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1.  Increased release of von Willebrand factor antigen from endothelial cells by anti-DNA autoantibodies. 
OBJECTIVE--To determine whether antibodies to double stranded DNA (anti-dsDNA) have a pathogenic role in systemic lupus erythematosus (SLE). METHODS--IgG was purified from 17 patients with SLE (median anti-dsDNA titre 1212 IU/ml) and nine healthy controls (median titre 40 IU/ml). Anti-dsDNA depleted polyclonal IgG (median anti-dsDNA titre 17 IU/ml) was also prepared from sera of the 17 patients by affinity chromatography on a DNA cellulose column. Binding to antiendothelial cell antibodies (AECA) and expression of von Willebrand factor (VWF) antigen by cultured human umbilical vein endothelial cells (HUVECs) were studied by flow cytometry. RESULTS--The percentage of HUVECs binding to AECA or expressing VWF was greater for cells incubated with IgG from patients with SLE than for cells incubated with control IgG, though values did not reach statistical significance; nevertheless, HUVECs incubated with IgG from patients expressed a greater mean fluorescence intensity with AECA (p = 0.0001) and greater VWF expression (p = 0.019). Both the fluorescence intensity and percentage of HUVECs binding to AECA or expressing VWF were significantly greater in HUVEC incubated with IgG containing anti-dsDNA than in those incubated with anti-dsDNA depleted IgG. The concentration of VWF in the supernatant was significantly increased in HUVECs incubated with IgG containing anti-dsDNA compared with control IgG or anti-dsDNA depleted IgG. Pretreatment of HUVECs with native DNA before incubation with IgG from lupus patients did not increase binding to AECA, or expression or release of VWF. CONCLUSIONS--Our study provides in vitro evidence that antibodies to DNA have a pathogenic role in the induction of inflammatory injury of the vascular endothelium in SLE.
PMCID: PMC1010083  PMID: 8572736
2.  Celecoxib increases miR-222 while deterring aromatase-expressing breast tumor growth in mice 
BMC Cancer  2014;14:426.
Background
Breast cancer is one of the most deadly diseases in women. Inhibiting the synthesis of estrogen is effective in treating patients with estrogen-responsive breast cancer. Previous studies have demonstrated that use of cyclooxygenase (COX) inhibitors is associated with reduced breast cancer risk.
Methods
In the present study, we employed an established mouse model for postmenopausal breast cancer to evaluate the potential mechanisms of the COX-2 inhibitor celecoxib. Aromatase-expressing MCF-7 cells were transplanted into ovariectomized athymic mice. The animals were given celecoxib at 1500 ppm or aspirin at 200 ppm by oral administration with androstenedione injection.
Results
Our results showed that both COX inhibitors could suppress the cancer xenograft growth without changing the plasma estrogen level. Protein expression of ERα, COX-2, Cyclin A, and Bcl-xL were reduced in celecoxib-treated tumor samples, whereas only Bcl-xL expression was suppressed in those treated with aspirin. Among the breast cancer-related miRNAs, miR-222 expression was elevated in samples treated with celecoxib. Further studies in culture cells verified that the increase in miR-222 expression might contribute to ERα downregulation but not the growth deterrence of cells.
Conclusion
Overall, this study suggested that both celecoxib and aspirin could prevent breast cancer growth by regulating proteins in the cell cycle and apoptosis without blocking estrogen synthesis. Besides, celecoxib might affect miR expression in an undesirable fashion.
doi:10.1186/1471-2407-14-426
PMCID: PMC4070644  PMID: 24923427
Celecoxib; Aspirin; Aromatase; miRNA
3.  Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication 
Cell Death and Differentiation  2012;20(3):419-429.
Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and HCMV infection in immunocompromised patients may trigger devastating disease. Cytotoxic lymphocytes control HCMV by releasing granzymes towards virus-infected cells. In mice, granzyme M (GrM) has a physiological role in controlling murine CMV infection. However, the underlying mechanism remains poorly understood. In this study, we showed that human GrM was expressed by HCMV-specific CD8+ T cells both in latently infected healthy individuals and in transplant patients during primary HCMV infection. We identified host cell heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a physiological GrM substrate. GrM most efficiently cleaved hnRNP K in the presence of RNA at multiple sites, thereby likely destroying hnRNP K function. Host cell hnRNP K was essential for HCMV replication not only by promoting viability of HCMV-infected cells but predominantly by regulating viral immediate-early 2 (IE2) protein levels. Furthermore, hnRNP K interacted with IE2 mRNA. Finally, GrM decreased IE2 protein expression in HCMV-infected cells. Our data suggest that targeting of hnRNP K by GrM contributes to the mechanism by which cytotoxic lymphocytes inhibit HCMV replication. This is the first evidence that cytotoxic lymphocytes target host cell proteins to control HCMV infections.
