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1.  Fulminant hepatic failure and acute renal failure as manifestations of concurrent Q fever and cytomegalovirus infection: a case report 
BMC Infectious Diseases  2014;14(1):651.
Coxiella burnetii is an obligate bacterial pathogen that causes Q fever. Cytomegalovirus (CMV) commonly exists as a latent infection in healthy people. Co-infection with both pathogens is rare.
Case presentation
We report an immunocompetent 53-year-old male farmer who presented with fulminant hepatic failure and acute renal failure. Empiric antibiotic treatment with intravenous penicillin G and levofloxacin were given, but hepatic and renal functions continued to deteriorate. A subsequent test of serum immunoglobulin M was positive for CMV, and administration of gancyclovir led to gradual recovery. A diagnosis of acute Q fever was confirmed by indirect immunofluorescence assay (IFA) on paired serum samples to demonstrate a significant rise in antibody titers. Antibiotic treatment was adjusted accordingly.
CMV co-infection should be considered in patients with acute Q fever when they do not respond to standard antimicrobial agents.
PMCID: PMC4264321  PMID: 25487053
Acute renal failure; Cytomegalovirus; Fulminant hepatic failure; Q fever
2.  When Are We Most Vulnerable to Temperature Variations in a Day? 
PLoS ONE  2014;9(12):e113195.
Daily temperature measures are commonly used when examining the association between temperature and mortality. In fact, temperature measures are available 24 hours a day and more detailed records may provide a better prediction of mortality compared to daily statistics. In this article, monthly stratified analysis modeling for mortality is conducted for the total population as well as the stratified elderly and younger subgroups. We identified the most significant time during the day that is associated with daily mortality. Surprisingly, the estimates of relative risk and magnitude of associations derived from the hourly temperature measures are similar or even stronger compared to those modeled by the daily statistics. This phenomenon remains true for lagged hourly temperature measures and the changing patterns of associations from January through December are revealed. In summary, people are the most vulnerable to temperature variations in the early morning around 5 am and the night time around 8 pm.
PMCID: PMC4251982  PMID: 25463354
3.  Effect of the Herbal Drug Guilu Erxian Jiao on Muscle Strength, Articular Pain, and Disability in Elderly Men with Knee Osteoarthritis 
Background. Guilu Erxian Jiao (GEJ) is a widely used Chinese herbal remedy for knee osteoarthritis, but its clinical efficacy is unknown. Methods. We enrolled 42 elderly male patients with knee OA, including 21 patients who received the herbal drug GEJ as the case group and 21 patients who did not receive GEJ as the control group. The effects of 12 weeks of GEJ treatment on muscle strength of lower limbs were measured by a Biodex dynamometer, with disability evaluated on the Lequesne index and articular pain measured on the visual analog scale (VAS) between the two groups on the baseline and after treatment. Results. There were significant increases in the levels of muscle strength of TQ/BW-ext-dominant and TQ/BW-flex-dominant between the two groups after treatment (P < 0.05). There were also significant increases in muscle strength of knee extensor muscles in the GEJ-treated group (n = 21) self-controlled before and after 12 weeks of treatment (all P < 0.01). There were significant decreases in articular pain (P < 0.01) and Lequesne index scores (P < 0.01) in the GEJ-treated group when compared to the non-GEJ-treated group. Conclusions. Our results showed that GEJ is effective and is tolerated well in elderly men with knee OA.
PMCID: PMC4182023  PMID: 25309612
4.  Nuclear envelope protein MAN1 regulates clock through BMAL1 
eLife  2014;3:e02981.
Circadian clocks serve as internal pacemakers that influence many basic homeostatic processes; consequently, the expression and function of their components are tightly regulated by intricate networks of feedback loops that fine-tune circadian processes. Our knowledge of these components and pathways is far from exhaustive. In recent decades, the nuclear envelope has emerged as a global gene regulatory machine, although its role in circadian regulation has not been explored. We report that transcription of the core clock component BMAL1 is positively modulated by the inner nuclear membrane protein MAN1, which directly binds the BMAL1 promoter and enhances its transcription. Our results establish a novel connection between the nuclear periphery and circadian rhythmicity, therefore bridging two global regulatory systems that modulate all aspects of bodily functions.
eLife digest
If rodents, or indeed humans, are kept in constant darkness for a number of days, they continue to show patterns of sleep and wakefulness that repeat roughly every 24 hr. This internal ‘circadian rhythm’ controls many aspects of animal physiology, including body temperature, blood pressure, and hormone levels. It does so by regulating the expression of key genes: this means that the activity of the proteins encoded by these genes also varies in accordance with the circadian rhythm.
