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1.  Increase in circulating Foxp3+CD4+CD25high regulatory T cells in nasopharyngeal carcinoma patients 
British Journal of Cancer  2007;96(4):617-622.
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus-associated disease with high prevalence in Southern Chinese. Using multiparametric flow cytometry, we identified significant expansions of circulating naïve and memory CD4+CD25high T cells in 56 NPC patients compared with healthy age- and sex-matched controls. These were regulatory T cells (Treg), as they overexpressed Foxp3 and GITR, and demonstrated enhanced suppressive activities against autologous CD4+CD25− T-cell proliferation in functional studies on five patients. Abundant intraepithelial infiltrations of Treg with very high levels of Foxp3 expression and absence of CCR7 expression were also detected in five primary tumours. Our current study is the first to demonstrate an expansion of functional Treg in the circulation of NPC patients and the presence of infiltrating Treg in the tumour microenvironment. As Treg may play an important role in suppressing antitumour immunity, our findings provide critical insights for clinical management of NPC.
PMCID: PMC2360054  PMID: 17262084
nasopharyngeal carcinoma; Treg; antitumour immunity; tumour infiltrating lymphocytes
2.  Effects of Dietary Fermented Chlorella vulgaris (CBT®) on Growth Performance, Relative Organ Weights, Cecal Microflora, Tibia Bone Characteristics, and Meat Qualities in Pekin Ducks 
Fermented Chlorella vulgaris was examined for its effects on growth performance, cecal microflora, tibia bone strength, and meat qualities in commercial Pekin ducks. A total of three hundred, day-old male Pekin ducks were divided into three groups with five replicates (n = 20 ducklings per replicate) and offered diets supplemented with commercial fermented C. vulgaris (CBT®) at the level of 0, 1,000 or 2,000 mg/kg, respectively for 6 wks. The final body weight was linearly (p = 0.001) increased as the addition of fermented C. vulgaris into diets increased. Similarly, dietary C. vulgaris linearly increased body weight gain (p = 0.001) and feed intake (p = 0.001) especially at the later days of the feeding trial. However, there was no C. vulgaris effect on feed efficiency. Relative weights of liver were significantly lowered by dietary fermented C. vulgaris (linear effect at p = 0.044). Dietary fermented C. vulgaris did not affect total microbes, lactic acid bacteria, and coliforms in cecal contents. Finally, meat quality parameters such as meat color (i.e., yellowness), shear force, pH, or water holding capacity were altered by adding fermented C. vulgaris into the diet. In our knowledge, this is the first report to show that dietary fermented C. vulgaris enhanced meat qualities of duck meats. In conclusion, our study indicates that dietary fermented C. vulgaris exerted benefits on productivity and can be employed as a novel, nutrition-based strategy to produce value-added duck meats.
PMCID: PMC4283193  PMID: 25557680
Fermented Chlorella vulgaris; Meat Quality; Performance; Pekin Duck
3.  Evaluation of Dietary Multiple Enzyme Preparation (Natuzyme) in Laying Hens 
The current experiment was designed to evaluate the efficacy of adding the multi-enzyme mixture (Natuzyme) into layers’ diets with different levels of energy and available phosphorus in relation to laying performance, egg qualities, blood cholesterol level, microflora and intestinal viscosity. Two hundred and fifty 43-wk-old Hy-Line commercial layers were divided into five groups with five replicates per group (10 birds per replicate) and fed one of five experimental diets. A corn and soybean meal-based control diet was formulated and used as a control diet. Two experimental control diets were formulated to reduce energy and crude protein contents (rE) or energy, crude protein and phosphorus contents (rEP). In addition, Natuzyme was added into either rE (rE-Natu500) or rEP (rEP-Natu500) diet to reach a concentration of 500 mg per kg of diet. The experiment lasted 8 weeks. There were no significant differences in feed intake, egg production, egg weight, egg qualities such as eggshell color or Haugh unit, total cholesterol, relative organ weights and cecal microflora profiles between any dietary treatments. Natu500 supplementation into the rE diet, but not rEP diet significantly increased egg mass and eggshell qualities such as strength and thickness, but it decreased cecal ammonia concentration and intestinal viscosity in laying hens. In conclusion, the present study shows that adding multiple enzyme preparation could improve performance of laying hens fed energy and protein restricted diets.