doi:10.1038/cdd.2012.132
PMCID: PMC3569982  PMID: 23099853
cytomegalovirus; cytotoxic lymphocyte; granzyme M; hnRNP K; transplantation
4.  Developing and Testing the Effectiveness of a Novel Health Qigong for Frail Elders in Hong Kong: A Preliminary Study 
Eight-Section Brocades and Yijin Jing consist of some routine movements that are too difficult for frail elders. A novel health qigong protocol was developed and its effectiveness for frail elders was examined using a randomized clinical trial (RCT). An expert panel performed functional anatomy analysis and safety field test prior to the RCT. The experimental group (n = 61, 83 ± 6 yr) was given a 12-week qigong exercise program, while the comparison group (n = 55, 84 ± 6 yr) participated in a newspaper reading program with the same duration and frequency. Pre-, mid-, post-, and follow-up assessments were conducted. At 12 weeks, the qigong group had significant improvements in thinking operations (F = 4.05, P = .02) and significant reduction of resting heart rate (F = 3.14, P = .045) as compared to the newspaper reading group. A trend of improvements in grip strength and a decreasing trend of depression levels were observed among the qigong group. Significant perceived improvements in physical health (F = 13.01, P = .001), activities of daily living (F = 5.32, P = .03), and overall health status (F = 15.26, P = .0001) were found. There are improvements in some aspects of psychosocial, cognitive, physical, and physiological domains. Clinical applications and possibilities for further research are discussed.
doi:10.1155/2013/827392
PMCID: PMC3784263  PMID: 24109493
5.  Innovative Therapy for Classic Galactosemia - Tale of Two HTS 
Classic Galactosemia is an autosomal recessive disorder caused by the deficiency of galactose-1-phosphate uridylyltransferase (GALT), one of the key enzymes in the Leloir pathway of galactose metabolism. While the neonatal morbidity and mortality of the disease are now mostly prevented by newborn screening and galactose restriction, long-term outcome for older children and adults with this disorder remains unsatisfactory. The pathophysiology of Classic Galactosemia is complex, but there is convincing evidence that galactose-1-phosphate (gal-1P) accumulation is a major, if not the sole pathogenic factor. Galactokinase (GALK) inhibition will eliminate the accumulation of gal-1P from both dietary sources and endogenous production, and efforts towards identification of therapeutic small molecule GALK inhibitors are reviewed in detail. Experimental and computational high-throughput screenings of compound libraries to identify GALK inhibitors have been conducted, and subsequent studies aimed to characterize, prioritize, as well as to optimize the identified positives have been implemented to improve the potency of promising compounds. Although none of the identified GALK inhibitors inhibit glucokinase and hexokinase, some of them cross-inhibit other related enzymes in the GHMP small molecule kinase superfamily. While this finding may render the on-going hit-to-lead process more challenging, there is growing evidence that such cross-inhibition could also lead to advances in antimicrobial and anti-cancer therapies.
doi:10.1016/j.ymgme.2011.09.028
PMCID: PMC3253915  PMID: 22018723
6.  A retrospective clinicopathological study on oral lichen planus and malignant transformation: Analysis of 518 cases 
Objective: To investigate the epidemiological and clinical characteristics of a relatively large cohort of patients with oral lichen planus (OLP) from eastern China. Study design: A total of 518 patients with histologically confirmed OLP in a long-term follow-up period (6 months-21.5 years) were retrospectively reviewed in our clinic. Results: Of the 518 patients, 353 females and 165 males were identified. The average age at diagnosis was 46.3 years (range 9-81 years) with the buccal mucosa being the most common site (87.8%). At initial presentation, white lichen and red lichen was seen in 52.3% and 47.7% patients, respectively. Of these, 5 (0.96%) patients previously diagnosed clinically and histopathologically as OLP developed oral cancer. All of them were the females with no a history of smoking or alcohol use. Conclusions: Clinical features of eastern Chinese OLP patients were elucidated. Notably, approximately 1% of OLP developed into cancer, which provides further evidence of potentially malignant nature of OLP.
