused by autoantibody-mediated bone marrow destruction or suppression. The bone marrows of IRP patients have remarkably increased erythroblastic islands (EIs).
Methodology and Principal Findings
We determined the immunoglobulin G (IgG) autoantibodies in some parts of EIs of IRP patients using immunofluorescence to investigate the biological function of EIs with IgG in the pathophysiology of IRP. The dominant class of autoantibodies detected in mononuclear cells was IgG (CD34 IgG, CD15 IgG, and GlycoA IgG), specifically IgG on GlycoA-positive cells (GlycoA IgG). Results show that extravascular hemolysis occurred in IRP through IgG autoantibodies in the EIs. These data included a high percentage of reticulocytes in the peripheral blood, hypererythrocytosis in the bone marrow, and high serum bilirubin. Furthermore, we examined the macrophages in the bone marrow of IRP patients. The results show that the number of activated macrophages relatively increased, and the phagocytic activity of macrophages significantly increased.
Conclusions and Significance
Increased EIs with IgG were the sites of erythroblast phagocytosis by the activated macrophages, rather than erythropoietic niches. The IgG autoantibodies in the EIs possibly functioned as adhesion molecules for a ring of erythroblasts around the macrophages, thereby forming morphologic EIs.
doi:10.1371/journal.pone.0095143
PMCID: PMC3989288  PMID: 24740145
16.  Analysis on the Relevance of Asthma Susceptibility with the Alteration of Integrin β 4 Expression 
PLoS ONE  2014;9(4):e95533.
Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the roles of expression imbalance of adhesion molecules in asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray assay. The results showed that the expression pattern of adhesion molecules was altered in peripheral blood leucocytes of asthma patients. In this study, we focused on one of the abnormally expressed molecule, integrin β4, which was down-regulated in all asthma patients, to analyze the relevance of asthma susceptibility with the alteration of integrin β4 expressions. Real time PCR was used to verify the down-regulation of integrin β4 in additional 38 asthma patients. Next, the 5′flanking region of integrin β4 DNA were amplified, sequenced and site-directed mutagenesis technology in correspondent variation sites were carried out. Among 4 variation sites found in 5′ flanking region of integrin β4, 3 were related to asthma susceptibility: -nt1029 G/A, -nt 1051 G/A, and -nt 1164 G/C. A reduction of human integrin β4 promoter activity was observed at mutants of these sites. This study demonstrates that various adhesion molecules in asthma patients are abnormally expressed. Mutations in 5′ flanking region result in reduced integrin β4 expression, which is related to increased risk of asthma.
doi:10.1371/journal.pone.0095533
PMCID: PMC3989341  PMID: 24740264
17.  Plasma Sphingolipids as Potential Indicators of Hepatic Necroinflammation in Patients with Chronic Hepatitis C and Normal Alanine Aminotransferase Level 
PLoS ONE  2014;9(4):e95095.
Accurate estimation of hepatic necroinflammation caused by chronic hepatitis C (CHC) is crucial for prediction of prognosis and design of therapeutic strategy, which is particularly true for CHC patients with normal alanine aminotransferase (ALT) level. Recent studies have shown that sphingolipids have a close relationship with hepatitis C virus infection. The present study aimed to identify plasma sphingolipids related to hepatic necroinflammation. We included 120 treatment-naïve CHC patients and 64/120 had normal ALT levels (<40 U/L). CHC patients who underwent liver biopsies were subjected to Scheuer scoring analysis for scope of hepatic inflammation. Plasma sphingolipids were detected by high-performance liquid chromatography tandem mass spectrometry. Our results showed 44 plasma sphingolipids were detected altogether. Of all detected sphingolipids, hexosylceramide (HexCer) (d18∶1/22∶0) and HexCer (d18∶1/24∶0) showed a significant difference among G0/G1, G2, and G3/G4 (P<0.05). For identifying hepatic necroinflammation (G≥2), after adjusting other factors, the odds ratio (OR) of HexCer (d18∶1/22∶0) reached 1.01 (95% confidence interval [CI]: 1.00–1.02). Furthermore, the area under the curve (AUC) of HexCer (d18∶1/22∶0) was 0.7 (P = 0.01) and approached that of ALT (AUC = 0.78). However, in CHC patients with normal ALT, HexCer (d18∶1/22∶0) was an independent factor (OR: 1.02, 95% CI: 1.01–1.03) to identify the hepatic necroinflammation (G≥2). HexCer (d18∶1/22∶0) not only showed the largest AUC (0.78, P = 0.001), but also exhibited the highest specificity of all indicators. These results indicate that plasma HexCer (d18∶1/22∶0) is a potential indicator to distinguish hepatic necroinflammation in CHC patients. For CHC with normal ALT, the ability of HexCer (d18∶1/22∶0) to distinguish hepatic necroinflammation might be superior to conventional serum indicators.
