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1.  Prophylaxis in older Canadian adults with hemophilia A: lessons and more questions 
BMC Hematology  2015;15:4.
Although prophylaxis is a standard of care for young children in developed countries, known to reduce the severity of hemophilic arthropathy, older adults with existing arthropathy have not traditionally used prophylaxis. Recent studies have shown that adults with hemophilia A are increasingly adopting prophylaxis but the characteristics of this treatment in older adults are not well understood. This multicenter observational study was conducted to describe how secondary/tertiary prophylaxis is being used in older adults (≥40 years of age) in comparison to younger adults with severe hemophilia A.
Eligible adult (≥18 years of age) Canadian males with baseline FVIII:C ≤2% from the participating centres were observed over a 2 year period.
Of the 220 adult severe hemophilia patients enrolled, 70% (155/220) used prophylaxis during the observational period. Only 27% (60/220) are older adults with very few >60 years of age. A lower proportion of older adults use prophylaxis compared to younger adults (58% vs. 75%, p = 0.016), with most patients in both groups using continuous prophylaxis (92 and 94% respectively). When considering all treatment modalities together, younger subjects use more factor concentrate than older subjects (2437 u/kg/year vs. 1702 u/kg/year, p = 0.027); however, older subjects on prophylaxis use 3447 u/kg/year and had an ABR of 12 while those on demand use 560 u/kg/year and had an ABR of 13.
A significant number of older adults use secondary/tertiary continuous prophylaxis in Canada, accounting for a significant fraction of factor concentrate utilization.
PMCID: PMC4331146
Hemophilia A; Adults; Prophylaxis; Bleeding; Aging; Factor VIII
2.  An Analysis of Seasonality of Sarcoidosis in the United States Veteran Population: 2000–2007 
The onset of sarcoidosis is thought to be seasonal, particularly Lofgren’s syndrome. However, there are conflicting data on seasonality by country and by radiographic stage.
The objective of this study was to determine if there is seasonality of the diagnosis of sarcoidosis in outpatients in the United States.
Methods and Results
Using time series methods, we performed a retrospective analysis of 3750 incident cases of sarcoidosis in the Veteran’s Health Administration national outpatient claims database (2000–2007). We did not find overall seasonality in the occurrence of new sarcoidosis in United States Veterans (p=0.9860), even after we subdivided the United States by northern (p=0.6824) and southern regions (p=0.4588).
The lack of seasonality in this study indicates that season is not a dominant factor in complex gene-environment-host interaction that precedes presentation of new sarcoidosis cases in the United States Veteran population.
PMCID: PMC4321897  PMID: 23461080
3.  The sodium channel-blocking antiepileptic drug phenytoin inhibits breast tumour growth and metastasis 
Molecular Cancer  2015;14(1):13.
Voltage-gated Na+ channels (VGSCs) are heteromeric protein complexes containing pore-forming α subunits and smaller, non-pore-forming β subunits. VGSCs are classically expressed in electrically excitable cells, e.g. neurons. VGSCs are also expressed in tumour cells, including breast cancer (BCa) cells, where they enhance cellular migration and invasion. However, despite extensive work defining in detail the molecular mechanisms underlying the expression of VGSCs and their pro-invasive role in cancer cells, there has been a notable lack of clinically relevant in vivo data exploring their value as potential therapeutic targets.
We have previously reported that the VGSC-blocking antiepileptic drug phenytoin inhibits the migration and invasion of metastatic MDA-MB-231 cells in vitro. The purpose of the present study was to establish whether VGSCs might be viable therapeutic targets by testing the effect of phenytoin on tumour growth and metastasis in vivo. We found that expression of Nav1.5, previously detected in MDA-MB-231 cells in vitro, was retained on cells in orthotopic xenografts. Treatment with phenytoin, at a dose equivalent to that used to treat epilepsy (60 mg/kg; daily), significantly reduced tumour growth, without affecting animal weight. Phenytoin also reduced cancer cell proliferation in vivo and invasion into surrounding mammary tissue. Finally, phenytoin significantly reduced metastasis to the liver, lungs and spleen.
