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1.  Concerted actions of the catechol O-methyltransferase and the cytosolic sulfotransferase SULT1A3 in the metabolism of catecholic drugs 
Biochemical pharmacology  2012;84(9):1186-1195.
Catecholic drugs had been reported to be metabolized through conjugation reactions, particularly methylation and sulfation. Whether and how these two Phase II conjugation reactions may occur in a concerted manner, however, remained unclear. The current study was designed to investigate the methylation and/or sulfation of five catecholic drugs. Analysis of the spent media of HepG2 cells metabolically labeled with [35S]sulfate in the presence of individual catecholic drugs revealed the presence of two [35S]sulfated metabolites for dopamine, epinephrine, isoproterenol, and isoetharine, but only one [35S]sulfated metabolite for apomorphine. Further analyses using tropolone, a catechol O-methyltransferase (COMT) inhibitor, indicated that one of the two [35S]sulfated metabolites of dopamine, epinephrine, isoproterenol, and isoetharine was a doubly conjugated (methylated and sulfated) product, since its level decreased proportionately with increasing concentrations of tropolone added to the labeling media. Moreover, while the inhibition of methylation resulted in a decrease of the total amount of [35S]sulfated metabolites, sulfation appeared to be capable of compensating the suppressed methylation in the metabolism of these four catecholic drugs. A two-stage enzymatic assay showed the sequential methylation and sulfation of dopamine, epinephrine, isoproterenol, and isoetharine mediated by, respectively, the COMT and the cytosolic sulfotransferase SULT1A3. Collectively, the results from the present study implied the concerted actions of the COMT and SULT1A3 in the metabolism of catecholic drugs.
doi:10.1016/j.bcp.2012.08.009
PMCID: PMC3622478  PMID: 22917559
Methylation; Sulfation; COMTs; SULTs; Catecholic drugs
2.  Sulfation of ractopamine and salbutamol by the human cytosolic sulfotransferases 
Journal of Biochemistry  2012;152(3):275-283.
Feed additives such as ractopamine and salbutamol are pharmacologically active compounds, acting primarily as β-adrenergic agonists. This study was designed to investigate whether the sulfation of ractopamine and salbutamol may occur under the metabolic conditions and to identify the human cytosolic sulfotransferases (SULTs) that are capable of sulfating two major feed additive compounds, ractopamine and salbutamol. A metabolic labelling study showed the generation and release of [35S]sulfated ractopamine and salbutamol by HepG2 human hepatoma cells labelled with [35S]sulfate in the presence of these two compounds. A systematic analysis using 11 purified human SULTs revealed SULT1A3 as the major SULT responsible for the sulfation of ractopamine and salbutamol. The pH dependence and kinetic parameters were analyzed. Moreover, the inhibitory effects of ractopamine and salbutamol on SULT1A3-mediated dopamine sulfation were investigated. Cytosol or S9 fractions of human lung, liver, kidney and small intestine were examined to verify the presence of ractopamine-/salbutamol-sulfating activity in vivo. Of the four human organs, the small intestine displayed the highest activity towards both compounds. Collectively, these results imply that the sulfation mediated by SULT1A3 may play an important role in the metabolism and detoxification of ractopamine and salbutamol.
doi:10.1093/jb/mvs073
PMCID: PMC3529569  PMID: 22763752
feed additive; ractopamine; salbutamol; sulfation; SULT
3.  Identification and Characterization of Zebrafish SULT1 ST9, SULT3 ST4, and SULT3 ST5 
By searching the GenBank database, we identified sequences encoding three new zebrafish cytosolic sulfotransferases (SULTs). These three new zebrafish SULTs, designated SULT1 ST9, SULT3 ST4, and SULT3 ST5, were cloned, expressed, purified, and characterized. SULT1 ST9 appeared to be mostly involved in the metabolism and detoxification of xenobiotics such as β-naphthol, β-naphthylamine, caffeic acid and gallic acid. SULT3 ST4 showed strong activity toward endogenous compound such as dehydroepiandrosterone (DHEA), pregnenolone, and 17β-estradiol. SULT3 ST5 showed weaker, but significant, activities toward endogenous compounds such as DHEA and corticosterone, as well as xenobiotics including mestranol, β-naphthylamine, β-naphthol, and butylated hydroxyl anisole (BHA). pH-dependency and kinetic constants of these three enzymes were determined with DHEA, β-naphthol, and 17β-estradiol as substrates. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to examine the expression of these three new zebrafish SULTs at different developmental stages during embryogenesis, through larval development, and on to maturity.