PMCID: PMC4213687  PMID: 25358369
Multiple Enzyme Preparation; Egg Qualities; Performance; Intestinal Viscosity
4.  ZNF313 is a novel cell cycle activator with an E3 ligase activity inhibiting cellular senescence by destabilizing p21WAF1 
Cell Death and Differentiation  2013;20(8):1055-1067.
ZNF313 encoding a zinc-binding protein is located at chromosome 20q13.13, which exhibits a frequent genomic amplification in multiple human cancers. However, the biological function of ZNF313 remains largely undefined. Here we report that ZNF313 is an ubiquitin E3 ligase that has a critical role in the regulation of cell cycle progression, differentiation and senescence. In this study, ZNF313 is initially identified as a XIAP-associated factor 1 (XAF1)-interacting protein, which upregulates the stability and proapoptotic effect of XAF1. Intriguingly, we found that ZNF313 activates cell cycle progression and suppresses cellular senescence through the RING domain-mediated degradation of p21WAF1. ZNF313 ubiquitinates p21WAF1 and also destabilizes p27KIP1 and p57KIP2, three members of the CDK-interacting protein (CIP)/kinase inhibitor protein (KIP) family of cyclin-dependent kinase inhibitors, whereas it does not affect the stability of the inhibitor of CDK (INK4) family members, such as p16INK4A and p15INK4B. ZNF313 expression is tightly controlled during the cell cycle and its elevation at the late G1 phase is crucial for the G1-to-S phase transition. ZNF313 is induced by mitogenic growth factors and its blockade profoundly delays cell cycle progression and accelerates p21WAF1-mediated senescence. Both replicative and stress-induced senescence are accompanied with ZNF313 reduction. ZNF313 is downregulated during cellular differentiation process in vitro and in vivo, while it is commonly upregulated in many types of cancer cells. ZNF313 shows both the nuclear and cytoplasmic localization in epithelial cells of normal tissues, but exhibits an intense cytoplasmic distribution in carcinoma cells of tumor tissues. Collectively, ZNF313 is a novel E3 ligase for p21WAF1, whose alteration might be implicated in the pathogenesis of several human diseases, including cancers.
PMCID: PMC3705597  PMID: 23645206
XAF1; CDK inhibitor; ubiquitin ligase; apoptosis; differentiation
5.  Relation between cognitive dysfunction and reduced vital capacity in amyotrophic lateral sclerosis 
Many patients with amyotrophic lateral sclerosis (ALS) with cognitive impairment have fronto‐temporal dysfunction. Whereas in some patients with ALS the fronto‐temporal dysfunction is undoubtedly due to the degenerative process associated with the disease, in others dysfunction cannot be accounted for by an irreversible degenerative process alone, as it also appears to involve a reversible process. We hypothesised that reduced vital capacity can be a key contributor to the fronto‐temporal dysfunction observed in patients with ALS.
To investigate the association between fronto‐temporal dysfunction and reduced vital capacity in ALS.
16 consecutive patients who conformed to a diagnosis of definite or probable ALS (El escorial criteria) were grouped by vital capacity, and their clinical characteristics and cognitive functions, including disease duration, attention, executive function and memory, were measured.
Patients with a reduced vital capacity performed significantly poorer in memory retention (p = 0.028), retrieval efficacy (p = 0.003), spoken verbal fluency (p = 0.03) and spoken verbal fluency indexes (p = 0.016) than those with a normal vital capacity.
The fronto‐temporal dysfunction in ALS might be attributable to potentially reversible secondary effects associated with reduced vital capacity, as well as to the primary degenerative process.
PMCID: PMC2095584  PMID: 17557798
7.  Taiwan Aneurysm Registry: Multivariate Analysis of Two-Month, One-Year, and Two-Year Outcomes after Endovascular and Microsurgical Treatment of Ruptured Aneurysms 
Interventional Neuroradiology  2013;19(1):35-42.