This is the first study showing that phenytoin reduces breast tumour growth and metastasis in vivo. We propose that pharmacologically targeting VGSCs, by repurposing antiepileptic or antiarrhythmic drugs, should be further studied as a potentially novel anti-cancer therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12943-014-0277-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4320839  PMID: 25623198
Antiepileptic; Breast cancer; Metastasis; Phenytoin; Voltage-gated Na+ channel
4.  A Metabolomics Approach to Stratify Patients Diagnosed with Diabetes Mellitus into Excess or Deficiency Syndromes 
The prevalence of type 2 diabetes continuously increases globally. The traditional Chinese medicine (TCM) can stratify the diabetic patients based on their different TCM syndromes and, thus, allow a personalized treatment. Metabolomics is able to provide metabolite biomarkers for disease subtypes. In this study, we applied a metabolomics approach using an ultraperformance liquid chromatography (UPLC) coupled with quadruple-time-of-flight (QTOF) mass spectrometry system to characterize the metabolic alterations of different TCM syndromes including excess and deficiency in patients diagnosed with diabetes mellitus (DM). We obtained a snapshot of the distinct metabolic changes of DM patients with different TCM syndromes. DM patients with excess syndrome have higher serum 2-indolecarboxylic acid, hypotaurine, pipecolic acid, and progesterone in comparison to those patients with deficiency syndrome. The excess patients have more oxidative stress as demonstrated by unique metabolite signatures than the deficiency subjects. The results provide an improved understanding of the systemic alteration of metabolites in different syndromes of DM. The identified serum metabolites may be of clinical relevance for subtyping of diabetic patients, leading to a personalized DM treatment.
PMCID: PMC4312632  PMID: 25667595
5.  Association of Hospitalizations for Asthma with Seasonal and Pandemic Influenza 
Respirology (Carlton, Vic.)  2014;19(1):10.1111/resp.12165.
Background and objective
Although influenza has been associated with asthma exacerbations, it is not clear the extent to which this association affects healthcare use in the United States (U.S.). The first goal of this project was to determine whether, and to what extent, the incidence of asthma hospitalizations is associated with seasonal variation in influenza. Second, we used influenza trends (2000-2008) to help predict asthma admissions during the 2009 H1N1 influenza pandemic.
We identified all hospitalizations between 1998 and 2008 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project during which a primary diagnosis of asthma was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We performed time series regression analyses to investigate the association of monthly asthma admissions with influenza incidence. Finally, we applied these time series regression models using 1998-2008 data, to forecast monthly asthma admissions during the 2009 influenza pandemic.
Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of asthma hospitalizations (p-value<0.0001). Use of influenza data to predict asthma admissions during the 2009 H1N1 pandemic improved the mean squared prediction error by 60.2%.
Influenza activity in the population is significantly associated with asthma hospitalizations in the U.S., and this association can be exploited to more accurately forecast asthma admissions. Our results suggest that improvements in influenza surveillance, prevention, and treatment may decrease hospitalizations of asthma patients.
PMCID: PMC3877191  PMID: 23931674
Asthma; Forecasting; Health Care Utilization; Influenza; Resource Allocation
6.  Activation of the Ubiquitin Proteasome Pathway by Silk Fibroin Modified Chitosan Nanoparticles in Hepatic Cancer Cells 
Silk fibroin (SF) is a protein with bulky hydrophobic domains and can be easily purified as sericin-free silk-based biomaterial. Silk fibroin modified chitosan nanoparticle (SF-CSNP), a biocompatible material, has been widely used as a potential drug delivery system. Our current investigation studied the bio-effects of the SF-CSNP uptake by liver cells. In this experiment, the characterizations of SF-CSNPs were measured by particle size analysis and protein assay. The average size of the SF-CSNP was 311.9 ± 10.7 nm, and the average zeta potential was +13.33 ± 0.3 mV. The SF coating on the SF-CSNP was 6.27 ± 0.17 μg/mL. Moreover, using proteomic approaches, several proteins involved in the ubiquitin proteasome pathway were identified by analysis of differential protein expressions of HepG2 cell uptake the SF-CSNP. Our experimental results have demonstrated that the SF-CSNP may be involved in liver cancer cell survival and proliferation.
PMCID: PMC4307326  PMID: 25588218
silk fibroin; chitosan nanoparticle; biomaterial; proteomics; ubiquitin proteasome pathway
7.  The influence of astragalus polysaccharide and β-elemene on LX-2 cell growth, apoptosis and activation 
BMC Gastroenterology  2014;14(1):224.
Activated hepatic stellate cells are the main source of excessive collagen deposition in liver fibrosis. Here we report the inhibitory effects of the combinational treatment of two natural products, astragalus polysaccharide (APS) and β-elemene (ELE) on the activation of human liver hepatic stellate cell line LX-2 cells.
Cultured LX-2 cells were treated with different concentrations of APS or ELE for 24 or 48 hours. Cell viability/apoptosis was measured by MTT assay and Annexin V/PI staining , activation related genes including α-SMA and CD44 expressions were measured by real-time PCR and western blot respectively.