A second mechanism used by the body to coordinate gene expression on a large scale entails making adjustments to the membrane that surrounds the cell nucleus. This ‘nuclear envelope’ consists mainly of lipids, but it also contains proteins that bind DNA. These proteins regulate gene expression by controlling how easy it is for other proteins that activate or repress genes to gain access to specific DNA sequences.
Lin et al. now reveal that these mechanisms work together. The first evidence for this was the discovery that the levels of three specific nuclear envelope proteins influence, and are influenced by, circadian rhythms. In particular, two of these proteins control the activity of the third, which is known as MAN1. This protein in turn triggers the expression of a gene called BMAL1, which is one of the small number of ‘clock genes’ that are responsible for generating the internal circadian rhythm.
As well as adding to our knowledge of circadian biology and the nuclear envelope, this study reveals a mechanism by which cells can orchestrate the expression of large numbers of genes. Such mechanisms allow a wide range of physiological and behavioral processes to be co-ordinated.
PMCID: PMC4150126  PMID: 25182847
nuclear envelope; circadian rhythm; MAN1; BMAL1; D. melanogaster; mouse
5.  Smart Grid as a Service: A Discussion on Design Issues 
The Scientific World Journal  2014;2014:535308.
Smart grid allows the integration of distributed renewable energy resources into the conventional electricity distribution power grid such that the goals of reduction in power cost and in environment pollution can be met through an intelligent and efficient matching between power generators and power loads. Currently, this rapidly developing infrastructure is not as “smart” as it should be because of the lack of a flexible, scalable, and adaptive structure. As a solution, this work proposes smart grid as a service (SGaaS), which not only allows a smart grid to be composed out of basic services, but also allows power users to choose between different services based on their own requirements. The two important issues of service-level agreements and composition of services are also addressed in this work. Finally, we give the details of how SGaaS can be implemented using a FIPA-compliant JADE multiagent system.
PMCID: PMC4163325  PMID: 25243214
6.  Pin1 positively affects tumorigenesis of esophageal squamous cell carcinoma and correlates with poor survival of patients 
Pin1 promotes oncogenesis by regulating multiple oncogenic signaling. In this study, we investigated the involvement of Pin1 in tumor progression and in the prognosis of human esophageal squamous cell carcinoma (ESCC).
We observed that proliferation, clonogenicity and tumorigenesis of CE81T cells were inhibited by Pin1 knockdown. We next analyzed Pin1 expression in clinical ESCC specimens. When compared to the corresponding non-tumor part, Pin1 protein and mRNA levels in tumor part were higher in 84% and 62% patients, respectively. By immunohistochemistry, we identified that high Pin1 expression was associated with higher primary tumor stage (p = 0.035), higher overall cancer stage (p = 0.047) and poor overall survival (p < 0.001). Furthermore, the association between expression of Pin1 and levels of β-catenin and cyclin D in cell line and clinical specimens was evaluated. β-catenin and cyclin D1 were decreased in CE81T cells with Pin1 knockdown. Cyclin D1 level correlated with Pin1 expression in clinical ESCC specimens.
Pin1 upregulation was associated with advanced stage and poor prognosis of ESCC. Pin1 knockdown inhibited aggressiveness of ESCC cells. β-catenin and cyclin D1 were positively regulated by Pin1. These results indicated that targeting Pin1 pathway could represent a potential modality for treating ESCC.
PMCID: PMC4256813  PMID: 25160749
Pin1; Esophageal squamous cell carcinoma; Tumorigenesis; β-catenin; Cyclin D1
7.  Persistent hypoglycemia as an early, atypical presentation of hepatocellular carcinoma: A case report and systematic review of the literature 
Oncology Letters  2014;8(4):1810-1814.
The current study presents a case of persistent hypoglycemia as the initial manifestation of advanced hepatocellular carcinoma (HCC), as well as a systematic review of the management of hypoglycemia associated with HCC. A 42-year-old female presented with loss of consciousness and a blood glucose level of 30 mg/dl (normal range, 80–140 mg/dl). Abdominal ultrasound and computed tomography were performed to investigate tenderness in the right upper quadrant, and the results revealed a hepatic mass of 15 cm in diameter, with metastasis. A diagnosis of insulinoma was ruled out by examining the insulin level. Prednisolone treatment was ineffective for relieving the persistent hypoglycemia, however, a single dose of palliative radiotherapy reduced the hypoglycemic episodes to once monthly. Due to the advanced disease, the patient refused further treatment, with the exception of a palliative therapy with glucose fluid. The patient succumbed to pneumonia with sepsis. A systematic review of the literature indicated that steroids were the most commonly used drug for hypoglycemia associated with HCC, however, in the majority of cases no effect was noted as observed in this study. Cytoreduction by surgery or systemic chemotherapy has been the most effective treatment. Although rare, hypoglycemia may be the initial symptom of HCC. Cytoreduction is the most effective method of treating hypoglycemia associated with HCC.