doi:10.1016/j.aquatox.2012.01.015
PMCID: PMC3521529  PMID: 22360938
Cytosolic sulfotransferase; SULT; 17β-estradiol; dehydroepiandrosterone; molecular cloning; developmental expression; zebrafish
4.  A comparative study of the sulfation of bile acids and a bile alcohol by the Zebra danio (Danio rerio) and human cytosolic sulfotransferases (SULTs) 
The current study was designed to examine the sulfation of bile acids and bile alcohols by the Zebra danio (Danio rerio) SULTs in comparison with human SULTs. A systematic analysis using the fifteen Zebra danio SULTs revealed that SULT3 ST2 and SULT3 ST3 were the major bile acid/alcohol-sulfating SULTs. Among the eleven human SULTs, only SULT2A1 was found to be capable of sulfating bile acids and bile alcohols. To further investigate the sulfation of bile acids and bile alcohols by the two Zebra danio SULT3 STs and the human SULT2A1, pH-dependence and kinetics of the sulfation of bile acids/alcohols were analyzed. pH-dependence experiments showed that the mechanisms underlying substrate recognition for the sulfation of lithocholic acid (a bile acid) and 5α-petromyzonol (a bile alcohol) differed between the human SULT2A1 and the Zebra danio SULT3 ST2 and ST3. Kinetic analysis indicated that both the two Zebra danio SULT3 STs preferred petromyzonol as substrate compared to bile acids. In contrast, the human SULT2A1 was more catalytically efficient toward lithocholic acid than petromyzonol. Collectively, the results imply that the Zebra danio and human SULTs have evolved to serve for the sulfation of, respectively, bile alcohols and bile acids, matching the cholanoid profile in these two vertebrate species.
doi:10.1016/j.jsbmb.2011.07.011
PMCID: PMC3515676  PMID: 21839837
Sulfotransferase; Sulfation; Zebra danio; Bile acid
5.  Identification, Characterization, and Ontogenic Study of a Catechol O-methyltransferase from Zebrafish 
To establish the zebrafish as a model for investigating the methylation pathway of drug metabolism, we embarked on the molecular cloning of the zebrafish catechol O-methyltransferase (COMT). By searching the GenBank database, a zebrafish nucleotide sequence encoding a putative COMT was identified. Based on the sequence information, we designed and synthesized oligonucleotides corresponding to its 5’- and 3’-coding regions of this zebrafish COMT. Using the first-strand cDNA reverse-transcribed from the total RNA isolated from a 3-month-old adult female zebrafish as the template, the cDNA encoding the zebrafish COMT was PCR-amplified. The recombinant zebrafish COMT protein was subsequently expressed in and purified from BL21 (DE3) Escherichia coli cells transformed with the pGEX-2TK expression vector harboring the zebrafish COMT cDNA. Upon enzymatic characterization, purified COMT displayed methylating activity toward dopamine, dopa, and catecholestrogens, as well as three representative catechol drugs, methyldopa, dobutamine, and isoproterenol. A reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed developmental stage-dependent expression of the zebrafish COMT during embryonic development and throughout the larval stage onto maturity. These results provide a foundation for investigating the involvement of COMT-mediated methylation in protection against the adverse effects of catechol drugs and other xenobiotic catechols during the developmental process.
doi:10.1016/j.aquatox.2010.12.016
PMCID: PMC3515678  PMID: 21371608
Catechol O-methyltransferase; developmental expression; methylation; molecular cloning; zebrafish
6.  A Target-specific Approach for the Identification of Tyrosine-sulfated Hemostatic Proteins 
Analytical biochemistry  2009;390(1):88-90.
Summary
A simple methodology for the identification of hemostatic proteins that are subjected to post-translational tyrosine sulfation was developed. The procedure involved sequence analysis of members of the three hemostatic pathways using Sulfinator prediction algorithm, followed by [35S]sulfate-labeling of cultured HepG2 human hepatoma cells, immunoprecipitation of targeted [35S]sulfate-labeled hemostatic proteins, and tyrosine O[35S]sulfate analysis of immunoprecipitated proteins. Three new tyrosine-sulfated hemostatic proteins, protein S, prekallikrein and plasminogen, were identified. Such a target-specific approach will allow for investigation of tyrosine-sulfated proteins of other biochemical/physiological pathways/processes and contribute to a better understating of the functional role of post-translational tyrosine sulfation.
doi:10.1016/j.ab.2009.04.002
PMCID: PMC2695991  PMID: 19351526
Hemostasis; tyrosine sulfation; post-translational protein modification
7.  Performance of Genotype Imputation for Low Frequency and Rare Variants from the 1000 Genomes 
PLoS ONE  2015;10(1):e0116487.
Genotype imputation is now routinely applied in genome-wide association studies (GWAS) and meta-analyses. However, most of the imputations have been run using HapMap samples as reference, imputation of low frequency and rare variants (minor allele frequency (MAF) < 5%) are not systemically assessed. With the emergence of next-generation sequencing, large reference panels (such as the 1000 Genomes panel) are available to facilitate imputation of these variants. Therefore, in order to estimate the performance of low frequency and rare variants imputation, we imputed 153 individuals, each of whom had 3 different genotype array data including 317k, 610k and 1 million SNPs, to three different reference panels: the 1000 Genomes pilot March 2010 release (1KGpilot), the 1000 Genomes interim August 2010 release (1KGinterim), and the 1000 Genomes phase1 November 2010 and May 2011 release (1KGphase1) by using IMPUTE version 2. The differences between these three releases of the 1000 Genomes data are the sample size, ancestry diversity, number of variants and their frequency spectrum. We found that both reference panel and GWAS chip density affect the imputation of low frequency and rare variants. 1KGphase1 outperformed the other 2 panels, at higher concordance rate, higher proportion of well-imputed variants (info>0.4) and higher mean info score in each MAF bin. Similarly, 1M chip array outperformed 610K and 317K. However for very rare variants (MAF≤0.3%), only 0–1% of the variants were well imputed. We conclude that the imputation of low frequency and rare variants improves with larger reference panels and higher density of genome-wide genotyping arrays. Yet, despite a large reference panel size and dense genotyping density, very rare variants remain difficult to impute.