Key words:Oral lichen planus, clinical features, malignant transformation, oral cancer.
doi:10.4317/medoral.17778
PMCID: PMC3505714  PMID: 22549677
7.  Identification of Novel Small Molecule Inhibitors of 4-diphosphocytidyl-2-C-methyl-D-erythritol (CDP-ME) kinase of Gram-negative bacteria 
Bioorganic & medicinal chemistry  2011;19(19):5886-5895.
The biosyntheses of isoprenoids is essential for the survival in all living organisms, and requires one of the two biochemical pathways: (a) Mevalonate (MVA) Pathway or (b) Methylerythritol Phosphate (MEP) Pathway. The latter pathway, which is used by all Gram-negative bacteria, some Gram-positive bacteria and a few apicomplexan protozoa, provides an attractive target for the development of new antimicrobials because of its absence in humans. In this report, we describe two different approaches that we used to identify novel small molecule inhibitors of Escherichia coli and Yersinia pestis 4-diphosphocytidyl-2-C-methyl D-erythritol (CDP-ME) kinases, key enzymes of the MEP pathway encoded by the E. coli ispE and Y. pestis ipk genes, respectively. In the first approach, we explored existing inhibitors of the GHMP kinases while in the second approach; we performed computational high-throughput screening of compound libraries by targeting the CDP-ME binding site of the two bacterial enzymes. From the first approach, we identified two compounds with 6-(benzylthio)-2-(2-hydroxyphenyl)-4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile and (Z)-3-methyl-4-((5-phenylfuran-2-yl)methylene)isoxazol-5(4H)-one scaffolds which inhibited Escherichia coli CDP-ME kinase in vitro. We then performed substructure search and docking experiments based on these two scaffolds and identified twenty three analogs for structure-activity relationship (SAR) studies. Three new compounds from the isoxazol-5(4H)-one series have shown inhibitory activities against E. coli and Y. pestis CDP-ME kinases with the IC50 values ranging from 7μM to 13μM. The second approach by computational high-throughput screening (HTS) of two million drug-like compounds yielded two compounds with benzenesulfonamide and acetamide moieties which, at a concentration of 20μM, inhibited 80% and 65%, respectively, of control CDP-ME kinase activity.
doi:10.1016/j.bmc.2011.08.012
PMCID: PMC3188437  PMID: 21903402
8.  Structure-activity analysis and cell-based optimization of human galactokinase inhibitors 
ACS medicinal chemistry letters  2011;2(9):667-672.
Classic Galactosemia is a rare human disease associated with the accumulation of toxic level of galactose-1-phosphate (gal-1P) caused by the inherited deficiency of galactose-1-phosphate uridyltransferase (GALT) activity. To reduce the toxic level of gal-1P in the patients, we have identified, via high-throughput screening, over 200 small molecule GALK inhibitors. We selected a 4-oxo-3,4-dihydro-2H-1,3-thiazine-5-carbonitrile scaffold for further structure-activity relationships characterization, lead optimization with regards to potency and efficacy to reduce gal-1P accumulation in patient cells.
doi:10.1021/ml200131j
PMCID: PMC3224021  PMID: 22125663
galactokinase; galactose-1-phosphate; dihydrothiazinone; GHMP kinases; galactosemia
9.  Caspase-3-mediated degradation of condensin Cap-H regulates mitotic cell death 
Cell Death and Differentiation  2010;18(6):996-1004.
Mitotic death is a major form of cell death in cancer cells that have been treated with chemotherapeutic drugs. However, the mechanisms underlying this form of cell death is poorly understood. Here, we report that the loss of chromosome integrity is an important determinant of mitotic death. During prolonged mitotic arrest, caspase-3 is activated and it cleaves Cap-H, a subunit of condensin I. The depletion of Cap-H results in the loss of condensin I complex at the chromosomes, thus affecting the integrity of the chromosomes. Consequently, DNA fragmentation by caspase-activated DNase is facilitated, thus driving the cell towards mitotic death. By expressing a caspase-resistant form of Cap-H, mitotic death is abrogated and the cells are able to reenter interphase after a long mitotic delay. Taken together, we provide new insights into the molecular events that occur during mitotic death.
doi:10.1038/cdd.2010.165
PMCID: PMC3131938  PMID: 21151026
mitotic cell death; caspase; condensin
10.  A positive role for c-Abl in Atm and Atr activation in DNA damage response 
DNA damage triggers Atm- and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events.
doi:10.1038/cdd.2010.106
PMCID: PMC3131864  PMID: 20798688
c-Abl; Atm; Atr; phosphorylation; DNA repair
11.  Galactose Toxicity in Animals 
IUBMB life  2009;61(11):1063-1074.
doi:10.1002/iub.262
PMCID: PMC2788023  PMID: 19859980
12.  Eradication of Helicobacter pylori infection reverses E‐cadherin promoter hypermethylation 
Gut  2006;55(4):463-468.