PMCID: PMC4156172  PMID: 25202415
hypoglycemia; hepatocellular carcinoma; review; steroids; signs and symptoms
8.  MAVTgsa: An R Package for Gene Set (Enrichment) Analysis 
BioMed Research International  2014;2014:346074.
Gene set analysis methods aim to determine whether an a priori defined set of genes shows statistically significant difference in expression on either categorical or continuous outcomes. Although many methods for gene set analysis have been proposed, a systematic analysis tool for identification of different types of gene set significance modules has not been developed previously. This work presents an R package, called MAVTgsa, which includes three different methods for integrated gene set enrichment analysis. (1) The one-sided OLS (ordinary least squares) test detects coordinated changes of genes in gene set in one direction, either up- or downregulation. (2) The two-sided MANOVA (multivariate analysis variance) detects changes both up- and downregulation for studying two or more experimental conditions. (3) A random forests-based procedure is to identify gene sets that can accurately predict samples from different experimental conditions or are associated with the continuous phenotypes. MAVTgsa computes the P values and FDR (false discovery rate) q-value for all gene sets in the study. Furthermore, MAVTgsa provides several visualization outputs to support and interpret the enrichment results. This package is available online.
PMCID: PMC4101957  PMID: 25101274
9.  Asymptomatic ratio for seasonal H1N1 influenza infection among schoolchildren in Taiwan 
Studies indicate that asymptomatic infections do indeed occur frequently for both seasonal and pandemic influenza, accounting for about one-third of influenza infections. Studies carried out during the 2009 pH1N1 pandemic have found significant antibody response against seasonal H1N1 and H3N2 vaccine strains in schoolchildren receiving only pandemic H1N1 monovalent vaccine, yet reported either no symptoms or only mild symptoms.
Serum samples of 255 schoolchildren, who had not received vaccination and had pre-season HI Ab serotiters <40, were collected from urban, rural areas and an isolated island in Taiwan during the 2005–2006 influenza season. Their hemagglutination inhibition antibody (HI Ab) serotiters against the 2005 A/New Caledonia/20/99 (H1N1) vaccine strain at pre-season and post-season were measured to determine the symptoms with the highest correlation with infection, as defined by 4-fold rise in HI titer. We estimate the asymptomatic ratio, or the proportion of asymptomatic infections, for schoolchildren during the 2005–6 influenza season when this vaccine strain was found to be antigenically related to the circulating H1N1 strain.
Fever has the highest correlation with the 2005–06 seasonal influenza A(H1N1) infection, followed by headache, cough, vomiting, and sore throat. Asymptomatic ratio for the schoolchildren is found to range between 55.6% (95% CI: 44.7-66.4)-77.9% (68.8-87.0) using different sets of predictive symptoms. Moreover, the asymptomatic ratio was 66.9% (56.6-77.2) when using US-CDC criterion of fever + (cough/sore throat), and 73.0 (63.3-82.8) when under Taiwan CDC definition of Fever + (cough or sore throat or nose) + ( headache or pain or fatigue).
Asymptomatic ratio for children is found to be substantially higher than that of the general population in literature. In providing reasonable quantification of the asymptomatic infected children spreading pathogens to others in a seasonal epidemic or a pandemic, our estimates of symptomatic ratio of infected children has important clinical and public health implications.
PMCID: PMC3938038  PMID: 24520993
Seasonal influenza; H1N1; Asymptomatic ratio; Asymptomatic infection; Taiwan; Symptoms
10.  Increased occurrence of native septic arthritis in adult cirrhotic patients: a population-based three-year follow-up study in Taiwan 
Przegla̜d Gastroenterologiczny  2014;9(6):342-347.
Due to impairment of immunity and metabolism, cirrhotic patients are prone to infection, osteoporosis, and osteonecrosis. However, it is unknown if cirrhotic patients are prone to native septic arthritis (NSA).
To assess the occurrence of NSA between cirrhotic and non-cirrhotic patients.
Material and methods
We used the Taiwan National Health Insurance Database to enrol 35,106 cirrhotic patients and 33,457 non-cirrhotic patients from January 1, 2004 to December 31, 2004. The medical record of each patient was individually followed for a 3-year period.