The majority of LX-2 cells showed morphological change in the presence of APS or ELE for 24 hours. Treatment with APS + ELE for 24 or 48 hours significantly inhabited the cell proliferation compared with APS or ELE treatment alone on LX-2 cells. APS + ELE may block the up-regulation of α-SMA and CD44 both in mRNA and protein levels through TGF-β pathway in LX-2 cells.
APS or ELE treatment alone on LX-2 cells could inhibit cell proliferation and induce apoptosis. The combinational treatment using APS + ELE significantly increased the killing efficiency on LX-2 cells. α-SMA and CD44 expressions was inhibited upon APS + ELE treatment through TGF-β pathway in LX-2 cells. The results indicated a novel treatment using natural products for liver diseases with anti-fibrotic effect.
PMCID: PMC4297370  PMID: 25551689
Astragalus polysaccharide; β-elemene; Hepatic stellate cells
8.  Sustained Delivery of a HIF-1 Antagonist for Ocular Neovascularization 
Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.
PMCID: PMC3871855  PMID: 24126220
age-related macular degeneration; angiogenesis; diabetic retinopathy; nanoparticles
9.  Cancer Immunotherapy Employing an Innovative Strategy to Enhance CD4+ T Cell Help in the Tumor Microenvironment 
PLoS ONE  2014;9(12):e115711.
Chemotherapy and/or radiation therapy are widely used as cancer treatments, but the antitumor effects they produce can be enhanced when combined with immunotherapies. Chemotherapy kills tumor cells, but it also releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen-specific cell-mediated immune responses. Promoting CD4+ T helper cell immune responses can be used to enhance the cross-presentation of the tumor antigen following chemotherapy. The pan HLA-DR binding epitope (PADRE peptide) is capable of generating antigen-specific CD4+ T cells that bind various MHC class II molecules with high affinity and has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses. Here, we investigated whether intratumoral injection of PADRE and the adjuvant CpG into HPV16 E7-expressing TC-1 tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and PADRE was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and PADRE also enhanced the generation of PADRE-specific CD4+ T cells and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci. The treatment regimen presented here represents a universal approach to cancer control.
PMCID: PMC4274108  PMID: 25531529
10.  Patient severity matters for night-shift workload for internal medicine residents in Taiwan 
Although work hour is an important factors for resident workload, other contributing factors, such as patient severity, with regards to resident workload have been scarcely studied.
A prospective observational cohort study was conducted in a general medicine unit in an academic medical center in Taiwan. Every event for which the nurses needed to call the on-call residents was recorded. To quantify the workload, the responses of on-duty residents to calls were analyzed. To allow comparisons of patient factors to be made, we classified all patients by assigning them stable, unstable, or do-not-resuscitate (DNR) codes. The reasons for the calls were categorized to facilitate the comparisons across these three groups.
From October 2009 to September 2011, a total of 2,518 patients were admitted to the general medicine unit. The nurses recorded a total of 847 calls from 730 call nights, ranging from 0 to 7 per night. Two peaks of calls, at 0-2 am and 6-7 am, were noted. Calls from stable, unstable, and DNR patients were 442 (52.2%), 95 (11.2%), and 298 (35.2%), respectively. For both unstable and DNR patients, the leading reason was abnormal vital signs (62.1% and 67.1%, respectively), while only 36.2% for stable patients. Both unstable and DNR patients required more bedside evaluation and management compared to stable patients.
Beyond work hours and patient census, patients with different clinical severity and palliative goal produce different workload for on-call residents.
PMCID: PMC4260207  PMID: 25467773
After-hours care; Workload; Resident; Hospitalist
11.  Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma 
The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.
Patients and methods
One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin (GP) chemotherapy and second-line EGFR tyrosine kinase inhibitor (TKI) or with first-line EGFR-TKI and second-line GP chemotherapy.
The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups (P=0.04). Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups (P=0.001). Among 61 cases with third-line pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different (P=0.001).
Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.