doi:10.1371/journal.pone.0095095
PMCID: PMC3988168  PMID: 24736528
18.  Unusual cases of pigmented villonodular synovitis after arthroplasty 
Pigmented Villonodular Synovitis (PVNS) is a relatively rare, benign proliferation lesion of the synovium of large joints. The etiology is varied and unclear. We had report a 79-year-old woman had PVNS after 14 years right hip arthroplasty with metal prosthesis. Here we report another 4 patients had PVNS after arthroplasty. The second one had PVNS in the 2th year after hip arthroplasty with bone cement prosthesis. The specimen was brown and like usual PVNS in tissue. The third case had PVNS in the 8th after arthroplasty with human bone prosthesis because of the recurrence of PVNS. The proliferated synovium became black from brown. There was brown and many groups black pigment in the tissue. The fourth one had PVNS in the 4th year after knee arthroplasty with polyethylene prosthesis. The specimen was yellow. There was no pigment in the tissue but multinucleated giant cells with unstained foreign body. The fifth patient had PVNS in the 10th month after the left hip arthroplasty with metal prosthesis. The macroscopy was yellow. There were hemosiderin particles in the tissue but black metal particles. This indicates that arthroplasty with prosthesis could cause some new disease or PVNS had new etiology with different pathological show.
PMCID: PMC4057877  PMID: 24955198
Pigmented villonodular synovitis; arthroplasty; etiology
19.  Changes in HIV Incidence among People Who Inject Drugs in Taiwan following Introduction of a Harm Reduction Program: A Study of Two Cohorts 
PLoS Medicine  2014;11(4):e1001625.
Kenrad Nelson and colleagues report on the association between HIV incidence and exposure to a national harm-reduction program among people who inject drugs in Taiwan.
Please see later in the article for the Editors' Summary
Background
Harm reduction strategies for combating HIV epidemics among people who inject drugs (PWID) have been implemented in several countries. However, large-scale studies using sensitive measurements of HIV incidence and intervention exposures in defined cohorts are rare. The aim of this study was to determine the association between harm reduction programs and HIV incidence among PWID.
Methods and Findings
The study included two populations. For 3,851 PWID who entered prison between 2004 and 2010 and tested HIV positive upon incarceration, we tested their sera using a BED HIV-1 capture enzyme immunoassay to estimate HIV incidence. Also, we enrolled in a prospective study a cohort of 4,357 individuals who were released from prison via an amnesty on July 16, 2007. We followed them with interviews at intervals of 6–12 mo and by linking several databases. A total of 2,473 participants who were HIV negative in January 2006 had interviews between then and 2010 to evaluate the association between use of harm reduction programs and HIV incidence. We used survival methods with attendance at methadone clinics as a time-varying covariate to measure the association with HIV incidence. We used a Poisson regression model and calculated the HIV incidence rate to evaluate the association between needle/syringe program use and HIV incidence. Among the population of PWID who were imprisoned, the implementation of comprehensive harm reduction programs and a lower mean community HIV viral load were associated with a reduced HIV incidence among PWID. The HIV incidence in this population of PWID decreased from 18.2% in 2005 to 0.3% in 2010. In an individual-level analysis of the amnesty cohort, attendance at methadone clinics was associated with a significantly lower HIV incidence (adjusted hazard ratio: 0.20, 95% CI: 0.06–0.67), and frequent users of needle/syringe program services had lower HIV incidence (0% in high NSP users, 0.5% in non NSP users). In addition, no HIV seroconversions were detected among prison inmates.