We compared the outcomes of endovascular coiling with microsurgical clipping of aneurysms in a Taiwanese population.
In an ambi-directional cohort design, patient baseline characteristics and clinical course after treatment for ruptured subarachnoid aneurysm were abstracted from medical records from three hospitals to examine and compare differences in post-operative outcomes between those treated with endovascular coiling and those treated with microsurgical clipping. Outcomes were measured, using the modified Rankin scale, two months, one year and two years postoperatively.
Of the 642 patients enrolled in the study, 281 underwent endovascular treatment and 361 underwent neurosurgery. The demographics and baseline characteristics of two groups were comparable except for a larger maximum target aneurysm lumen size (p=0.02) in the endovascular group. Patients who underwent the endovascular procedure tended to have a better quality of life than those who had neurosurgery (p<0.01). When the severity of symptom data was pooled into two groups (Rankin values 0-2 and 3-6) a statistically significant relationship was found between the severity of symptoms and age, Hunt and Hess grade, number of target aneurysms detected, and log of maximum target aneurysm lumen size (all p≤0.01). After controlling for potential confounding factors and using the lumped Rankin outcome data, no significant difference in outcome was found between the two procedures at either time point.
Our study indicated that endovascular coiling achieves results comparable to surgical clipping for patients with ruptured subarachnoid aneurysms in a Taiwanese population.
PMCID: PMC3601615  PMID: 23472721
aneurysm, hemorrhage, microsurgery, endovascular coiling, size, outcome, quality of life
8.  Effect of Bacillus Subtilis-based Direct-fed Microbials on Immune Status in Broiler Chickens Raised on Fresh or Used Litter 
Type of dietary direct-fed microbials (DFMs) or poultry litter could directly influence the composition of gut microbiota. Gut microbiota plays an important role in shaping the developing immune system and maintaining the homeostasis of the mature immune system in mammal and chickens. The present study was carried out to investigate the interaction among litter, DFMs and immunity in broiler chickens exposed to a field-simulated environment. Immune status of broiler chickens was assessed by serum antibodies against Eimeria spp. and Clostridium spp. and intestinal cytokine mRNA expression. The current experimental design had a 3 ×2 factorial arrangement of treatments with three types of litter, i.e., fresh litter or used litter that was obtained from a farm with no disease outbreak (used litter) or a farm with history of a gangrenous dermatitis outbreak (GD litter), and two dietary treatments with or without DFMs. It was found that either DFM addition or type of litter significantly affected anticoccidial antibody levels of broiler chickens at d 42. In general, dietary DFMs increased the anticoccidial antibodies in the fresh-litter raised chickens, but lowered the levels in the GD-litter raised chickens. Serum antibodies against Clostridium perfringens α-toxin were significantly (p<0.05) higher in chickens raised on GD litter compared with those raised on fresh litter. Cytokine mRNA expression was significantly (p<0.05) altered by either the type of litter or DFMs. Of interest, dietary DFMs lowered interferon-γ, interleukin 1beta, and CXCLi2 cytokine mRNA expression in chickens raised on fresh litter but increased them in GD-litter raised chickens. In conclusion, dietary DFMs modulate various immune parameters of broiler chickens, but the DFM-mediated effects were dependent upon the type of litter on which chickens were raised.
PMCID: PMC4093815  PMID: 25049746
Direct-fed Microbials; Cytokines; Broiler Chickens; Used Litter; Immunity
9.  Effects of Serial Passage on the Characteristics and Chondrogenic Differentiation of Canine Umbilical Cord Matrix Derived Mesenchymal Stem Cells 
Mesenchymal stem cells (MSCs) are often known to have a therapeutic potential in the cell-mediated repair for fatal or incurable diseases. In this study, canine umbilical cord MSCs (cUC-MSCs) were isolated from umbilical cord matrix (n = 3) and subjected to proliferative culture for 5 consecutive passages. The cells at each passage were characterized for multipotent MSC properties such as proliferation kinetics, expression patterns of MSC surface markers and self-renewal associated markers, and chondrogenic differentiation. In results, the proliferation of the cells as determined by the cumulative population doubling level was observed at its peak on passage 3 and stopped after passage 5, whereas cell doubling time dramatically increased after passage 4. Expression of MSC surface markers (CD44, CD54, CD61, CD80, CD90 and Flk-1), molecule (HMGA2) and pluripotent markers (sox2, nanog) associated with self-renewal was negatively correlated with the number of passages. However, MSC surface marker (CD105) and pluripotent marker (Oct3/4) decreased with increasing the number of subpassage. cUC-MSCs at passage 1 to 5 underwent chondrogenesis under specific culture conditions, but percentage of chondrogenic differentiation decreased with increasing the number of subpassage. Collectively, the present study suggested that sequential subpassage could affect multipotent properties of cUC-MSCs and needs to be addressed before clinical applications.