PMCID: PMC4279200  PMID: 25561769
Epidermal growth factor receptor (EGFR) mutation; lung adenocarcinoma; pemetrexed; bevacizumab
12.  Hepatic stellate cells secretes type I collagen to trigger epithelial mesenchymal transition of hepatoma cells 
Liver fibrosis is a risk factor for hepatoma. Activated hepatic stellate cells (HSCs) play a critical role in progression of hepatoma. Resected hepatoma patients with high α-SMA+HSCs infiltration had worse survival, OR: 2.2 and p=0.0434. We hypothesized that HSCs could increase the epithelial-mesenchymal transition (EMT) ability of hepatoma cells. In murine model of liver fibrosis with injection of ML1 mice HCC cell line, E-cadherin was lost at the margin of tumor nodule around α-SMA+HSC sites. In subcutaneous tumor model, HSCs could increase the metastatic nodules in the lung, and the expression of E-cadherin was decreased and the Slug was induced. To elucidate the effect of HSCs on hepatoma cells, HSC-T6 was co-cultured with ML1 and the condition medium of HSC-T6 can trigger ML1 cell morphological change, down-expression of E-cadherin, induction of Slug expression, and cell migration. Proteomic analysis of the condition medium showed that collagen I was the target molecule. Collagen type I alone also induced EMT of ML1 cells. Knockdown of collagen type I in HSC-T6 could decrease its induction of EMT on ML1 cells. In conclusion, HSC can secrete collagen type I to trigger hepatoma cells to undergo EMT for metastasis.
PMCID: PMC4266709  PMID: 25520865
Hepatic stellate cell; collagen type I; epithelial-mesenchymal transition
13.  Loss-of-Function Mutants and Overexpression Lines of the Arabidopsis Cyclin CYCA1;2/TARDY ASYNCHRONOUS MEIOSIS Exhibit Different Defects in Prophase-I Meiocytes but Produce the Same Meiotic Products 
PLoS ONE  2014;9(11):e113348.
In Arabidopsis, loss-of-function mutations in the A-type cyclin CYCA1;2/TARDY ASYNCHRONOUS MEIOSIS (TAM) gene lead to the production of abnormal meiotic products including triads and dyads. Here we report that overexpression of TAM by the ASK1:TAM transgene also led to the production of triads and dyads in meiosis, as well as shriveled seeds, in a dominant fashion. However, the partial loss-of-function mutant tam-1, an ASK1:TAM line, and the wild type differed in dynamic changes in chromosome thread thickness from zygotene to diplotene. We also found that the pericentromeric heterochromatin regions in male meiocytes in tam-1 and tam-2 (a null allele) frequently formed a tight cluster at the pachytene and diplotene stages, in contrast to the infrequent occurrences of such clusters in the wild type and the ASK1:TAM line. Immunolocalization studies of the chromosome axial component ASY1 revealed that ASY1 was highly expressed at the appropriate male meiotic stages but not localized to the chromosomes in tam-2. The level of ASY1, however, was greatly reduced in another ASK1:TAM line with much overexpressed TAM. Our results indicate that the reduction and increase in the activity of TAM differentially affect chromosomal morphology and the action of ASY1 in prophase I. Based on these results, we propose that either the different meiotic defects or a common defect such as missing ASY1 on the chromosomal axes triggers a hitherto uncharacterized cell cycle checkpoint in the male meiocytes in the tam mutants and ASK1:TAM lines, leading to the production of the same abnormal meiotic products.
PMCID: PMC4234643  PMID: 25402453
14.  Therapeutic effect of a hydroxynaphthoquinone fraction on dextran sulfate sodium-induced ulcerative colitis 
World Journal of Gastroenterology : WJG  2014;20(41):15310-15318.
AIM: To evaluate the therapeutic effect of hydroxynaphthoquinone mixture (HM) on dextran sulfate sodium (DSS)-induced colitis and explore the underlying mechanisms.
METHODS: BALB/c mice received 3.5% DSS for 6 d to induce ulcerative colitis. Groups of mice were orally administered HM 3.5, 7 and 14 mg/kg and mesalazine 200 mg/kg per day for 7 d. During the experiment, clinical signs and body weight, stool consistency and visible fecal blood were monitored and recorded daily. A disease activity index score was calculated for each animal. At the conclusion of the experiment, the colonic histopathological lesions were evaluated. Myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) levels were determined. Protein expression levels of TNF-α, nuclear factor-κB (NF-κB) p65, inhibitor of κB (IκB) and phosphorylation of IκB (p-IκB) were analyzed by Western blot analysis.
RESULTS: Administration of 3.5% DSS for 6 d successfully induced acute colitis associated with soft stool, diarrhea, rectal bleeding, and colon shortening, as well as a loss of body weight. Administration of HM effectively attenuated the severity of colonic mucosa injury. For histopathological analysis, HM treatment improved histological alterations and lowered pathological scores compared with the DSS only group. This manifested as a reduction in the extent of colon injury and inflammatory cell infiltration, as well as the degree of mucosal destruction. In addition, HM at doses of 7 and 14 mg/kg significantly decreased MPO activity in colonic tissue (0.98 ± 0.22 U/g vs 1.32 ± 0.24 U/g, 0.89 ± 0.37 U/g vs 1.32 ± 0.24 U/g tissue, P < 0.05) and serum TNF-α levels (68.78 ± 7.34 ng/L vs 88.98 ± 17.79 ng/L, 64.13 ± 14.13 ng/L vs 88.98 ± 17.79 ng/L, P < 0.05). Furthermore, HM down-regulated the expression of TNF-α, NF-κB p65 and p-IκBα in colonic tissue while up-regulating IκBα protein expression. These results suggest that the significant anti-inflammatory effect of HM may be attributable to its inhibition of TNF-α production and NF-κB activation.