doi:10.1371/journal.pone.0116487
PMCID: PMC4306552  PMID: 25621886
8.  Heterosis and Combining Ability Estimates in Isoflavone Content Using Different Parental Soybean Accessions: Wild Soybean, a Valuable Germplasm for Soybean Breeding 
PLoS ONE  2015;10(1):e0114827.
Isoflavone, a group of secondary metabolites in soybean, is beneficial to human health. Improving isoflavone content in soybean seeds has become one of the most important breeding objectives. However, the narrow genetic base of soybean cultivars hampered crop improvement. Wild soybean is an extraordinarily important gene pool for soybean breeding. In order to select an optimal germplasm for breeding programs to increase isoflavone concentration, 36 F1 soybean progenies from different parental accessions (cultivars, wild, Semi-wild and Interspecific) with various total isoflavone (TIF) concentration (High, Middle, Low) were analyzed for their isoflavone content. Results showed that male parents, except for Cultivars, showed positive GCA effects. In particular, wild soybean had higher positive GCA effects for TIF concentration. Both MP and BP heterosis value declined in the hybrid in which male parents were wild soybean, semi-wild soybean, interspecific offspring and cultivar in turn. In general, combining ability and heterosis in hybrids which had relative higher TIF concentration level parents showed better performance than those which had lower TIF concentration level parents. These results indicated characteristics of isoflavone content were mainly governed by additive type of gene action, and wild relatives could be utilized for breeding of soybean cultivars with this trait. A promising combination was found as the best potential hybrid for isoflavone content improvement.
doi:10.1371/journal.pone.0114827
PMCID: PMC4301644  PMID: 25607952
9.  Comparison of complications in one-stage bilateral total knee arthroplasty with and without drainage 
Purpose
The aim of this meta-analysis was to compare the complication rates of one-stage bilateral total knee arthroplasty (TKA) with and without drainage in order to identify whether there was no clinical significance and the value of drainage.
Methods
Randomized controlled trials (RCTs) based on bilateral TKA with and without drainage were identified via a search of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Wanfang databases, and Google Scholar, which were published up to May 2014. Methodological quality was assessed by the Physiotherapy Evidence Database scale. After data extraction, we compared the outcomes using fixed-effects or random-effects models depending on the heterogeneity.
Results
Three RCTs involving 125 one-stage bilateral TKA patients with an average follow-up of 14 months met the predetermined inclusion criteria. There were 56 total complications in TKA without drainage and 17 with drainage. Except for less erythema and ecchymosis around the wound in the drainage group, there were no statistical differences in wound healing, wound infection, swelling, and deep vein thrombosis in one-stage bilateral TKA with and without drainage.
Conclusion
The current evidences confirm that both drainage and non-drainage have similar clinical value in one-stage bilateral TKA. However, the conclusion should be used with caution due to the limitations of the current study.
doi:10.1186/s13018-014-0140-1
PMCID: PMC4299130  PMID: 25585542
Drainage; One-stage; Bilateral; Total knee arthroplasty; Randomized controlled trials
10.  The Effects of Mixtures of Dichloroacetate and Trichloroacetate on Induction of Oxidative Stress in Livers of Mice after Subchronic Exposure 
Dichloroacetate (DCA) and trichloroacetate (TCA) are drinking water chlorination byproducts previously found to induce oxidative stress (OS) in hepatic tissues of B6C3F1 male mice. To assess the effects of mixtures of the compounds on OS, groups of male B6C3F1 mice were treated daily by gavage with DCA at doses of 7.5, 15, or 30 mg/kg/day, TCA at doses of 12.5, 25, or 50 mg/kg/day and three mixtures of DCA and TCA (Mix I, Mix II and Mix III), for 13 weeks. The concentrations of the compounds in Mix I, II and III corresponded to those producing approximately 15, 25 and 35%, respectively, of maximal induction of OS by individual compounds. Livers were assayed for production of superoxide anion (SA), lipid peroxidation (LP) and DNA single strand breaks (SSB). DCA, TCA and the mixtures produced dose-dependent increases in the three tested biomarkers. Mix. I and II effects on the three biomarkers, and Mix. III effect on SA production were found to be additive, while Mix. III effects on LP and DNA-SSB were shown to be greater than additive. Induction of OS in livers of B6C3F1 mice after sub-chronic exposure to DCA and TCA was previously suggested as an important mechanism in chronic hepatotoxicity/hepatocarcinogenicity induced by these compounds. Hence, there may be rise in exposure risk to these compounds as these agents co-exist in drinking water.
doi:10.1080/15287394.2013.864576
PMCID: PMC4100325  PMID: 24593144
11.  Maternal diet–induced microRNAs and mTOR underlie β cell dysfunction in offspring 
The Journal of Clinical Investigation  2014;124(10):4395-4410.