PMCID: PMC4093376  PMID: 25049827
Mesenchymal Stem Cell; Umbilical Cord Matrix; Canine; Multipotent; Differentiation
10.  Plasma haemostatic markers, endothelial function and ambulatory blood pressure changes with home versus hospital cardiac rehabilitation: the Birmingham Rehabilitation Uptake Maximisation Study 
Heart  2006;92(12):1732-1738.
Cardiac rehabilitation is an accepted therapeutic intervention in patients after myocardial infarction or coronary revascularisation. The effects of cardiac rehabilitation programmes, whether home based or hospital based, on haemostatic indices (as reflected by fibrinogen, plasma viscosity, fibrin D‐dimer (an index of thrombogenesis), von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble P‐selectin (an index of platelet activation)), vasomotor function (using flow‐mediated dilatation (FMD)) and ambulatory blood pressure (ABP) in patients with coronary heart disease are unknown.
81 patients (66 men, mean (SD) 59 (11) years) after myocardial infarction or coronary revascularisation were randomised to comprehensive hospital‐based (n = 40) or home‐based (n = 41) cardiac rehabilitation. Plasma levels of vWf, D‐dimer, fibrinogen, soluble P‐selectin and plasma viscosity, as well as FMD and 24‐h ABP, were measured at baseline and after 3 months of cardiac rehabilitation.
In patients who completed cardiac rehabilitation, levels of vWf, fibrinogen and D‐dimer were significantly lower and FMD improved (all p⩽0.001), whereas levels were unchanged in controls. Significant reductions were also observed in 24‐h mean systolic blood pressure, diastolic blood pressure and mean aortic pressure after completion of cardiac rehabilitation (all p<0.05). No significant differences were observed between the hospital‐based and home‐based cardiac rehabilitation programmes on these indices.
Cardiac rehabilitation improves haemostasis, endothelial function and ABP in patients with coronary heart disease, with no significant differences between home‐based and hospital‐based cardiac rehabilitation programmes. These effects may contribute to the beneficial effects of cardiac rehabilitation programmes on CV outcomes.
PMCID: PMC1861270  PMID: 16807272
11.  Calpain system protein expression in basal-like and triple-negative invasive breast cancer 
Annals of Oncology  2012;23(9):2289-2296.
Basal-like and triple-negative breast tumours encompass an important clinical subgroup and biomarkers that can prognostically stratify these patients are required.
Materials and methods
We investigated two breast cancer tissue microarrays for the expression of calpain-1, calpain-2 and calpastatin using immunohistochemistry. The first microarray was comprised of invasive tumours from 1371 unselected patients, and the verification microarray was comprised of invasive tumours from 387 oestrogen receptor (ER)-negative patients.
The calpain system contains a number of proteases and an endogenous inhibitor, calpastatin. Calpain activity is implicated in important cellular processes including cytoskeletal remodelling, apoptosis and survival. Our results show that the expression of calpastatin and calpain-1 are significantly associated with various clinicopathological criteria including tumour grade and ER expression. High expression of calpain-2 in basal-like or triple-negative disease was associated with adverse breast cancer-specific survival (P = 0.003 and <0.001, respectively) and was verified in an independent cohort of patients. Interestingly, those patients with basal-like or triple-negative disease with a low level of calpain-2 expression had similar breast cancer-specific survival to non-basal- or receptor- (oestrogen, progesterone or human epidermal growth factor receptor 2 (HER2)) positive disease.