CONCLUSION: HM had a favorable therapeutic effect on DSS-induced ulcerative colitis, supporting its further development and clinical application in inflammatory bowel disease.
PMCID: PMC4223264  PMID: 25386079
Arnebia euchroma (Royle) Johnst; Hydroxynaphthoquinones; Inflammatory bowel disease; Dextran sulfate sodium-induced ulcerative colitis; Nuclear factor-κB activation
15.  Leukocyte Telomere Length-Related rs621559 and rs398652 Genetic Variants Influence Risk of HBV-Related Hepatocellular Carcinoma 
PLoS ONE  2014;9(11):e110863.
Recent genome-wide association studies (GWAS) have identified eleven leukocyte telomere length (LTL)-related single nucleotide polymorphisms (SNPs). Since LTL has been associated with risk of many malignancies, LTL-related SNPs may contribute to cancer susceptibility. To test this hypothesis in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we genotyped these eleven LTL-related SNPs in a case-control set including 1186 HBV-related HCC cases, 508 chronic HBV carriers and 1308 healthy controls at the discovery stage. The associations of HCC risk with these SNPs were further confirmed in an independent case-control set. We found that 1p34.2 rs621559 and 14q21 rs398652 were significantly associated with HBV-related HCC risk (both P<0.005 after Bonferroni corrections). There was no significant difference of either rs621559 or rs398652 genotypes between chronic HBV carriers and healthy controls, demonstrating that the association was not due to predisposition to HBV infection. In the pooled analyses (1806 HBV-related HCC cases and 1954 controls), we observed a decreased HCC risk, 0.72-times, associated with the 1p34.2 rs621559 AA genotype compared to the GG genotype (P = 1.6×10−6). Additionally, there was an increased HCC risk, 1.27-fold, associated with the rs398652 GG genotype (P = 3.3×10−6). A statistical joint effect between the rs621559 GG and rs398652 GG genotypes may exist in elevating risk of HBV-related HCC. We show, for the first time, that rs398652 and rs621559 might be marker genetic variants for risk of HBV-related HCC in the Chinese population.
PMCID: PMC4218833  PMID: 25365256
16.  Thoracolumbar fracture dislocations treated by posterior reduction, interbody fusion and segmental instrumentation 
Indian Journal of Orthopaedics  2014;48(6):568-573.
Literature describing the application of modern segmental instrumentation to thoracic and lumbar fracture dislocation injuries is limited and the ideal surgical strategy for this severe trauma remains controversial. The purpose of this article was to investigate the feasibility and efficacy of single-stage posterior reduction with segmental instrumentation and interbody fusion to treat this type of injury.
Materials and Methods:
A retrospective review of 30 patients who had sustained fracture dislocation of the spine and underwent single stage posterior surgery between January 2007 and December 2011 was performed. All the patients underwent single stage posterior pedicle screw fixation, decompression and interbody fusion. Demographic data, medical records and radiographic images were reviewed thoroughly.
Ten females and 20 males with a mean age of 39.5 years were included in this study. Based on the AO classification, 13 cases were Type B1, 4 cases were B2, 4 were C1, 6 were C2 and 3 cases were C3. The average time of the surgical procedure was 220 min and the average blood loss was 550 mL. All of the patients were followed up for at least 2 years, with an average of 38 months. The mean preoperative kyphosis was 14.4° and reduced to -1.1° postoperatively. At the final followup, the mean kyphosis was 0.2°. The loss of correction was small (1.3°) with no significant difference compared to postoperative kyphotic angle (P = 0.069). Twenty seven patients (90%) achieved definitive bone fusion on X-ray or computed tomography imaging within 1 year followup. The other three patients were suspected possible pseudarthrosis. They remained asymptomatic without hardware failure or local pain at the last followup.
Single stage posterior reduction using segmental pedicle screw instrumentation, combined with decompression and interbody fusion for the treatment of thoracic or lumbar fracture-dislocations is a safe, less traumatic and reliable technique. This procedure can achieve effective reduction, sagittal angle correction and solid fusion.