There were 341 (0.5%) patients having NSA in a follow-up period of 3 years: 214 cirrhotic and 127 non-cirrhotic patients. The incidence density of hospitalisation for NSA was 2.03 episodes/1000 person-years in cirrhotic patients, and 1.27 episodes/1000 person-years in non-cirrhotic patients. After adjustment for age, gender, and other comorbid disorders, Cox's regression analysis showed that cirrhotic patients had a higher occurrence of NSA than non-cirrhotic patients(hazard ratio (HR) = 1.51, 95% confidence interval (CI) = 1.19–1.90; p = 0.001). The patients with complicated cirrhosis were more prone to have NSA than those with non-complicated cirrhosis (HR = 1.46, 95% CI = 1.09–1.96, p = 0.011).
This analysis demonstrates that cirrhotic patients have a higher risk of NSA, particularly those with complicated cirrhosis.
PMCID: PMC4300349  PMID: 25653729
arthritis; cirrhosis; septic arthritis
11.  Identification of Novel sRNAs in Mycobacterial Species 
PLoS ONE  2013;8(11):e79411.
Bacterial small RNAs (sRNAs) are short transcripts that typically do not encode proteins and often act as regulators of gene expression through a variety of mechanisms. Regulatory sRNAs have been identified in many species, including Mycobacterium tuberculosis, the causative agent of tuberculosis. Here, we use a computational algorithm to predict sRNA candidates in the mycobacterial species M. smegmatis and M. bovis BCG and confirmed the expression of many sRNAs using Northern blotting. Thus, we have identified 17 and 23 novel sRNAs in M. smegmatis and M. bovis BCG, respectively. We have also applied a high-throughput technique (Deep-RACE) to map the 5′ and 3′ ends of many of these sRNAs and identified potential regulators of sRNAs by analysis of existing ChIP-seq datasets. The sRNAs identified in this work likely contribute to the unique biology of mycobacteria.
PMCID: PMC3828370  PMID: 24244498
12.  Using Oxidized Low-Density Lipoprotein Autoantibodies to Predict Restenosis after Balloon Angioplasty in Patients with Acute Myocardial Infarction 
PLoS ONE  2013;8(10):e74726.
Oxidized low-density lipoproteins (oxLDL) and oxidized low-density lipoprotein autoantibodies (OLAB) have been detected in human plasma and atherosclerotic lesions. OLAB appear to play a role in the clearance of oxLDL from circulation. Higher levels of OLAB appear to be associated with a reduced risk of a wide range of cardiovascular diseases. We investigated the prognostic value of plasma oxLDL and OLAB in patients undergoing primary coronary balloon angioplasty for acute ST-elevation myocardial infarction (STEMI).
Plasma oxLDL and OLAB concentrations were measured in 56 patients with acute STEMI before primary angioplasty, and then 3 days, 7 days and 1 month after the acute event. Follow-up angiography was repeated 6 months later to detect the presence of restensosis (defined as >50% luminal diameter stenosis). The thrombolysis in myocardial infarction (TIMI) risk score was calculated to determine the relationship between OLAB/oxLDL ratio and TIMI risk scores.
Of the 56 patients, 18 (31%) had angiographic evidence of restenosis. Plasma OLAB concentrations were significantly lower in the restenosis group before angioplasty (181±114 vs. 335±257 U/L, p = 0.003), and at day 3 (155±92 vs. 277±185 U/L, p<0.001) and day 7 (177±110 vs. 352±279 U/L, p<0.001) after the acute event. There was no difference in oxLDL concentration between the two groups. The ratio of OLAB/oxLDL positively correlated with TIMI risk scores before angioplasty (p for trend analysis, p = 0.004), at day 3 (p = 0.008) and day 7 (p<0.001) after STEMI.
A relative deficit of OLAB, and hence likely impaired clearance of oxLDL, is associated with the risk of arterial restenosis after primary angioplasty for acute STEMI.
PMCID: PMC3789725  PMID: 24098346
13.  Identifying Gene Set Association Enrichment Using the Coefficient of Intrinsic Dependence 
PLoS ONE  2013;8(3):e58851.