A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis.
doi:10.1172/JCI74237
PMCID: PMC4191023  PMID: 25180600
12.  Copy Number Variation Analysis by Ligation-Dependent PCR Based on Magnetic Nanoparticles and Chemiluminescence 
Theranostics  2015;5(1):71-85.
A novel system for copy number variation (CNV) analysis was developed in the present study using a combination of magnetic separation and chemiluminescence (CL) detection technique. The amino-modified probes were firstly immobilized onto carboxylated magnetic nanoparticles (MNPs) and then hybridized with biotin-dUTP products, followed by amplification with ligation-dependent polymerase chain reaction (PCR). After streptavidin-modified alkaline phosphatase (STV-AP) bonding and magnetic separation, the CL signals were then detected. Results showed that the quantification of PCR products could be reflected by CL signal values. Under optimum conditions, the CL system was characterized for quantitative analysis and the CL intensity exhibited a linear correlation with logarithm of the target concentration. To validate the methodology, copy numbers of six genes from the human genome were detected. To compare the detection accuracy, multiplex ligation-dependent probe amplification (MLPA) and MNPs-CL detection were performed. Overall, there were two discrepancies by MLPA analysis, while only one by MNPs-CL detection. This research demonstrated that the novel MNPs-CL system is a useful analytical tool which shows simple, sensitive, and specific characters which are suitable for CNV analysis. Moreover, this system should be improved further and its application in the genome variation detection of various diseases is currently under further investigation.
doi:10.7150/thno.10117
PMCID: PMC4265749  PMID: 25553099
Copy number variation; Ligation-dependent PCR; Magnetic nanoparticles; Chemiluminescence.
13.  Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats 
Background
Exposure to paraquat results in acute lung injury. A systemic inflammatory response has been widely established as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of Xuebijing prevents inflammatory response-induced diseases. This study investigated whether consumption of Xuebijing protected rats against paraquat-induced acute lung injury.
Methods
Adult male Sprague Dawley rats were randomly divided into four groups: control group; paraquat group; paraquat + Xuebijing group; and paraquat + dexamethasone group. Rats in the paraquat, paraquat + Xuebijing and paraquat + dexamethasone groups were intraperitoneally injected with paraquat (30 mg/kg) or administered paraquat and Xuebijing at 8 mL/kg or dexamethasone at 5 mg/kg, respectively, via an injection into the tail vein. Lung p38 MAPK, NF-κB65, IkB, p-IκB-α, HIF-1α, Nrf2 and TGF-β1 expression were essayed using western blotting. IL-6, TNF-α, IL-1β, IL-10, TGF-β1 and PIIIP were measured using ELISA. ROS, oxidised glutathione and glutathione activity were measured.
Results
After inducing acute lung injury with paraquat for 24 h, Xuebijing was observed to block lung p-p38 MAPK, NF-κB65, HIF-1α, p-IκB-α and TGF-β1 expression, and increased Nrf2 and IkB expression. The numbers of neutrophils and lymphocytes and total number of cells were significantly lower in the Xuebijing group compared with the control group. IL-6, TNF-α, IL-1β, TGF-β1 and PIIIP levels were significantly decreased in the Xuebijing group. ROS and oxidised glutathione activity were markedly inhibited by Xuebijing. Histological evaluation showed attenuation of the effects of Xuebijing on paraquat-induced lung injury. Compared with the paraquat + dexamethasone group, the Xuebijing + paraquat group showed no significant differences.
Conclusions
Inhibiting the expression of p38 MAPK and NF-κB65 was crucial for the protective effects of Xuebijing on paraquat-induced acute lung injury. The findings suggest that Xuebijing could effectively ameliorate paraquat-induced acute lung injury in rats. Xuebijing was as effective as dexamethasone at improving paraquat-induced lung injury by regulating lung inflammation, lung function and oxidative stress responses.