Expression of the large catalytic subunit of m-calpain (calpain-2) is significantly associated with clinical outcome of patients with triple-negative and basal-like disease.
PMCID: PMC3425372  PMID: 22745213
basal; breast cancer; calpain; calpastatin; triple negative
12.  The Effects of Betel-Nut Chewing on the Buccal Mucosa: A Histological Study 
British Journal of Cancer  1970;24(3):433-441.
Sixty-two “leukoplakias” from the cheeks of betel-nut chewers in West Malaysia were studied histologically. Ten biopsies were from non-tobacco betel-nut chewers. An amorphous von Kossa positive layer was seen on the keratin surface in 42 specimens. Tobacco did not appear essential for its formation, and it appeared to be significantly associated with parakeratosis. Its possible significance as a cuticle-like layer prolonging contact between carcinogens and the mucosa is discussed.
Parakeratosis appeared to be the most common form of cornification seen, and the mitotic activity in parakeratinized leukoplakias appeared to be significantly greater than orthokeratinized leukoplakias.
Comparison with studies on other population samples using different quids suggested that severe histological changes were more likely to be seen when tobacoo-containing quids were chewed as compared to non-tobacco-containing quids.
An attempt to correlate the histological changes seen with the clinical habit in leukoplakias from chewers using tobacco-containing quids suggested that epithelial atrophy appeared to be significantly related to the duration of the habit but not to the “intensity” of the habit.
PMCID: PMC2008616  PMID: 5475751
13.  Effect of Dietary Antimicrobials on Immune Status in Broiler Chickens 
This study evaluated the effects of dietary anticoccidial drugs plus antibiotic growth promoters (AGPs) on parameters of immunity in commercial broiler chickens. Day-old chicks were raised on used litter from a farm with endemic gangrenous dermatitis to simulate natural pathogen exposure and provided with diets containing decoquinate (DECX) or monensin (COBN) as anticoccidials plus bacitracin methylene disalicylate and roxarsone as AGPs. As a negative control, the chickens were fed with a non-supplemented diet. Immune parameters examined were concanavalin A (ConA)-stimulated spleen cell proliferation, intestine intraepithelial lymphocyte (IEL) and spleen cell subpopulations, and cytokine/chemokine mRNA levels in IELs and spleen cells. ConA-induced proliferation was decreased at 14 d post-hatch in DECX-treated chickens, and increased at 25 and 43 d in COBN-treated animals, compared with untreated controls. In DECX-treated birds, increased percentages of MHC2+ and CD4+ IELS were detected at 14 d, but decreased percentages of these cells were seen at 43 d, compared with untreated controls, while increased TCR2+ IELs were evident at the latter time. Dietary COBN was associated with decreased fractions of MHC2+ and CD4+ IELs and reduced percentages of MHC2+, BU1+, and TCR1+ spleen cells compared with controls. The levels of transcripts for interleukin-4 (IL-4), IL-6, IL-17F, IL-13, CXCLi2, interferon-γ (IFN-γ), and transforming growth factorβ4 were elevated in IELs, and those for IL-13, IL-17D, CXCLi2, and IFN-γ were increased in spleen cells, of DECX- and/or COBN-treated chickens compared with untreated controls. By contrast, IL-2 and IL-12 mRNAs in IELs, and IL-4, IL-12, and IL-17F transcripts in spleen cells, were decreased in DECX- and/or COBN-treated chickens compared with controls. These results suggest that DECX or COBN, in combination with bacitracin and roxarsone, modulate the development of the chicken post-hatch immune system.