PMCID: PMC4232825  PMID: 25404768
Fracture dislocation; posterior interbody fusion; segmental instrumentation; spine trauma; thoracolumbar spine; Spine; spinal fractures; dislocations; spinal fusion; instrumentation
17.  Sol-Gel Zinc Oxide Humidity Sensors Integrated with a Ring Oscillator Circuit On-a-Chip 
Sensors (Basel, Switzerland)  2014;14(11):20360-20371.
The study develops an integrated humidity microsensor fabricated using the commercial 0.18 μm complementary metal oxide semiconductor (CMOS) process. The integrated humidity sensor consists of a humidity sensor and a ring oscillator circuit on-a-chip. The humidity sensor is composed of a sensitive film and branch interdigitated electrodes. The sensitive film is zinc oxide prepared by sol-gel method. After completion of the CMOS process, the sensor requires a post-process to remove the sacrificial oxide layer and to coat the zinc oxide film on the interdigitated electrodes. The capacitance of the sensor changes when the sensitive film adsorbs water vapor. The circuit is used to convert the capacitance of the humidity sensor into the oscillation frequency output. Experimental results show that the output frequency of the sensor changes from 84.3 to 73.4 MHz at 30 °C as the humidity increases 40 to 90 %RH.
PMCID: PMC4279487  PMID: 25353984
humidity sensor; ring oscillator circuit; zinc oxide nanowire
18.  Comparison of concurrent chemoradiotherapy versus neoadjuvant chemotherapy followed by radiation in patients with advanced nasopharyngeal carcinoma in endemic area: experience of 128 consecutive cases with 5 year follow-up 
BMC Cancer  2014;14(1):787.
Combined radiotherapy and chemotherapy is considered the standard of care for locally advanced nasopharyngeal carcinoma (LA-NPC) in Epstein-Barr virus infection endemic area. This study compared the long-term outcomes between LA-NPC patients treated with neoadjuvant chemotherapy followed by radiotherapy (NACT) and those treated with concurrent chemoradiotherapy (CCRT).
From 2003 to 2007, a total of 128 histopathologically proven LA-NPC patients receiving either NACT or CCRT were consecutively enrolled at the National Cheng Kung University Hospital in Taiwan. NACT consisted of 3-week cycles of mitomycin, epirubicin, and cisplatin on day 1 and fluorouracil and leucovorin on day 8 (MEPFL) or weekly alternated cisplatin on day 1 and fluorouracil and leucovorin on day 8 (P-FL). CCRT comprised 3-week cycles of cisplatin (Cis 100) or 4-week cycles of cisplatin and fluorouracil (PF4). The first failure site, disease free survival (DFS), overall survival (OS), and other prognostic factors were analyzed.
Thirty-eight patients (30%) received NACT. Median follow-up duration was 53 months. More patients with advanced nodal disease (N2-N3) (86.8% vs 67.8%, p =0.029) and advanced clinical stage (stage IVA-IVB) enrolled in the NACT group (55.2% vs 26.7%, p =0.002). For NACT, both MEPFL and P-FL had similar 5-year DFS and OS (52.9% vs 50%, p =0.860 and 73.5% vs 62.5%, p =0.342, respectively). For CCRT, both PF4 and Cis 100 had similar 5-year DFS and OS (62.8% vs 69.6%, p =0.49 and 72.9% vs 73.9%, p =0.72, respectively). Compared to CCRT, NACT had similar 5-year DFS and OS (51.5% vs 65.1%, p =0.28 and 71.7% vs 74.3%, p =0.91, respectively). Among patients who were recurrence-free in the first 2 years after treatment, those treated with NACT experienced poorer locoregional control compared to those treated with CCRT (Hazard ratio =2.57, 95% confidence interval: 1.02 to 6.47, p =0.046).
For LA-NPC, both CCRT and NACT were similarly efficacious treatment strategies in terms of long-term disease control and survival probability. Close locoregional follow-up is recommended for patients receiving NACT, because these patients are more prone to develop locoregional failure than patients receiving CCRT.
PMCID: PMC4228264  PMID: 25351202
Neoadjuvant chemotherapy; Concurrent chemoradiation; Nasopharyngeal carcinoma; Outcome
19.  Unveiling nonessential gene deletions that confer significant morphological phenotypes beyond natural yeast strains 
BMC Genomics  2014;15(1):932.
Phenotypes are variable within species, with high phenotypic variation in the fitness and cell morphology of natural yeast strains due to genetic variation. A gene deletion collection of yeast laboratory strains also contains phenotypic variations, demonstrating the involvement of each gene and its specific function. However, to date, no study has compared the phenotypic variations between natural strains and gene deletion mutants in yeast.