doi:10.1186/1472-6882-14-498
PMCID: PMC4301062  PMID: 25511395
Xuebijing; Paraquat; Acute lung injury; p38 MAPK; NF-κB65; Rat
14.  ‘Cool and quiet’ therapy for malignant hyperthermia following severe traumatic brain injury: A preliminary clinical approach 
Malignant hyperthermia increases mortality and disability in patients with brain trauma. A clinical treatment for malignant hyperthermia following severe traumatic brain injury, termed ‘cool and quiet’ therapy by the authors of the current study, was investigated. Between June 2003 and June 2013, 110 consecutive patients with malignant hyperthermia following severe traumatic brain injury were treated using mild hypothermia (35–36°C) associated with small doses of sedative and muscle relaxant. Physiological parameters and intracranial pressure were monitored, and the patients slowly rewarmed following the maintenance of mild hypothermia for 3–12 days. Consecutive patients who had undergone normothermia therapy were retrospectively analyzed as the control. In the mild hypothermia group, the recovery rate was 54.5%, the mortality rate was 22.7%, and the severe and mild disability rates were 11.8 and 10.9%, respectively. The mortality rate of the patients, particularly that of patients with a Glasgow Coma Scale (GCS) score of between 3 and 5 differed significantly between the hypothermia group and the normothermia group (P<0.05). The mortality of patients with a GCS score of between 6 and 8 was not significantly different between the two groups (P> 0.05). The therapy using mild hypothermia with a combination of sedative and muscle relaxant was beneficial in decreasing the mortality of patients with malignant hyperthermia following severe traumatic brain injury, particularly in patients with a GCS score within the range 3–5 on admission. The therapy was found to be safe, effective and convenient. However, rigorous clinical trials are required to provide evidence of the effectiveness of ‘cool and quiet’ therapy for hyperthermia.
doi:10.3892/etm.2014.2130
PMCID: PMC4280981  PMID: 25574217
traumatic brain injury; malignant hyperthermia; mild hypothermia; ‘cool and quiet’ therapy
15.  Increased Th17 cells in flow cytometer-sorted CD45RO-positive memory CD4 T cells from patients with systemic lupus erythematosus 
Lupus Science & Medicine  2014;1(1):e000062.
Objectives
Th17/IL-17 dysregulation is involved in human autoimmunity, and recent evidence suggests the character of long-lived differentiated memory cells in Th17. By directly measuring the peripheral blood mononuclear cells (PBMC), elevated circulating frequencies of Th17 cells have been reported in systemic lupus erythematosus (SLE) with inconsistent results regarding the correlation with disease activities. In this study, the association between circulating Th17 frequencies and disease activities or laboratory parameters was examined in flow cytometer-sorted CD45RO-positive memory CD4 T cells from SLE.
Methods
PBMC samples were obtained from 48 female lupus patients and another 48 age- and sex-matched healthy individuals. We examined frequencies of Th17 cells by sorting the purified CD4 T cells bearing the CD45RO marker, followed by intracellular IL-17A staining after in vitro activation. Frequencies of Th1 and TFoxp3 cells were also measured by intracellular IFN-γ and Foxp3 staining, respectively. The SLE disease activity index (SLEDAI) and other laboratory parameters were further correlated with frequencies of different T cell subsets.
Results
In SLE, increased frequencies of Th17 cells were found with a positive correlation in SLEDAI. Higher frequencies of Th17 cells were found in lupus nephritis. There was a positive correlation between frequencies of Th17 cells and daily proteinuria amount.
Conclusions
By examining the sorted CD45RO-positive memory CD4 T cells, we confirm the dysregulation of Th17/IL-17 in SLE, implicating the potential to treat lupus patients with selective IL-17/IL-17R blockades.
doi:10.1136/lupus-2014-000062
PMCID: PMC4271411  PMID: 25553252
Lupus Nephritis; Systemic Lupus Erythematosus; T Cells; Th17; Flow cytometry sorter
16.  The Prevalence and Prognosis of Resistant Hypertension in Patients with Heart Failure 
PLoS ONE  2014;9(12):e114958.
Background
Resistant hypertension is associated with adverse clinical outcome in hypertensive patients. However, the prognostic significance of resistant hypertension in patients with heart failure remains uncertain.
Methods and Results
The 1 year survival and heart failure re-hospitalization rate of 1288 consecutive patients admitted to a university hospital for either newly diagnosed heart failure or an exacerbation of prior chronic heart failure was analyzed. Resistant hypertension was defined as uncontrolled blood pressure (>140/90 mmHg) despite being compliant with an antihypertensive regimen that includes 3 or more drugs (including a diuretic). A total of 176 (13.7%) heart failure patients had resistant hypertension. There was no difference in all cause mortality, cardiovascular mortality, and heart failure related re-hospitalization between patients with versus without resistant hypertension. Diabetes [hazard ratio = 1.62, 95% confidence interval = 1.13–2.34; P = 0.010] and serum sodium >139 mmol/L (hazard ratio = 1.54, 95% confidence interval = 1.06–2.23; P = 0.024) were independently associated with resistant hypertension. Patients with resistant hypertension had a relatively higher survival rate (86.9% vs. 83.8%), although the difference was not significant (log-rank x2 = 1.00, P = 0.317). In patients with reduced ejection fraction, heart failure related re-hospitalization was significantly lower in patients with resistant hypertension (45.8% vs. 59.1%, P = 0.050).
Conclusions
Resistant hypertension appears to be not associated with adverse clinical outcome in patients with heart failure, in fact may be a protective factor for reduced heart failure related re-hospitalization in patients with reduced ejection fraction.
doi:10.1371/journal.pone.0114958
PMCID: PMC4260939  PMID: 25490405
17.  Uniportal video-assisted thoracoscopic left basilar segmentectomy 
Journal of Thoracic Disease  2014;6(12):1834-1836.