PMCID: PMC4092964  PMID: 25049577
Decoquinate; Monensin; Bacitracin; Roxarsone; Immunity; Broiler
14.  The neurosurvival factor Humanin inhibits beta cell apoptosis via Stat3 activation and delays and ameliorates diabetes in NOD mice 
Pancreatic beta cell apoptosis is important in the pathogenesis and potential treatment of Type 1 diabetes. We investigated whether Humanin, a recently described survival factor for neurons, could improve the survival of beta cells and delay or treat diabetes in the NOD model. Humanin reduced apoptosis induced by serum starvation in NIT-1 cells and decreased apoptosis induced by cytokine treatment. Humanin induced Stat3 and ERK phosphorylation over a 24 hour time course. Specific inhibition of Stat3 resulted in nullifying the protective effect of Humanin. Humanin normalized glucose tolerance in diabetic NOD mice treated for 6-weeks and their pancreata revealed decreased lymphocyte infiltration and severity. In addition, Humanin delayed/prevented the onset of diabetes in NOD mice treated for 20 weeks. In summary, Humanin treatment decreases cytokine-induced apoptosis in beta cells in vitro and improved glucose tolerance and onset of diabetes in NOD mice in vivo. This indicates that Humanin may be useful for islet protection and survival in a spectrum of diabetes-related therapeutics.
PMCID: PMC2932671  PMID: 19800083
Humanin; beta cell; survival; apoptosis; NOD mouse
15.  Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese 
Genes and Immunity  2009;10(5):414-420.
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 × 10−9; TNFSF4, rs844648, OR=1.22, P=2.47 × 10−3; TNFSF4, rs2205960, OR=1.30, P=2.41 × 10−4). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 × 10−3). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 × 10−8, respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 × 10−3), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.
PMCID: PMC2834352  PMID: 19357697
SLE; BANK1; TNFSF4; Chinese; genetic association
16.  Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer 
British Journal of Cancer  2009;100(2):298-304.
This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m−2 at week 1 and 250 mg m−2 weekly thereafter until disease progression. Oxaliplatin (100 mg m−2) and leucovorin (100 mg m−2) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m−2) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1–65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5–6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-α levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.
PMCID: PMC2634707  PMID: 19127259
Cetuximab; chemotherapy; epidermal growth factor; epidermal growth factor receptor; gastric cancer; transforming growth factor-α
18.  The Effect of Betel-nut Chewing on the Buccal Mucosa of 296 Indians and Malays in West Malaysia. A Clinical Study 
British Journal of Cancer  1970;24(3):427-432.
Changes in the buccal mucosa of 296 Indian and Malay betel-nut chewers in Perak, West Malaysia, were studied clinically. 167 out of 212 Indian subjects incorporated tobacco in their quids, while 45 out of 84 Malay subjects incorporated. “Gambir”. The Indians appeared to show a higher proportion of mucosal changes, particularly when tobacco was used. “Gambir” did not appear to be potent in the production of mucosal changes. Comparison with studies in other parts of the world suggested comparable findings with respect to both tobacco and non-tobacco chewing samples, and there would appear to be some evidence that tobacco-containing quids are likely to produce a higher proportion of mucosal changes as compared to non-tobacco-containing quids. An attempt to demonstrate a dose-effect relationship by dividing the subjects into “slight” and “heavy” chewers did not yield significant differences between these two categories in each of the groups.
PMCID: PMC2008618  PMID: 5475750
19.  Incremental shuttle walking is associated with activation of haemostatic and haemorheological markers in patients with coronary artery disease: the Birmingham rehabilitation uptake maximisation study (BRUM) 
Heart  2005;91(11):1413-1417.
Objective: To test the hypothesis that an incremental shuttle walk test (ISWT) affects plasma indices of endothelial damage and dysfunction (von Willebrand factor (vWf)), platelet activation (soluble P-selectin), thrombogenesis (D-dimer), fibrinogen, and plasma viscosity more adversely in coronary artery disease (CAD) than in health. ISWT is a standardised walking test that provokes maximal performance and correlates strongly with maximum oxygen uptake.
Methods: Research indices were measured before a practice ISWT and immediately after the second ISWT in 53 patients with CAD (48 men, mean (SD) age 59 (10) years) and in 19 matched healthy controls (16 men, 61 (10) years). Data were analysed before and after ISWT.