Conclusions
Although our data are affected by participation bias, they strongly suggest that comprehensive harm- reduction services and free treatment were associated with reversal of a rapidly emerging epidemic of HIV among PWID.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
About 35 million people worldwide are currently infected with HIV, the virus that causes AIDS, and about 2.3 million people become newly infected every year. HIV is mainly transmitted through unprotected sex with an infected partner. However, people who inject drugs (PWID) have a particularly high risk of HIV infection because blood transfer through needle and syringe sharing can transmit the virus. It is estimated that 5%–10% of all people living with HIV are PWID. Indeed, in some regions of the world the primary route of HIV transmission is through shared drug injection equipment and the prevalence (the proportion of a population that has a specific disease) of HIV infection among PWID is very high. In Asia, for example, more than a quarter of PWID are HIV positive. Because the high prevalence of HIV among PWID poses a global health challenge, bodies such as the Joint United Nations Programme on HIV/AIDS endorse harm reduction strategies to prevent risky injection behaviors among PWID. These strategies include the provision of clean needles and syringes, opioid substitution therapy such as methadone maintenance treatment, and antiretroviral treatment for HIV-positive PWID.
Why Was This Study Done?
Although harm reduction strategies for combating HIV epidemics among PWID have been implemented in several countries, few large-scale studies have examined the association between HIV incidence (the proportion of new cases of HIV in a population per year) and exposure to harm reduction programs among PWID. In this cohort study (an investigation that determines the characteristics of a group of people and then follows them over time), the researchers determine the association between harm reduction programs and HIV incidence among PWID in Taiwan. HIV infections used to be rare among the 60,000 PWID living in Taiwan, but after the introduction of a new HIV strain into the country in 2003, an HIV epidemic spread rapidly. In response, the Taiwanese government introduced a pilot program of harm reduction that included the provision of clean needles and syringes and health education in July 2005. The program was expanded to include methadone maintenance treatment in early 2006 and implemented nationwide in June 2006.
What Did the Researchers Do and Find?
The researchers enrolled two study populations. The first cohort comprised 3,851 PWID who were incarcerated for illicit drug use between 2004 and 2010 and who tested positive for HIV upon admission into prison. By using the BED assay, which indicates whether an HIV infection is recent, the researchers were able to determine the HIV incidence among the prisoners. In 2004, the estimated HIV incidence among prisoners with a history of drug injection was 6.44%. The incidence peaked in 2005 at 18.2%, but fell to 0.3% in 2010.
The second study population comprised 2,473 individuals who were HIV negative on January 1, 2006, and who had been incarcerated for drug use crimes but were released on July 16, 2007, during an amnesty. The researchers regularly interviewed these participants between their release and 2010 about their use of harm reduction interventions, and obtained other data about them (for example, diagnosis of HIV infection) from official databases. Analysis of all these data indicated that, in this cohort, attendance at methadone maintenance treatment clinics and frequent use of needle and syringe services were both associated with a significantly lower HIV incidence.
What Do These Findings Mean?
These findings suggest that the introduction of a comprehensive harm reduction program in Taiwan was associated with a significant reduction in the HIV incidence rate among PWID. These findings must be interpreted with caution, however. First, because the participants in the study were selected from PWID with histories of incarceration, the findings may not be representative of all PWID in Taiwan or of PWID in other countries. Second, PWID who chose to use needle and syringe services or methadone maintenance treatment clinics might have shared other unknown characteristics that affected their risk of HIV infection. Finally, some of the reduction in HIV incidence seen during the study is likely to be associated with the availability of free treatment, which has been offered to all HIV-positive individuals in Taiwan since 1997. Despite these limitations, these findings suggest that countries with a high prevalence and incidence of HIV among PWID should provide comprehensive harm reduction services to their populations to reduce risky drug injection behaviors.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001625.
Information is available from the US National Institute of Allergy and Infectious diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on injecting drug users and HIV/AIDS and on harm reduction and HIV prevention (in English and Spanish)
The US National Institute on Drug Abuse also provides information about drug abuse and HIV/AIDS (in English and Spanish)
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it
Personal stories about living with HIV/AIDS are available through Avert, Nam/aidsmap, and Healthtalkonline
doi:10.1371/journal.pmed.1001625
PMCID: PMC3979649  PMID: 24714449
20.  Transcriptome profiling and genome-wide DNA binding define the differential role of fenretinide and all-trans RA in regulating the death and survival of human hepatocellular carcinoma Huh7 cells 
Biochemical pharmacology  2013;85(7):10.1016/j.bcp.2013.01.023.