Uniportal video-assisted thoracoscopic surgery (VATS) has recently been introduced as an acceptable alternative to the traditional three-port VATS. Uniportal VATS lobectomy and segmentectomy actually gained increasing popularity. Until now there have been few reports about uniportal VATS basilar segmentectomy; we herein reported our experience with a patient who suffered from recurrent hemoptysis with 1-cm nodule in the basilar segment of the left lower lobe. A left basilar segmentectomy was performed through a single port. Operating time was 90 minutes, and postoperative course was uneventful. Pathology revealed cryptococcosis. Follow-up at 6 months after surgery demonstrated a normal chest computed tomographic (CT) scan and complete recovery without complications.
doi:10.3978/j.issn.2072-1439.2014.12.18
PMCID: PMC4283307  PMID: 25589984
Lobectomy; segmentectomy; wedge resection; postoperative complications; surgery/incisions/exposure/techniques; thoracoscopy/video-assisted thoracoscopic surgery (VATS)
18.  A Novel High Sensitivity Sensor for Remote Field Eddy Current Non-Destructive Testing Based on Orthogonal Magnetic Field 
Sensors (Basel, Switzerland)  2014;14(12):24098-24115.
Remote field eddy current is an effective non-destructive testing method for ferromagnetic tubular structures. In view of conventional sensors' disadvantages such as low signal-to-noise ratio and poor sensitivity to axial cracks, a novel high sensitivity sensor based on orthogonal magnetic field excitation is proposed. Firstly, through a three-dimensional finite element simulation, the remote field effect under orthogonal magnetic field excitation is determined, and an appropriate configuration which can generate an orthogonal magnetic field for a tubular structure is developed. Secondly, optimized selection of key parameters such as frequency, exciting currents and shielding modes is analyzed in detail, and different types of pick-up coils, including a new self-differential mode pick-up coil, are designed and analyzed. Lastly, the proposed sensor is verified experimentally by various types of defects manufactured on a section of a ferromagnetic tube. Experimental results show that the proposed novel sensor can largely improve the sensitivity of defect detection, especially for axial crack whose depth is less than 40% wall thickness, which are very difficult to detect and identify by conventional sensors. Another noteworthy advantage of the proposed sensor is that it has almost equal sensitivity to various types of defects, when a self-differential mode pick-up coil is adopted.
doi:10.3390/s141224098
PMCID: PMC4299100  PMID: 25615738
non-destructive testing; remote field eddy current; sensor; orthogonal magnetic field; finite element simulation
19.  Clinical significance of chromosome 1p/19q loss of heterozygosity and Sox17 expression in oligodendrogliomas 
Objective: To study chromosome 1p/19q loss of heterozygosity (LOH) and Sox17 protein expression in oligodendrogliomas and correlate this loss with clinicopathological features. Methods: This study included 100 cases of oligodendrogliomas at the First Affiliated Hospital of Xinjiang Medical University from 2003 to 2014. The cases included paraffin-embedded tissues from 50 low-grade oligodendrogliomas and 50 anaplastic oligodendrogliomas. Chromosome 1p/19q LOH was detected by fluorescence in situ hybridization (FISH) and Sox17 protein expression was analyzed by immunohistochemistry. Clinicopathological characteristics of the oligodendrogliomas were compared and prognosis analyzed using Cox regression and Kaplan-Meier analyses. Results: The LOH positivity rate of 1p/19q was 52% in 50 cases of low-grade oligodendrogliomas and 68% in 50 cases of anaplastic oligodendrogliomas (P = 0.102). The rates of Sox17 expression were significantly different in oligodendrogliomas (82%) and anaplastic oligodendrogliomas (62%, P = 0.026). Single factor analysis determined that 1p/19q LOH (P = 0.000), Sox17 protein expression (P = 0.000), location (P = 0.001), chemotherapy (P = 0.000), and radiation therapy (P = 0.001) were associated with oligodendroglioma patient prognosis. Cox multiple factors regression analysis determined that 1p/19q LOH and Sox17 expression were independent prognostic factors of oligodendrogliomas. Conclusion: In this study, oligodendroglioma patients with 1p/19q LOH and Sox17 protein expression had a better prognosis. Thus, analysis of 1p/19q LOH and Sox17 protein expression could significantly enhance diagnostic accuracy, guide treatment, and improve the prognosis.
PMCID: PMC4313992
Oligodendroglioma; 1p/19q LOH; Sox17; prognosis; clinical features
20.  Effect of Melilotus extract on lung injury via the upregulation of tumor necrosis factor-α-induced protein-8-like 2 in septic mice 
Molecular Medicine Reports  2014;11(3):1675-1684.