Background
E‐cadherin methylation is important in gastric carcinogenesis. Reversing hypermethylation may halt the carcinogenic process. We have previously reported that Helicobacter pylori infection is associated with E‐cadherin methylation in chronic gastritis patients.
Aim
To examine if eradication of H pylori could reverse E‐cadherin methylation.
Methods
Patients with dyspepsia and positive for H pylori infection, with a mucosal biopsy showing chronic active gastritis, were randomised to receive H pylori eradication therapy (group 1, n = 41) or no treatment (group 2, n = 40), and were followed up prospectively. Gastric mucosae were taken for methylation assay at week 0 (before treatment) and week 6 (after treatment). Archived specimens of intestinal metaplasia with H pylori infection (n = 22) and without (n = 19) were retrieved for methylation analysis. Methylation was assessed using methylation specific polymerase chain reaction and sequencing.
Results
Methylation at E‐cadherin was detected in 46% (19/41) and 17% (7/41) of patients at weeks 0 and 6, respectively, in group 1 (p = 0.004); 78.9% (15/19) of specimens were unmethylated after eradication of H pylori. Mucosal biopsy showed chronic inactive gastritis in 35 patients, intestinal metaplasia in one, and normal mucosa in five at week 6. Methylation was detected in 47.5% (19/40) and 52.5% (21/40) of patients at weeks 0 and 6, respectively, in group 2 (P = 0.5). Gastric mucosal biopsy showed persistent chronic active gastritis in all cases. Methylation frequency did not differ in H pylori positive or negative intestinal metaplastic specimens (72.7% v 63%; p = 0.5).
Conclusion
H pylori eradication therapy could reverse methylation in patients with chronic gastritis. This demonstrates an environmental effect on methylation.
doi:10.1136/gut.2005.077776
PMCID: PMC1856151  PMID: 16428266
E‐cadherin methylation; gastric cancer; intestinal metaplasia;  Helicobacter pylori
13.  ARHI: A new target of galactose toxicity in Classic Galactosemia# 
Bioscience hypotheses  2008;1(5):263-271.
In humans, deficiency of galactose-1-phosphate uridyltransferase (GALT) activity can lead to a potentially lethal disease called Classic Galactosemia. Although a galactose-restricted diet can prevent the acute lethality associated with the disorder, chronic complications persist in many well-treated patients. Approximately 85% of young women with Classic Galactosemia experience hypergonadotropic hypogonadism and premature ovarian failure (POF). Others suffer from mental retardation, growth restriction, speech dyspraxia, and ataxia. Despite decades of intense biochemical characterization, little is known about the molecular etiology, as well as the chronology of the pathological events leading to the poor outcomes. Several hypotheses have been proposed, most of which involved the accumulation of the intermediates and/or the deficit of the products, of the blocked GALT pathway. However, none of these hypotheses satisfactorily explained the absence of patient phenotypes in the GALT-knockout mice. Here we proposed that the gene encoded the human tumor suppressor gene aplysia ras homolog I (ARHI) is a target of toxicity in Classic Galactosemia, and because ARHI gene is lost in rodents in through evolution, it thus accounts for the lack of clinical phenotypes in the GALT-knockout mice.
doi:10.1016/j.bihy.2008.06.011
PMCID: PMC2613282  PMID: 19122833
14.  Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications 
Gut  2005;54(11):1610-1614.
Background: Identifying risk factors for the development of complications of chronic hepatitis B (CHB) is important for setting up treatment criteria.
Aim: To determine risk factors for the development of complications in Asian CHB patients.
Patients and methods: A total of 3233 Chinese CHB patients (mean follow up 46.8 months) were monitored for liver biochemistry, viral serology, hepatitis B virus (HBV) DNA levels, acute exacerbation, hepatitis B e antigen (HBeAg) seroconversion, and development of cirrhotic complications and hepatocellular carcinoma.