The morphological variance was compared between 110 most distinct gene deletion strains and 36 typical natural yeast strains using a generalized linear model. The gene deletion strains had higher morphological variance than the natural strains. Thirty-six gene deletion mutants conferred significant morphological changes beyond that of the natural strains, revealing the importance of the genes with high genetic interaction and specific cellular functions for species conservation.
Based on the morphological analysis, we discovered gene deletion mutants whose morphologies were not seen in nature. Our multivariate approach to the morphological diversity provided a new insight into the evolution and species conservation of yeast.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-932) contains supplementary material, which is available to authorized users.
PMCID: PMC4221665  PMID: 25344683
Yeast; Saccharomyces cerevisiae; Cell morphology; Phenotypic diversity; Gene function; Species conservation
20.  Storage-Efficient 16-Bit Hybrid IP Traceback with Single Packet 
The Scientific World Journal  2014;2014:659894.
Since adversaries may spoof their source IPs in the attacks, traceback schemes have been proposed to identify the attack source. However, some of these schemes' storage requirements increase with packet numbers. Some even have false positives because they use an IP header's fragment offset for marking. Thus, we propose a 16-bit single packet hybrid IP traceback scheme that combines packet marking and packet logging with high accuracy and low storage requirement. The size of our log tables can be bounded by route numbers. We also set a threshold to determine whether an upstream interface number is stored in a log table or in a marking field, so as to balance the logging frequency and our computational loads. Because we store user interface information on small-degree routers, compared with current single packet traceback schemes, ours can have the lowest storage requirements. Besides, our traceback achieves zero false positive/negative rates and guarantees reassembly of fragmented packets at the destination.
PMCID: PMC4217332  PMID: 25386612
21.  Ileocolonic anastomosis after right hemicolectomy for colon cancer: functional end-to-end or end-to-side? 
The purpose of this study was to compare short-term clinical outcomes of ileocolonic functional end-to-end anastomosis (FEEA) and end-to-side anastomosis (ESA) following resection of the right colon for cancer.
We enrolled 379 patients who underwent ileocolonic anastomosis following resection of the right colon for cancer by a single surgeon, from January 2009 through June 2012. Patient characteristics, operative results, and postoperative complications were analyzed.
A total of 164 patients received ESA and 215 patients received FEEA. The FEEA group had a lower incidence of anastomotic error (0.9% versus 4.3%; P = 0.04) and a shorter operating time (140.4 ± 14.9 min versus 150.5 ± 20.1 min; P = 0.001). The length of hospital stay (10.9 ± 3.5 days versus 11.3 ± 4.0 days; P = 0.36) and anastomotic leakage (1.8% versus 0.5%; P = 0.20) were similar in both groups. No relevant differences between FEEA and ESA were observed for blood loss, retrieved lymph nodes, first flatus and postoperative complications.
An FEEA after right hemicolectomy for colon cancer is a safe and reliable anastomotic technique, resulting in a favorable outcome in selected patients with the right colon cancer.
PMCID: PMC4198793  PMID: 25287418
anastomosis; colon cancer; right hemicolectomy
22.  Magnetic liposomes for colorectal cancer cells therapy by high-frequency magnetic field treatment 
Nanoscale Research Letters  2014;9(1):497.
In this study, we developed the cancer treatment through the combination of chemotherapy and thermotherapy using doxorubicin-loaded magnetic liposomes. The citric acid-coated magnetic nanoparticles (CAMNP, ca. 10 nm) and doxorubicin were encapsulated into the liposome (HSPC/DSPE/cholesterol = 12.5:1:8.25) by rotary evaporation and ultrasonication process. The resultant magnetic liposomes (ca. 90 to 130 nm) were subject to characterization including transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray diffraction (XRD), zeta potential, Fourier transform infrared (FTIR) spectrophotometer, and fluorescence microscope. In vitro cytotoxicity of the drug carrier platform was investigated through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using L-929 cells, as the mammalian cell model. In vitro cytotoxicity and hyperthermia (inductive heating) studies were evaluated against colorectal cancer (CT-26 cells) with high-frequency magnetic field (HFMF) exposure. MTT assay revealed that these drug carriers exhibited no cytotoxicity against L-929 cells, suggesting excellent biocompatibility. When the magnetic liposomes with 1 μM doxorubicin was used to treat CT-26 cells in combination with HFMF exposure, approximately 56% cells were killed and found to be more effective than either hyperthermia or chemotherapy treatment individually. Therefore, these results show that the synergistic effects between chemotherapy (drug-controlled release) and hyperthermia increase the capability to kill cancer cells.