Gene set testing problem has become the focus of microarray data analysis. A gene set is a group of genes that are defined by a priori biological knowledge. Several statistical methods have been proposed to determine whether functional gene sets express differentially (enrichment and/or deletion) in variations of phenotypes. However, little attention has been given to analyzing the dependence structure among gene sets. In this study, we have proposed a novel statistical method of gene set association analysis to identify significantly associated gene sets using the coefficient of intrinsic dependence. The simulation studies show that the proposed method outperforms the conventional methods to detect general forms of association in terms of control of type I error and power. The correlation of intrinsic dependence has been applied to a breast cancer microarray dataset to quantify the un-supervised relationship between two sets of genes in the tumor and non-tumor samples. It was observed that the existence of gene-set association differed across various clinical cohorts. In addition, a supervised learning was employed to illustrate how gene sets, in signaling transduction pathways or subnetworks regulated by a set of transcription factors, can be discovered using microarray data. In conclusion, the coefficient of intrinsic dependence provides a powerful tool for detecting general types of association. Hence, it can be useful to associate gene sets using microarray expression data. Through connecting relevant gene sets, our approach has the potential to reveal underlying associations by drawing a statistically relevant network in a given population, and it can also be used to complement the conventional gene set analysis.
PMCID: PMC3597597  PMID: 23516564
14.  High mortality of pneumonia in cirrhotic patients with ascites 
BMC Gastroenterology  2013;13:25.
Cirrhotic patients with ascites are prone to develop various infectious diseases. This study aimed to evaluate the occurrence and effect of major infectious diseases on the mortality of cirrhotic patients with ascites.
We reviewed de-identified patient data from the National Health Insurance Database, derived from the Taiwan National Health Insurance Program, to enroll 4,576 cirrhotic patients with ascites, who were discharged from Taiwan hospitals between January 1, 2004 and June 30, 2004. We collected patients’ demographic and clinical data, and reviewed diagnostic codes to determine infectious diseases and comorbid disorders of their hospitalizations. Patients were divided into an infection group and non-infection group and hazard ratios (HR) were determined for specific infectious diseases.
Of the total 4,576 cirrhotic patients with ascites, 1,294 (28.2%) were diagnosed with infectious diseases during hospitalization. The major infectious diseases were spontaneous bacterial peritonitis (SBP) (645, 49.8%), urinary tract infection (151, 11.7%), and pneumonia (100, 7.7%). After adjusting for patients’ age, gender, and other comorbid disorders, the HRs of infectious diseases for 30-day and 90-day mortality of cirrhotic patients with ascites were 1.81 (1.54-2.11) and 1.60 (1.43-1.80) respectively, compared to those in the non-infection group. The adjusted HRs of pneumonia, urinary tract infection (UTI), spontaneous bacterial peritonitis (SBP), and sepsis without specific focus (SWSF) were 2.95 (2.05-4.25), 1.32 (0.86-2.05), 1.77 (1.45-2.17), and 2.19 (1.62-2.96) for 30-day mortality, and 2.57 (1.93-3.42), 1.36 (1.01-1.82), 1.51 (1.29-1.75), and 2.13 (1.70-2.66) for 90-day mortality, compared to those in the non-infection group.
Infectious diseases increased 30-day and 90-day mortality of cirrhotic patients with ascites. Among all infectious diseases identified, pneumonia carried the highest risk for mortality.
PMCID: PMC3599048  PMID: 23390924
Cirrhosis; Ascites; Infections; Pneumonia; Spontaneous bacterial peritonitis
15.  The Risk of Cellulitis in Cirrhotic Patients: A Nationwide Population-Based Study in Taiwan 
Gut and Liver  2012;6(4):482-485.
Cellulitis is a common infectious disease. However, the risk of cellulitis in cirrhotic patients is not well established, and whether liver cirrhosis is a risk factor for cellulitis remains unknown. This study evaluated the relationship between cellulitis and liver cirrhosis.
The National Health Insurance Database, which was derived from the Taiwan National Health Insurance program, was used to identify patients. The study group consisted of 39,966 patients with liver cirrhosis, and the comparison group consisted of 39,701 randomly selected age- and sex-matched patients.
During the 3-year follow-up period, 2,674 (6.7%) patients with liver cirrhosis developed cellulitis, and 1,587 (4.0%) patients without liver cirrhosis developed cellulitis (p<0.001). Following a Cox's regression analysis adjusted for age, sex, and underlying medical disorders, the cirrhotic patients demonstrated a greater risk for the occurrence of cellulitis than the non-cirrhotic patients during the 3-year period (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.55 to 1.77; p<0.001). Additionally, cirrhotic patients with complications also had a greater risk for the occurrence of cellulitis than those patients without complications (HR, 1.23; 95% CI, 1.14 to 1.33; p<0.001).
We conclude that cirrhotic patients have a greater risk of cellulitis than non-cirrhotic patients.
PMCID: PMC3493730  PMID: 23170154
Cellulitis; Liver cirrhosis
16.  Association of response to hepatitis B vaccination and survival in dialysis patients 
BMC Nephrology  2012;13:97.