Results: Median age for HBeAg seroconversion and development of complications was 35 years and 57.2 years, respectively. Patients with alanine aminotransferase (ALT) levels of 0.5–1 times the upper limit of normal (ULN) and 1–2× ULN had an increased risk for the development of complications compared with patients with ALT levels <0.5× ULN (p<0.0001 for both). HBeAg/antibody to hepatitis B e antigen status, and number of episodes, duration, and peak ALT levels of acute exacerbations were not associated with an increased risk of complications. In patients with complications, 43.6% had HBV DNA levels less than 1.42×105 copies/ml. Male sex, stigmata of chronic liver disease, old age, low albumin, and high α fetoprotein levels on presentation were independently associated with increased cumulative risk of complications. Male sex, presence of hepatitis symptoms, old age, low albumin level, and presence of complications on presentation were independently associated with shorter survival.
Conclusion: Prolonged low level viraemia causing insidious and continual liver damage, as reflected by ALT levels of 0.5–2× ULN, is the most likely pathway for the development of complications in Asian CHB patients.
doi:10.1136/gut.2005.065136
PMCID: PMC1774768  PMID: 15871997
HBeAg seroconversion; alanine aminotransferase; cirrhosis related complications; hepatocellular carcinoma; survival
15.  Impact of a severe acute respiratory syndrome outbreak in the emergency department: an experience in Taiwan 
Emergency Medicine Journal : EMJ  2004;21(6):660-662.
Objectives: To evaluate the impact of a severe acute respiratory syndrome (SARS) outbreak in the emergency department (ED).
Methods: Computerised records of all ED visits in January and May 2003 were analysed and compared, representing before and during the SARS epidemic respectively. Data were grouped into two categories. Group 1 was the indicators of impact on patients, including visitor's condition classification, number of patients that died on arrival (DOA), received cardiopulmonary resuscitation, underwent endotracheal intubation, needed mechanical ventilation, discharged against medical advice (AAD), died in the ED, and the admission rate to wards. Group 2 was the indicators of impact on the quality of medical care, including number of visits that returned within 72 hours (early returns), underwent chest radiography, upper abdomen sonography or computed tomography, and the length of stay.
Results: There were 6650 and 3901 consecutive encounters in January and May 2003 respectively. There were significant differences on condition classifications (p = 0.000), increased rate of patients that underwent endotracheal intubation (p = 0.003), needed mechanical ventilation (p = 0.020), and admission (p = 0.000). The rate of AAD decreased significantly (p = 0.024). There was no significant difference on early returns, although the length of stay in the ED increased (p = 0.043). The number of visits that underwent chest radiological examination increased (p = 0.000) and upper abdomen sonography (p = 0.007) decreased significantly in May.
Conclusions: SARS had an impact on the medical service system and decreased visits by 40% in the ED. Patients visiting the ED had more severe conditions than before. The impact of SARS on quality of medical care can be minimised when adequate infection control measures are applied.
doi:10.1136/emj.2003.010678
PMCID: PMC1726484  PMID: 15496687
16.  Treatment of severe proliferative lupus nephritis: the current state 
Annals of the Rheumatic Diseases  2003;62(9):799-804.
doi:10.1136/ard.62.9.799
PMCID: PMC1754677  PMID: 12922948
17.  Human uveal melanoma expresses NG2 immunoreactivity 
Background/aims: NG2 is the rat homologue of the human melanoma proteoglycan (HMP), also known as the high molecular weight melanoma associated antigen. Most cutaneous melanomas, as well as glioblastomas, chondrosarcomas, and some leukaemias express NG2 immunoreactivity, recognised using monoclonal antibody (mAb) 9.2.27. This antibody has also been used for molecular targeting in targeted α therapy for melanoma. The purpose of this study was to evaluate the expression of NG2 immunoreactivity in human uveal melanoma and normal ocular tissue using mAb 9.2.27.
Methods: Enucleated eyes from 26 patients with choroidal or ciliary body melanoma (n=26) were available as paraffin sections, and stained with haematoxylin and eosin to assess for tumour cell type and histopathology. Additional slides were investigated for NG2 immunoreactivity using mAb 9.2.27 and alkaline phosphatase anti-alkaline phosphatase (APAAP) immunostaining. Two independent observers graded immunostaining using a semiquantitative scale from 0 (negative) to 3 (strong).