As a Traditional Chinese Medicine, Melilotus extracts have been reported to function as an anti-inflammatory agent, antioxidant and inhibitor of capillary permeability. The present study aimed to identify the mechanisms by which Melilotus interferes with inflammation-associated and oxidative stress pathways during sepsis. An animal model of cecal ligation-perforation (CLP)-induced sepsis was established. Two hours prior to surgery, animals in the treatment group were administered 25 mg/kg Melilotus extract tablets and subsequently every 8 h. At 24 h post-administration, pathological modifications in lung tissue and expression levels of tumor necrosis factor-α-induced protein-8-like 2 (TIPE2) expression, nuclear factor (NF)-κB, toll-like receptor 4 (TLR4), heme oxygenase-1 (HO-1), inhibitor of κB kinase (IκB), pro-inflammatory mediators (interleukin-6 and tumor necrosis factor-α), myeloperoxidase (MPO), malondialdehyde (MDA) and superoxide dismutase (SOD), were examined. The results showed that Melilotus extract had a marked effect on the pathological manifestation of lung tissue and lung inflammatory response, the upregulation of TIPE2, HO-1 and IκB expression, and the inhibition of TLR4 and NF-κB activities. In addition, following treatment with Melilotus extract, the model animals demonstrated decreased levels of MPO and MDA as well as increased levels of SOD. In conclusion, these results indicated that Melilotus extract may be a potential therapeutic agent for the treatment of CLP-induced lung injury, the mechanism of which proceeded via inflammation- and oxidation-associated pathways by increasing TIPE2 expression.
doi:10.3892/mmr.2014.2965
PMCID: PMC4270336  PMID: 25405912
tumour necrosis factor-α-induced protein-8-like 2; Melilotus extract; sepsis; mice; lung injury
21.  The safety and immunogenicity of a MF59-adjuvanted H5N1 prepandemic influenza vaccine in healthy adults primed with homologous or heterologous H5N1 vaccines: an observational study 
BMC Infectious Diseases  2014;14(1):587.
Background
World Health Organization (WHO) has recommended individuals with increased risk of contracting influenza A H5N1 infection to be immunized against the virus during the inter-pandemic period. Safety and immunogenicity of H5N1 vaccine among participants primed with homologous or heterologous H5N1 vaccines produced by diverse manufactures have not been reported.
Methods
Healthy individuals aged 20 to 60 years old were recruited and stratified into three groups: participants without priming (control group), participants primed with A/Indonesia/05/2005 vaccine, participants primed with A/Vietnam/1194/2004 vaccine and A/Indonesia/05/2005 vaccine. Enrolled participants received two doses of MF59-adjuvanted A/Vietnam/1194/2004 vaccine (study vaccine). Solicited reactions were recorded by vaccine recipients. Blood samples were obtained for hemagglutination inhibition test.
Results
A total of 131 participants were enrolled. No significant adverse events were recorded. Tenderness, fatigue and general muscle ache were the most common solicited reactions which alleviated within one week of immunization. Three weeks after two doses of the study vaccine, 63%, 68% and 88% were in seroprotective status in the control group, A/Indonesia/05/2005 primed group and A/Vietnam/1194/2004 and A/Indonesia/05/2005 primed group, respectively. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 showed high immune response after booster with one dose of the study vaccine.
Conclusion
The study vaccine did not cause severe adverse events. It elicited mostly mild to moderate reactions among participants. Participants primed with A/Vietnam/1194/2004 and A/Indonesia/05/2005 vaccine showed higher immune response than those without priming or primed with A/Indonesia/05/2005 vaccine. The report suggested those with an increased risk of influenza A H5N1 virus exposure may benefit from receiving influenza A H5N1 priming during the inter-pandemic period if the antigenicity of the pandemic influenza strain is similar to that of the priming strain.
doi:10.1186/s12879-014-0587-z
PMCID: PMC4236496  PMID: 25394941
A/Vietnam/1194/2004; A/Indonesia/05/2005; H5N1 vaccine; Priming
22.  Surgical algorithm for heterogeneous bilateral quadruple pulmonary nodules 
A 65-year old female with no history of smoking reported experiencing 6 months of tightness in the chest. Chest computed tomography showed two pulmonary nodules in the left upper lobe (one in S3 segment, the other in S4 segment), one nodule in the left lower lobe and a ground-glass opacity (GGO) in the right upper lobe. Synchronous bilateral thoracoscopic wedge resections of the lung were performed to investigate the nodules. Intraoperative frozen section pathology revealed that the two nodules in the left upper lobe were malignant, the nodule in the left lower lobe was a benign lesion and the GGO in the right upper lobe was an atypical adenomatous hyperplasia. As a result, a left upper lobectomy with lymph node dissection was performed. The final pathological diagnosis of the nodule in the left S3 segment was well differentiated adenocarcinoma (pT1bN0M0, IA), the nodule in the left S4 segment was moderately to poorly differentiated adenocarcinoma (pT1aN0M0, IA), the nodule in the left lower lobe was cryptococcal granuloma and the GGO in the right upper lobe was adenocarcinoma in situ. The patient is currently following a favourable course in her recovery. Here, we would like to share the surgical algorithm used for the treatment of heterogeneous bilateral quadruple pulmonary nodules.
doi:10.1093/icvts/ivt219
PMCID: PMC3805185  PMID: 24057862
Synchronous multiple primary lung cancers; Adenocarcinoma; Cryptococcosis; Surgery
23.  Nosocomial Neonatal Legionellosis Associated with Water in Infant Formula, Taiwan 
Emerging Infectious Diseases  2014;20(11):1921-1924.