Results: Despite no significant difference in total distance walked between patients and controls, vWf (162 (45) before v 170 (48) UI/dl after) and fibrinogen (2.9 (0.7) v 3.1 (0.7) g/l) concentrations, plasma viscosity (1.63 (0.12) v 1.71 (0.14) mPa·s), and D-dimer (0.20 (interquartile range 0.10–0.30) v 0.21 (0.12–0.31 mg/l; all p < 0.05), but not soluble P-selectin, were significantly increased after ISWT in patients with CAD, even after correction for plasma volume change. Only fibrinogen (2.5 (0.7) v 2.7 (0.7 g/l) and plasma viscosity (1.60 (0.08) v 1.64 (0.08) mPa·s; both p < 0.01) increased among controls. The increment of fibrinogen was significantly higher in patients than in controls (p  =  0.035) and correlated with total walking distance (r  =  0.46, p < 0.001) and peak heart rate (r  =  0.28, p  =  0.02). The increment of plasma viscosity rise also significantly correlated with total distance walked (r  =  0.66, p < 0.001).
Conclusions: ISWT in patients with CAD appears to increase fibrinogen, vWf, and D-dimer compared with healthy controls.
PMCID: PMC1769168  PMID: 15774609
incremental shuttle walk test; haemostatic markers; fibrinogen; soluble P-selectin; von Willebrand factor; coronary artery disease; exercise
20.  Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease 
Clinical Endocrinology  2008;68(4):555-560.
Retinol-binding protein 4 (RBP4) is a recently identified adipokine that is elevated in the serum in several insulin-resistant states. We investigated the relationship between non-alcoholic fatty liver disease (NAFLD) and serum RBP4 in nondiabetic adults.
One hundred and fifty-nine nondiabetic, non-alcoholic subjects (95 males and 64 females) participated in this study. Division of subjects into a NAFLD group (n = 73; 45 males and 28 females) or a normal group (n = 86; 50 males and 36 females) was based on the presence of fatty liver disease determined by sonography.
Serum RBP4 levels in the NAFLD group were significantly higher than those in the normal group (62·8 ± 16·0 mg/l vs. 51·7 ± 14·6 mg/l, P < 0·0001). Multiple logistic regression analysis revealed that the RBP4 level was an independent factor associated with NAFLD (P = 0·0042). In addition, serum RBP4 levels were positively correlated with serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and γ-glutamyltranspeptidase (GGT) levels. The significant association between serum RBP4 and GGT levels remained even after adjusting for age, gender, body mass index, the homeostasis model of assessment (HOMA) value and the presence of NAFLD (r = 0·3097, P = 0·0002).
Serum RBP4 levels are significantly associated with NAFLD and liver enzymes.
PMCID: PMC2344088  PMID: 17941908
21.  The melanocyte inducing factor MITF is stably expressed in cell lines from human clear cell sarcoma 
British Journal of Cancer  2003;89(6):1072-1078.
PMCID: PMC2376962  PMID: 12966428
EWS/ATF1; MITF; melanocytes; clear cell sarcoma
22.  Characterization of pncA mutations of pyrazinamide-resistant Mycobacterium tuberculosis in Korea. 
Journal of Korean Medical Science  2001;16(5):537-543.
Pyrazinamide (PZA) is one of the most important drugs for the treatment of Mycobacterium tuberculosis infection. However, the increasing frequency of PZA-resistant strains limits its effectiveness. In Korea, most PZA-resistant strains also exhibit both isoniazid and rifampin resistance making it essential to identify these resistant strains accurately and rapidly for effective treatment of mycobacterial infection. In this study, the characteristics and frequency of mutations of the pncA gene encoding pyrazinamidase were investigated in PZA-resistant clinical isolates from Korea. Automated DNA sequencing was used to evaluate the usefulness of DNA-based detection of PZA resistance. Among 95 PZA-resistant clinical isolates, 92 (97%) exhibited mutations potentially affecting either the production or the activity of the enzyme. Mutations were found throughout the pncA gene including the upstream region. Single nucleotide replacement appeared to be the major mutational event (69/92), although multiple substitutions as well as insertion and deletion of nucleotides were also identified. The high frequency of pncA mutations observed in this study supports the usefulness of DNA-based detection of PZA-resistant M. tuberculosis. Having verified the scattered and diverse mutational characteristics of the pncA gene, automated DNA sequencing seems to be the best strategy for rapid detection of PZA-resistant M. tuberculosis.