Results: Immunostaining for mAb 9.2.27 could not be graded in 7/26 cases with dense pigmentation of the tumour. For the remaining cases, grade 2 (moderate) or more immunostaining was seen in 18/19 tumours (95%). The retina, retinal pigment epithelium (RPE), and choroid displayed weak immunostaining (grade 0.5–1.5) in the majority of melanoma affected eyes. Normal retina and choroid (n=5) appeared negative for mAb 9.2.27. Optic nerve axon bundles in both control and melanoma affected eyes displayed moderate immunostaining.
Conclusion: In the present study, the majority of human uveal melanomas expressed NG2 immunoreactivity, as detected using mAb 9.2.27. This antibody may be a suitable candidate for radioimmunotherapy to target ocular melanoma.
PMCID: PMC1771662  PMID: 12714409
chondroitin sulphate proteoglycan; monoclonal antibodies; radioimmunotherapy; retina
18.  Aspirin inhibits the growth of Helicobacter pylori and enhances its susceptibility to antimicrobial agents 
Gut  2003;52(4):490-495.
Background and aim: The role of Helicobacter pylori and aspirin in peptic ulcer formation and recurrence remains an important clinical topic. The interaction between aspirin and H pylori in vitro is also not clear. We investigated the effect of aspirin on the growth of H pylori and on the susceptibility of H pylori to antimicrobials.
Methods: Time killing studies of H pylori were performed with different concentrations of aspirin and salicylate. Growth of bacteria was assessed spectrophotometrically and by viable colony count. The effects of aspirin on the efficiency of colony formation and on metronidazole induced mutation to rifampicin resistance in H pylori were determined. Minimal inhibitory concentrations (MICs) of aspirin and metronidazole were tested by the standard agar dilution method. MICs of amoxycillin and clarithromycin were determined by the E test method.
Results: Aspirin and salicylate inhibited the growth of H pylori in a dose dependent manner and bactericidal activity was due to cell lysis. Aspirin 400 μg/ml caused a 2 logs decrease in colony forming units/ml at 48 hours, and suppressed the normal ability of metronidazole to induce new mutations to rifampicin. The IC90 of aspirin was 512 μg/ml. Increased susceptibility of amoxycillin, clarithromycin, and metronidazole to H pylori was observed at 1 mM (180 μg/ml) aspirin.
Conclusions: Aspirin inhibited the growth of H pylori, suppressed the mutagenic effect of metronidazole, and enhanced the susceptibility of H pylori to antimicrobial agents. This mechanism is important in future drug development for effective clearing and overcoming resistance.
PMCID: PMC1773581  PMID: 12631656
Helicobacter pylori; aspirin; mutagenesis; resistance; antimicrobials
19.  Double blind, randomised, placebo controlled study of four weeks of lansoprazole for the treatment of functional dyspepsia in Chinese patients 
Gut  2002;51(4):502-506.
Background: The use of proton pump inhibitors for the treatment of functional dyspepsia is controversial and the role of Helicobacter pylori infection in functional dyspepsia is uncertain.
Aim: To evaluate the efficacy of different doses of lansoprazole for the treatment of functional dyspepsia in Chinese patients.
Method: Patients with a clinical diagnosis of functional dyspepsia according to the Rome II criteria and normal upper gastrointestinal endoscopy were recruited and randomised to receive: (1) lansoprazole 30 mg,(2) lansoprazole 15 mg, or (3) placebo, all given daily for four weeks. Dyspepsia symptom scores and quality of life (SF-36 score) were evaluated before and four weeks after treatment.
Results: A total of 453 patients were randomised. There was no difference in the proportion of patients with complete symptom relief in the lansoprazole 30 mg (23%) and lansoprazole 15 mg (23%) groups compared with the placebo group (30%). The proportion of H pylori positive patients with a complete response was similar with lansoprazole 30 mg (34%) and lansoprazole 15 mg (20%) versus placebo (22%). All symptom subgroups (ulcer-like, dysmotility-like, reflux-like, and unspecified dyspepsia) had similar proportions of patients with complete symptom relief after treatment.
Conclusion: Proton pump inhibitor treatment is not superior to placebo for the management of functional dyspepsia in Chinese patients.
PMCID: PMC1773405  PMID: 12235071
Helicobacter pylori; functional dyspepsia; proton pump inhibitor; Chinese
20.  A randomised controlled trial of endoscopic sphincterotomy in acute cholangitis without common bile duct stones 
Gut  2002;51(2):245-247.