We report 2 cases of neonatal Legionella infection associated with aspiration of contaminated water used in hospitals to make infant formula. The molecular profiles of Legionella strains isolated from samples from the infants and from water dispensers were indistinguishable. Our report highlights the need to consider nosocomial legionellosis among neonates who have respiratory symptoms.
doi:10.3201/eid2011.140542
PMCID: PMC4214307  PMID: 25340315
water; infant formula; Legionella; neonatal legionellosis; neonate; nosocomial infection; Taiwan; bacteria
24.  A pilot study of angiogenin in heart failure with preserved ejection fraction: a novel potential biomarker for diagnosis and prognosis? 
Characteristics of heart failure with preserved ejection fraction (HFPEF) have not yet been fully understood. The objectives of this pilot study are to detect protein expression profile in the sera of HFPEF patients, and to identify potential biomarkers for the disease. Five hundred and seven proteins were detected in the sera of healthy volunteers and patients with either HFPEF or hypertension using antibody microarrays (three in each group). The results showed that the serum concentrations of 17 proteins (e.g. angiogenin, activin A and artemin) differed considerably between HFPEF and non-HFPEF patients (hypertensive patients and healthy controls), while a protein expression pattern distinct from that in non-HFPEF patients was associated with HFPEF patients. The up-regulation of angiogenin in both HFPEF patients with LVEF ≥50% (P = 0.004) and a subset of HFPEF patients with LVEF = 41–49% (P < 0.001) was further validated in 16 HFPEF patients and 16 healthy controls. Meanwhile, angiogenin distinguished HFPEF patients from controls with a mean area under the receiver operating characteristic curve of 0.88 (P < 0.001) and a diagnostic cut-off point of 426 ng/ml. Moreover, the angiogenin levels in HFPEF patients were positively correlated with Lg(N-terminal pro-B-type natriuretic peptide, NT-proBNP) (P < 0.001). In addition, high angiogenin level (≥426 ng/ml) was a predictor of all-cause death within a short-term follow-up duration, but not in the longer term of 36 months. This pilot study indicates that the aforementioned 17 potential biomarkers, such as angiogenin, may hold great promise for both diagnosis and prognosis assessment of HFPEF.
doi:10.1111/jcmm.12344
PMCID: PMC4224553  PMID: 25124701
heart failure with preserved ejection fraction; angiogenin; biomarker; proteomics
25.  Gefitinib loaded folate decorated bovine serum albumin conjugated carboxymethyl-beta-cyclodextrin nanoparticles enhance drug delivery and attenuate autophagy in folate receptor-positive cancer cells 
Background
Active targeting endocytosis mediated by the specific interaction between folic acid and its receptor has been a hotspot in biological therapy of many human cancers. Various studies have demonstrated that folate and its conjugates could facilitate the chemotherapeutic drug delivery into folate receptor (FR)-positive tumor cells in vitro and in vivo. In order to utilize FA-FR binding specificity to achieve targeted delivery of drugs into tumor cells, we prepared Gefitinib loaded folate decorated bovine serum albumin conjugated carboxymethyl-β-cyclodextrin nanoparticles for enhancing drug delivery in cancer cells. On this context, the aim of our study was to develop a novel nano-delivery system for promoting tumor-targeting drug delivery in folate receptor-positive Hela cells.
Results
We prepared folic acid (FA)-decorated bovine serum albumin (BSA) conjugated carboxymethyl-β-cyclodextrin (CM-β-CD) nanoparticles (FA-BSA-CM-β-CD NPs) capable of entrapping a hydrophobic Gefitinib. It was observed that nanoparticles are monodisperse and spherical nanospheres with an average diameter of 90.2 nm and negative surface charge of −18.6 mV. FA-BSA-CM-β-CD NPs could greatly facilitate Gefitinib uptake and enhance the toxicity to folate receptor-positive Hela cells. Under the reaction between FA and FR, Gefitinib loaded FA-BSA-CM-β-CD NPs induced apoptosis of Hela cells through elevating the expression of caspase-3 and inhibited autophagy through decreasing the expressing of LC3. It also confirmed that clathrin-mediated endocytosis and macropinocytosis exerted great influence on the internalization of both NPs.
Conclusions
These results demonstrated that FA may be an effective targeting molecule and FA-BSA-CM-β-CD NPs provided a new strategy for the treatment of human cancer cells which over-expressed folate receptors.
doi:10.1186/s12951-014-0043-7
PMCID: PMC4219096  PMID: 25358257
Folate; Folate receptors; Carboxymethyl-β-Cyclodextrin; Bovine serum albumin; Nanoparticles; Gefitinib

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