The status of immunocompromised patients is well recognized in end stage renal disease (ESRD). As described recently, this acquired immune dysfunction in the uremic milieu may be one of the main pathogenic factors for mortality in ESRD. The aim of this study was to determine the relationship between the immune response following a hepatitis B vaccination (HBV vaccination) and the survival of maintenance dialysis patients.
A total of 156 patients (103 on hemodialysis and 53 on continuous ambulatory peritoneal dialysis) were recruited. After receiving a full dose of the HBV vaccination, all patients were followed up for to 5 years to evaluate the association of patient survival, cause of mortality, and immune response.
The response rate to the hepatitis B vaccination was 70.5%. There was no significant association between the immune response and the 5-year survival rate (p =0.600) or between the post-vaccination anti-HBs titers and the 5-year survival rate (p = 0.201). The logistic prediction model with the coefficient as non-response following HBV vaccination, diabetes mellitus, old age, and low albumin level could significantly predict infection-cause mortality (sensitivity = 0.842, specificity = 0.937).
There was no significant association between the immune response to HBV vaccination and the 5-year survival rate. However, non-response following HBV vaccination might be associated with infection-cause mortality in dialysis patients.
PMCID: PMC3471045  PMID: 22935561
Hepatitis B vaccination; Immune response; Post-vaccination anti-HBs titers
17.  Recursive Feature Selection with Significant Variables of Support Vectors 
The development of DNA microarray makes researchers screen thousands of genes simultaneously and it also helps determine high- and low-expression level genes in normal and disease tissues. Selecting relevant genes for cancer classification is an important issue. Most of the gene selection methods use univariate ranking criteria and arbitrarily choose a threshold to choose genes. However, the parameter setting may not be compatible to the selected classification algorithms. In this paper, we propose a new gene selection method (SVM-t) based on the use of t-statistics embedded in support vector machine. We compared the performance to two similar SVM-based methods: SVM recursive feature elimination (SVMRFE) and recursive support vector machine (RSVM). The three methods were compared based on extensive simulation experiments and analyses of two published microarray datasets. In the simulation experiments, we found that the proposed method is more robust in selecting informative genes than SVMRFE and RSVM and capable to attain good classification performance when the variations of informative and noninformative genes are different. In the analysis of two microarray datasets, the proposed method yields better performance in identifying fewer genes with good prediction accuracy, compared to SVMRFE and RSVM.
PMCID: PMC3426197  PMID: 22927888
18.  An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010 
BMC Infectious Diseases  2011;11:346.
In 2010, an outbreak of coxsackievirus A6 (CA6) hand, foot and mouth disease (HFMD) occurred in Taiwan and some patients presented with onychomadesis and desquamation following HFMD. Therefore, we performed an epidemiological and molecular investigation to elucidate the characteristics of this outbreak.
Patients who had HFMD with positive enterovirus isolation results were enrolled. We performed a telephone interview with enrolled patients or their caregivers to collect information concerning symptoms, treatments, the presence of desquamation, and the presence of nail abnormalities. The serotypes of the enterovirus isolates were determined using indirect immunofluorescence assays. The VP1 gene was sequenced and the phylogenetic tree for the current CA6 strains in 2010, 52 previous CA6 strains isolated in Taiwan from 1998 through 2009, along with 8 reference sequences from other countries was constructed using the neighbor-joining command in MEGA software.
Of the 130 patients with laboratory-confirmed CA6 infection, some patients with CA6 infection also had eruptions around the perioral area (28, 22%), the trunk and/or the neck (39, 30%) and generalized skin eruptions (6, 5%) in addition to the typical presentation of skin eruptions on the hands, feet, and mouths. Sixty-six (51%) CA6 patients experienced desquamation of palms and soles after the infection episode and 48 (37%) CA6 patients developed onychomadesis, which only occurred in 7 (5%) of 145 cases with non-CA6 enterovirus infection (p < 0.001). The sequences of viral protein 1 of CA6 in 2010 differ from those found in Taiwan before 2010, but are similar to those found in patients in Finland in 2008.
HFMD patients with CA6 infection experienced symptoms targeting a broader spectrum of skin sites and more profound tissue destruction, i.e., desquamation and nail abnormalities.
PMCID: PMC3297538  PMID: 22168544
Coxsackievirus A6; Hand; foot; and mouth disease; Onychomadesis
19.  Different Clinical Characteristics Among Aeromonas hydrophila, Aeromonas veronii biovar sobria and Aeromonas caviae Monomicrobial Bacteremia 
Journal of Korean Medical Science  2011;26(11):1415-1420.