PMCID: PMC4169134  PMID: 25246875
Liposomes; Magnetic nanoparticle; Colorectal cancer; High-frequency magnetic field; Drug controlled release
23.  Security Enhanced EMV-Based Mobile Payment Protocol 
The Scientific World Journal  2014;2014:864571.
Near field communication has enabled customers to put their credit cards into a smartphone and use the phone for credit card transaction. But EMV contactless payment allows unauthorized readers to access credit cards. Besides, in offline transaction, a merchant's reader cannot verify whether a card has been revoked. Therefore, we propose an EMV-compatible payment protocol to mitigate the transaction risk. And our modifications to the EMV standard are transparent to merchants and users. We also encrypt the communications between a card and a reader to prevent eavesdropping on sensitive data. The protocol is able to resist impersonation attacks and to avoid the security threats in EMV. In offline transactions, our scheme requires a user to apply for a temporary offline certificate in advance. With the certificate, banks no longer need to lower customer's credits for risk control, and users can have online-equivalent credits in offline transactions.
PMCID: PMC4181509  PMID: 25302334
24.  Influence of Per3 genotypes on circadian rhythmicity in flight cadets after militarized management 
Objective: The purpose of this study was to explore the effect of PERIOD3 (PER3) genotypes on circadian rhythmicity in flight cadets after militarized management. Methods: We performed a preliminary study in 146 newly enrolled male flight cadets. Venous blood samples were collected, and genotyping of PER3 (4/5) was determined by using PCR. The morningness-eveningness questionnaire (MEQ) survey was given to flight cadets upon enrollment and after militarized management for 24 months respectively. Comparison of frequency distribution of PER3 genotypes between cases and controls (120 well-matched civilians) was performed using the X2 test. We also compared the circadian rhythmicity upon enrollment and 24 months after enrollment in flight cadets, and analyzed the connection of changes in circadian clock with PER3 genotypes. Results: The frequency distribution of PER3 genotypes in flight cadets was not significantly different from that in controls subjects. MEQ survey results showed chronotype within flight cadet group varied widely at the two time-points: the moderately morning type (50%) and the neither type (41.1%) upon enrollment; the neither type (76.7%) and the moderately morning type (21.2%) 24 months after enrollment. The circadian rhythm of individuals with the PER3 (5/5) genotype showed no significant difference before and after 24 months of militarized management, whereas notable changes were found in individuals with the PER3 (4/4) genotype (n=116, X2=37.26, P < 0.001). Conclusion: In conclusion, we provide some evidence that circadian rhythm of flight cadets with the PER3 (5) allele are less likely to be affected compared to those with the PER3 (4) allele.
PMCID: PMC4230062  PMID: 25400784
Circadian rhythmicity; PER3 gene; flight cadet; militarized management
25.  The Functional TP53 rs1042522 and MDM4 rs4245739 Genetic Variants Contribute to Non-Hodgkin Lymphoma Risk 
PLoS ONE  2014;9(9):e107047.
As a heterogeneous kind of malignances, Non-Hodgkin lymphoma (NHL) is the most common hematologic cancer worldwide with the significantly increased morbidity in China. Accumulated evidences demonstrated that oncoprotein MDM4 plays a crucial role in the TP53 tumor suppressor signaling pathway. An rs4245739 A>C polymorphism locating in the MDM4 3′-untranslated region creates a miR-191 target site and results in allele-specific MDM4 expression. In this study, we examined the association between this polymorphism as well as the TP53 Arg72Pro (rs1042522 G>C) genetic variant and Non-Hodgkin Lymphoma (NHL) risk in a Chinese Han population. Genotypes were determined in 200 NHL cases and 400 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. We found significantly increased NHL risk among carriers of the TP53 72Pro allele compared with those with the 72Arg allele (P = 0.002 for the Pro/Pro genotype). We also observed a significantly decreased NHL risks among carriers of the MDM4 rs4245739 C allele compared with those with the A allele in Chinese (P = 0.014 for the AC genotype). Stratified analyses revealed the associations between these SNPs and NHL risk are especially noteworthy in young or male individuals. Additionally, the associations are much pronounced in NHL patients with B-cell lymphomas or grade 3 or 4 disease. Our results indicate that the TP53 Arg72Pro and the MDM4 rs4245739 polymorphisms contribute to NHL susceptibility and support the hypothesis that genetic variants in the TP53 pathway genes can act as important modifiers of NHL risk.
PMCID: PMC4159297  PMID: 25203442

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