PMCID: PMC3057581  PMID: 11641519
23.  Hypodipsic hypernatremia with intact AVP response to non-osmotic stimuli induced by hypothalamic tumor: a case report. 
Journal of Korean Medical Science  2001;16(5):677-682.
Anatomical lesions of hypothalamic area associated with hypodipsic hypernatremia have been reported only rarely. We report here a case of hypodipsic hypernatremia induced by a hypothalamic lesion. A 25-yr-old man, who had been treated with radiation for hypothalamic tumor 5-yr before, was admitted for evaluation of hypernatremia and hypokalemia. He never felt thirst despite the elevated plasma osmolality and usually refused to drink intentionally. Plasma arginine vasopressin (AVP) level was normal despite the severe hypernatremic hyperosmolar state and urine was not properly concentrated, while AVP secretion was rapidly induced by water deprivation and urine osmolality also progressively increased to the near maximum concentration range. All of these findings were consistent with an isolated defect in osmoregulation of thirst, which was considered as the cause of chronic hypernatremia in the patient without an absolute deficiency in AVP secretion. Hypokalemia could be induced by activation of the renin-angiotensin-aldosterone system as a result of volume depletion. However, inappropriately low values of plasma aldosterone levels despite high plasma renin activity could not induce symptomatic hypokalemia and metabolic alkalosis. The relatively low serum aldosterone levels compared with high plasma renin activity might result from hypernatremia. Hypernatremia and hypokalemia were gradually corrected by intentional water intake only.
PMCID: PMC3057589  PMID: 11641544
24.  Serologic heterogeneity of HLA-A24 correlates with allelic types in the Korean population. 
Journal of Korean Medical Science  2000;15(6):623-626.
HLA-A24 is the second most frequently expressed HLA-A type in Koreans (GF 22.8%). Four different serologic reaction patterns were observed in Korean A24 positive samples using a commercial serologic typing kit. To clarify the nature of serologic heterogeneity, thirteen A24 positive DNA samples representing the four different serologic reaction patterns were subjected to DNA sequencing analysis of the amplified HLA-A genes from each sample. Four A*24 alleles (A*2402101, A*2403, A*2408, and A*2421) were associated with the four unique serologic reaction patterns. During this study, a novel allele, A*2421, was characterized. The new sequence is similar to A*2402101, differing at codon 127 (AAA-->AAC; K-->N). By comparing putative amino acid sequences and serologic reaction patterns of A*24 allelic products identified in this study, several crucial sites for A24- and A9-specific antibody binding were predicted: 127K for A24 antibody binding, and 62E-65G and 166D-167G for A9 antibody binding. This information will be helpful for accurately assigning HLA-A24 types by serology and for predicting serologic types of new alleles.
PMCID: PMC3054702  PMID: 11194186
25.  Deletion of SMN and NAIP genes in Korean patients with spinal muscular atrophy. 
Childhood-onset proximal spinal muscular atrophies (SMAs) are an autosomal recessive, clinically heterogeneous group of neuronopathies characterized by selective degeneration of anterior horn cells. The causative genes to be reported are survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes. The deletion of telomeric copy of SMN (SMN(T)) gene was observed in over 95% of SMAs. The deletion rate of NAIP gene is 20-50% according to disease severity. The objective of this article is to genetically characterize the childhood-onset spinal muscular atrophy in Koreans. Five Korean families (14 constituents containing 5 probands) with SMA were included in this study. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the deletion analysis of SMN(T). Multiplex PCR method was used for NAIP analysis. Four probands showed deletion of SMNT gene. Deletion of SMN(C) (centromeric SMN) gene was found in one proband who did not show the deletion of SMN(T) gene and in the father of one proband who showed the deletion of SMN(T) gene. The deletion of NAIP gene was not found among all the studied individuals. The extent of deletion in Koreans was smaller than that in other studied population. PCR-RFLP deletion analysis can be applied to diagnose SMA and make a prenatal diagnosis.
PMCID: PMC3054589  PMID: 10719817

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