Fenretinide is significantly more effective in inducing apoptosis in cancer cells than all-trans retinoic acid (ATRA). The current study uses a genome-wide approach to understand the differential role fenretinide and ATRA have in inducing apoptosis in Huh7 cells. Fenretinide and ATRA-induced gene expressions and DNA bindings were profiled using microarray and chromatin immunoprecipitation with anti-RXRα antibody. The data showed that fenretinide was not a strong transcription regulator. Fenretinide only changed the expressions of 1 093 genes, approximately three times less than the number of genes regulated by ATRA (2 811). Biological function annotation demonstrated that both fenretinide and ATRA participated in pathways that determine cell fate and metabolic processes. However, fenretinide specifically induced Fas/TNFα-mediated apoptosis by increasing the expression of pro-apoptotic genes i.e., DEDD2, CASP8, CASP4, and HSPA1A/B; whereas, ATRA induced the expression of BIRC3 and TNFAIP3, which inhibit apoptosis by interacting with TRAF2. In addition, fenretinide inhibited the expression of the genes involved in RAS/RAF/ERK-mediated survival pathway. In contrast, ATRA increased the expression of SOSC2, BRAF, MEK, and ERK genes. Most genes regulated by fenretinide and ATRA were bound by RXRα, suggesting a direct effect. This study revealed that by regulating fewer genes, the effects of fenretinide become more specific and thus has fewer side effects than ATRA. The data also suggested that fenretinide induces apoptosis via death receptor effector and by inhibiting the RAS/RAF/ERK pathway. It provides insight on how retinoid efficacy can be improved and how side effects in cancer therapy can be reduced.
doi:10.1016/j.bcp.2013.01.023
PMCID: PMC3857153  PMID: 23396089
retinoic acid receptor; retinoid x receptor; nuclear receptor; hepatocellular carcinoma; ChIP-Seq
21.  Associations of Lipoprotein Lipase Gene rs326 with Changes of Lipid Profiles after a High-Carbohydrate and Low-Fat Diet in Healthy Chinese Han Youth  
To investigate the effects of a high-carbohydrate and low-fat (HC/LF) diet on plasma lipids and apolipoproteins (Apos) of healthy Chinese Han youth with different genotypes of lipoprotein lipase gene (LPL) rs326, 56 subjects were given a washout diet of 30.1% fat and 54.1% carbohydrate for seven days, followed by the HC/LF diet of 13.8% fat and 70.1% carbohydrate for six days, with no total energy restriction. Plasma glucose, triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), Apo B-100 and Apo A-I were analyzed at baseline and before and after the HC/LF diet. The results show that, when compared with before the HC/LF diet, only the male G carriers experienced increased HDL-C (p = 0.008) and Apo A-I (p = 0.005) after the HC/LF diet. Decreased TC in both males and females and increased TG in females were found regardless of the genotype after the HC/LF diet. LDL-C decreased in all the subjects although the decrease was not significant in the female G carriers. These results demonstrate that the G allele of LPL rs326 associates with the elevated levels of HDL-C and Apo A-I after the HC/LF diet in males of the healthy Chinese Han Youth.
doi:10.3390/ijerph110404544
PMCID: PMC4025011  PMID: 24762672
apolipoproteins; HC/LF diet; high density lipoprotein cholesterol; single nucleotide polymorphism; lipoprotein lipase
22.  Effects of R219K polymorphism of ATP-binding cassette transporter 1 gene on serum lipids ratios induced by a high-carbohydrate and low-fat diet in healthy youth 
Biological Research  2014;47(1):4.
Background
Diets are the important players in regulating plasma lipid profiles. And the R219K polymorphism at the gene of ATP-binding cassette transporter 1(ABCA1) was reported to be associated with the profiles. However, no efforts have been made to investigate the changes of lipid profiles after a high-carbohydrate and low-fat diet in different subjects with different genotypes of this polymorphism. This study was to evaluate the effects of ABCA1 R219K polymorphism on serum lipid and apolipoprotein (apo) ratios induced by a high-carbohydrate/low-fat (high-CHO) diet. After a washout diet of 54.1% carbohydrate for 7 days, 56 healthy young subjects (22.89 ± 1.80 years old) were given a high-CHO diet of 70.1% carbohydrate for 6 days. Height, weight, waist circumference, hip circumference, glucose (Glu), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoA-1 and apoB-100 were measured on the 1st, 8th and 14th days of this study. Body mass index (BMI), waist-to-hip ratios (WHR), log(TG/HDL-C), TC/HDL-C, LDL-C/HDL-C and apoA-1/apoB-100 were calculated. ABCA1 R219K was analyzed by a PCR-RFLP method.