This study aimed to compare the clinical presentations of Aeromonas hydrophila, A. veronii biovar sobria and A. caviae monomicrobial bacteremia by a retrospective method at three hospitals in Taiwan during an 8-yr period. There were 87 patients with A. hydrophila bacteremia, 45 with A. veronii biovar sobria bacteremia and 22 with A. caviae bacteremia. Compared with A. hydrophila and A. veronii biovar sobria bacteremia, A. caviae bacteremia was more healthcare-associated (45 vs 30 and 16%; P = 0.031). The patients with A. caviae bacteremias were less likely to have liver cirrhosis (27 vs 62 and 64%; P = 0.007) and severe complications such as shock (9 vs 40 and 47%; P = 0.009) and thrombocytopenia (45 vs 67 and 87%; P = 0.002). The APACHE II score was the most important risk factor of Aeromonas bacteremia-associated mortalities. The APACHE II scores of A. caviae bacteremias were lower than A. hydrophila bacteremia and A. veronii biovar sobria bacteremia (7 vs 14 and 16 points; P = 0.002). In conclusion, the clinical presentation of A. caviae bacteremia was much different from A. hydrophila and A. veronii biovar sobria bacteremia. The severity and mortality of A. caviae bacteremia were lower than A. hydrophila or A. veronii biovar sobria bacteremia.
PMCID: PMC3207043  PMID: 22065896
Aeromonas hydrophilia; Aeromonas veronii biovar sobria; Aeromonas caviae; Bacteremia
20.  Molecular basis of the recognition of the ap65-1 gene transcription promoter elements by a Myb protein from the protozoan parasite Trichomonas vaginalis 
Nucleic Acids Research  2011;39(20):8992-9008.
Iron-inducible transcription of the ap65-1 gene in Trichomonas vaginalis involves at least three Myb-like transcriptional factors (tvMyb1, tvMyb2 and tvMyb3) that differentially bind to two closely spaced promoter sites, MRE-1/MRE-2r and MRE-2f. Here, we defined a fragment of tvMyb2 comprising residues 40–156 (tvMyb240–156) as the minimum structural unit that retains near full binding affinity with the promoter DNAs. Like c-Myb in vertebrates, the DNA-free tvMyb240–156 has a flexible and open conformation. Upon binding to the promoter DNA elements, tvMyb240–156 undergoes significant conformational re-arrangement and structure stabilization. Crystal structures of tvMyb240–156 in complex with promoter element-containing DNA oligomers showed that 5′-a/gACGAT-3′ is the specific base sequence recognized by tvMyb240–156, which does not fully conform to that of the Myb binding site sequence. Furthermore, Lys49, which is upstream of the R2 motif (amino acids 52–102) also participates in specific DNA sequence recognition. Intriguingly, tvMyb240–156 binds to the promoter elements in an orientation opposite to that proposed in the HADDOCK model of the tvMyb135–141/MRE-1-MRE-2r complex. These results shed new light on understanding the molecular mechanism of Myb–DNA recognition and provide a framework to study the molecular basis of transcriptional regulation of myriad Mybs in T. vaginalis.
PMCID: PMC3203581  PMID: 21771861
21.  Early Treatment with Alglucosidase Alfa Prolongs Long Term Survival of Infants with Pompe Disease 
Pediatric research  2009;66(3):329-335.
In a previous 52-week trial, treatment with alglucosidase alfa markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 months old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alfa at either 20 mg/kg biweekly (n=8) or 40 mg/kg biweekly (n=8), for up to a total of 3 years. These children continued to exhibit the benefits of alglucosidase alfa at the age of 36 months. Cox regression analyses showed that over the entire study period, alglucosidase alfa treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, as compared to an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 mg/kg and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival, and improved cardiomyopathy.
PMCID: PMC3129995  PMID: 19542901
22.  Correction: Serological Evidence of Subclinical Transmission of the 2009 Pandemic H1N1 Influenza Virus Outside of Mexico 
PLoS ONE  2011;6(5):10.1371/annotation/edeb5a9c-04b2-4d09-ae2b-6d527bf27c81.
PMCID: PMC3103590
23.  Risk Factors for Delayed Diagnosis of Scabies in Hospitalized Patients From Long-Term Care Facilities 
Delayed diagnosis of scabies can cause an institutional outbreak, which causes considerably economic burden to control. This study was to find the risk factors for delayed diagnosis of scabies in hospitalized patients from long-term care facilities.
We conducted a retrospective analysis of the hospitalized patients from long-term care facilities, diagnosed to have scabies between January 2006 and December 2008. A stepwise logistic regression analysis was performed to determine the risk factors for delayed diagnosis of scabies.