Results
The results indicate that the male subjects of all the genotypes had higher WHR than their female counterparts on the 1st, 8th and 14th days of this study. The male K carriers had higher log(TG/HDL-C) and TC/HDL-C than the female carriers on the 1st and 14th days, and higher LDL-C/HDL-C on the 14th day. When compared with that on the 8th day, TC/HDL-C was decreased regardless of the genotypes and genders on the 14th day. Log(TG/HDL-C) was increased in the males with the RR genotype and the female K carriers. Lowered BMI, Glu and LDL-C/HDL-C were found in the male K carriers, but only lowered BMI in the female K carriers and only lowered LDL-C/HDL-C in the females with the RR genotype.
Conclusions
These results suggest that ABCA1 R219K polymorphism is associated differently in males and females with elevated log(TG/HDL-C) and decreased LDL-C/HDL-C induced by the high-CHO diet.
doi:10.1186/0717-6287-47-4
PMCID: PMC4060374  PMID: 25027185
Apolipoprotein; ATP-binding cassette transporter 1 gene; Gene polymorphism; High-carbohydrate/low-fat diet; Lipid ratios
23.  Epigenetic modifications of chronic hypoxia-mediated neurodegeneration in Alzheimer’s disease 
Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly people. AD is characterized by progressive and gradual decline in cognitive function and memory loss. While familial early-onset AD is usually associated with gene mutations, the etiology of sporadic late-onset form of AD is largely unknown. It has been reported that environmental factors and epigenetic alterations significantly contribute to the process of AD. Our previous studies have documented that chronic hypoxia is one of the environmental factors that may trigger the AD development and aggravate the disease progression. In this review, we will summarize the pathological effects of chronic hypoxia on the onset and development of AD and put forward the possible molecule mechanisms underlying the chronic hypoxia mediated AD pathogenesis. Finally, we propose that epigenetic regulations may represent new opportunity for the therapeutic intervention of this disease.
doi:10.1186/2047-9158-3-7
PMCID: PMC3994488  PMID: 24650677
Alzheimer’s disease; Chronic hypoxia; Epigenetic modification; DNA methylation; Histone acetylation
24.  Hypoxia-Inducible MiR-210 Is an Independent Prognostic Factor and Contributes to Metastasis in Colorectal Cancer 
PLoS ONE  2014;9(3):e90952.
MicroRNA-210 (miR-210), the master hypoxamir, plays pleiotropic roles in certain cancers; however, its role in the development of human colorectal cancer remains unclear. Herein, we report that miR-210 is frequently up-regulated in colorectal cancer tissues, with high miR-210 expression significantly correlating with large tumor size, lymph node metastasis, advanced clinical stage and poor prognosis. Functionally, miR-210 overexpression promotes the migration and invasion of colorectal cancer cells. Furthermore, miR-210 can be induced by hypoxia and mediates the hypoxia-induced metastasis of colorectal cancer cells. In addition, vacuole membrane protein 1 (VMP1) is identified as the direct and functional target of miR-210. Thus, miR-210 is a useful biomarker for hypoxic tumor cells and a prognostic factor that plays an essential role in colorectal cancer metastasis.
doi:10.1371/journal.pone.0090952
PMCID: PMC3954583  PMID: 24632577
25.  Complete Resequencing of 40 Genomes Reveals Domestication Events and Genes in Silkworm (Bombyx) 
Science (New York, N.Y.)  2009;326(5951):433-436.
A single–base pair resolution silkworm genetic variation map was constructed from 40 domesticated and wild silkworms, each sequenced to approximately threefold coverage, representing 99.88% of the genome. We identified ∼16 million single-nucleotide polymorphisms, many indels, and structural variations. We find that the domesticated silkworms are clearly genetically differentiated from the wild ones, but they have maintained large levels of genetic variability, suggesting a short domestication event involving a large number of individuals. We also identified signals of selection at 354 candidate genes that may have been important during domestication, some of which have enriched expression in the silk gland, midgut, and testis. These data add to our understanding of the domestication processes and may have applications in devising pest control strategies and advancing the use of silkworms as efficient bioreactors.
doi:10.1126/science.1176620
PMCID: PMC3951477  PMID: 19713493

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