A total of 706 episodes with scabies were identified retrospectively in 399 hospitalized patients from long-term care facilities. Of these, 44 episodes were considered as delayed diagnosis of scabies. These patients were more associated with chronic usage of steroid (73% vs. 10%, P < 0.001) and had longer duration of hospitalization than the others (30 vs. 13 days, P < 0.001). After logistic regression, steroid therapy was the risk factor of delayed diagnosis of scabies (odds ratio: 23.493).
In the patients from long-term care facilities, clinical physicians should pay more attention to those with chronic usage of steroid to avoid delayed diagnosis of scabies.
Scabies; Delayed diagnosis; Risk factor; Long-term care facility
PMCID: PMC3140926  PMID: 21811533
24.  Serological Evidence of Subclinical Transmission of the 2009 Pandemic H1N1 Influenza Virus Outside of Mexico 
PLoS ONE  2011;6(1):e14555.
Relying on surveillance of clinical cases limits the ability to understand the full impact and severity of an epidemic, especially when subclinical cases are more likely to be present in the early stages. Little is known of the infection and transmissibility of the 2009 H1N1 pandemic influenza (pH1N1) virus outside of Mexico prior to clinical cases being reported, and of the knowledge pertaining to immunity and incidence of infection during April–June, which is essential for understanding the nature of viral transmissibility as well as for planning surveillance and intervention of future pandemics.
Methodology/Principal Findings
Starting in the fall of 2008, 306 persons from households with schoolchildren in central Taiwan were followed sequentially and serum samples were taken in three sampling periods for haemagglutination inhibition (HI) assay. Age-specific incidence rates were calculated based on seroconversion of antibodies to the pH1N1 virus with an HI titre of 1∶40 or more during two periods: April–June and September–October in 2009. The earliest time period with HI titer greater than 40, as well as a four-fold increase of the neutralization titer, was during April 26–May 3. The incidence rates during the pre-epidemic phase (April–June) and the first wave (July–October) of the pandemic were 14.1% and 29.7%, respectively. The transmissibility of the pH1N1 virus during the early phase of the epidemic, as measured by the effective reproductive number R0, was 1.16 (95% confidence interval (CI): 0.98–1.34).
Approximately one in every ten persons was infected with the 2009 pH1N1 virus during the pre-epidemic phase in April–June. The lack of age-pattern in seropositivity is unexpected, perhaps highlighting the importance of children as asymptomatic transmitters of influenza in households. Although without virological confirmation, our data raise the question of whether there was substantial pH1N1 transmission in Taiwan before June, when clinical cases were first detected by the surveillance network.
PMCID: PMC3022590  PMID: 21267441
25.  OSU-A9, a potent indole-3-carbinol derivative, suppresses breast tumor growth by targeting the Akt–NF-κB pathway and stress response signaling 
Carcinogenesis  2009;30(10):1702-1709.
The molecular heterogeneity of human tumors challenges the development of effective preventive and therapeutic strategies. To overcome this issue, a rational approach is the concomitant targeting of clinically relevant cellular abnormalities with combination therapy or a potent multi-targeted agent. OSU-A9 is a novel indole-3-carbinol derivative that retains the parent compound's ability to perturb multiple components of oncogenic signaling, but provides marked advantages in chemical stability and antitumor potency. Here, we show that OSU-A9 exhibits two orders of magnitude greater potency than indole-3-carbinol in inducing apoptosis in various breast cancer cell lines with distinct genetic abnormalities, including MCF-7, MDA-MB-231 and SKBR3, with the half maximal inhibitory concentration in the range of 1.2–1.8 μM vis-à-vis 200 μM for indole-3-carbinol. This differential potency was paralleled by OSU-A9’s superior activity against multiple components of the Akt–nuclear factor-kappa B (NF-κB) and stress response signaling pathways. Notable among these were the increased estrogen receptor (ER)-β/ERα expression ratio, reduced expression of HER2 and CXCR4 and the upregulation of aryl hydrocarbon receptor expression and its downstream target NF-E2 p45-regulated factor (Nrf2). Non-malignant MCF-10A cells were resistant to OSU-A9’s antiproliferative effects. Daily oral administration of OSU-A9 at 25 and 50 mg/kg for 49 days significantly inhibited MCF-7 tumor growth by 59 and 70%, respectively, without overt signs of toxicity or evidence of induced hepatic biotransformation enzymes. In summary, OSU-A9 is a potent, orally bioavailable inhibitor of the Akt–NF-κB signaling network, targeting multiple aspects of breast tumor pathogenesis and progression. Thus, its translational potential for the treatment or prevention of breast cancer warrants further investigation.
PMCID: PMC2757549  PMID: 19706645

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