Background: Biliary decompression with endoscopic sphincterotomy (EPT) is beneficial in patients with biliary obstruction due to common bile duct (CBD) stones. However, it is not known whether EPT with decompression of the bile duct is beneficial in patients with acute cholangitis and gall bladder stones but without evidence of CBD stones.
Aim: A randomised controlled study to assess the effect of EPT on the outcome of patients suffering from acute cholangitis with gall bladder stones but with no CBD stones on initial endoscopic retrograde cholangiopancreatography.
Patients: A total of 111 patients were recruited into the study.
Methods and results: Fifty patients were randomised to receive EPT while 61 patients received no endoscopic intervention. There was a significant difference in the duration of fever in the EPT and non-EPT groups (mean (SD): 3.2 (2.2) days v 4.3 (2.1) days; p<0.001). Duration of hospital stay was also shorter in the EPT group than in the non-EPT group (mean (SD): 8.1 (3.0) v 9.1 (3.2) days; p=0.04). Patients were followed up for a mean (SD) of 42.4 (11.1) months. Twenty three patients (20.3%) developed recurrent acute cholangitis (RAC): 14 patients (12.6%) in the EPT group and nine patients (8.1%) in the non-EPT group (p=0.09).
Conclusion: EPT in patients with acute cholangitis without CBD stones decreased the duration of acute cholangitis and reduced hospital stay but it did not decrease the incidence of RAC.
PMCID: PMC1773318  PMID: 12117888
acute cholangitis; recurrent acute cholangitis; endoscopic sphinterotomy
21.  Risk factors for ulcer development in patients with non-ulcer dyspepsia: a prospective two year follow up study of 209 patients 
Gut  2002;51(1):15-20.
Background and aims: A subset of non-ulcer dyspepsia (NUD) disorders can evolve into peptic ulcer disease. This prospective study attempted to determine the independent risk factors for ulcer formation in NUD patients, and compared the natural history of Helicobacter pylori positive and negative NUD subjects.
Methods: From May 1997 to April 1999, consecutive NUD patients were enrolled into the study. Endoscopy was performed routinely on enrolment, at the end of the second and 12th months, and whenever there was a dyspepsia attack. Patients were prospectively followed up for two years.
Results: Peptic ulcers occurred in 16 of 209 NUD patients during the two year follow up period. Multivariate analysis of 13 host and bacterial factors demonstrated that advanced age (odds ratio 2.90), H pylori infection (odds ratio 3.59), and use of non-steroidal anti-inflammatory drugs (NSAID; odds ratio 4.46) were independently significant in predicting subsequent peptic ulcer development. NUD patients with all three risk factors had a 75% (3/4) risk of developing peptic ulcer but the ulcer incidence in patients without any of the risk parameters was only 1.2% (1/84). The resolution rate of symptoms in the H pylori positive NUD patients was similar to the H pylori negative patients (57.9% v 49.1%; 95% confidence interval (CI) −5 to 22). However, rates for subsequent peptic ulcer and erosion development were significantly higher in H pylori positive patients than in H pylori negative patients (ulcer 12.6% v 3.5%, 95% CI 1–16; erosion 23.2% v 12.3%, 95% CI 1–21).
Conclusion: A small but significant proportion of NUD patients develop peptic ulcer after long term follow up. H pylori infection, NSAID use, and advanced age are independent risk factors for subsequent ulcer formation. Follow up endoscopy is strongly indicated for an NUD patient with multiple risk factors for ulcer formation when symptoms recur.
PMCID: PMC1773281  PMID: 12077085
dyspepsia; peptic ulcer; risk factors; Helicobacter pylori
22.  Effect of somatostatin on the sphincter of Oddi in patients with acute non-biliary pancreatitis 
Lai, K | Lo, G | Cheng, J | Fu, M | Wang, E | Chan, H | Wang, Y | Hsu, P | Lin, C
Gut  2001;49(6):843-846.
BACKGROUND—Somatostatin has been used to prevent pancreatitis after endoscopic retrograde cholangiopancreatography but its effect on acute non-biliary pancreatitis is still unclear.
AIM—The purpose of this study was to evaluate the function of the sphincter of Oddi (SO) and the effect of somatostatin on patients with non-biliary pancreatitis.
METHODS—Twenty patients (18 males, two females) with acute pancreatitis (alcoholic 18, idiopathic two) received SO manometry within one week after admission. After baseline measurement, a bolus dose of somatostatin (Stilamin, Serono) 250 µg was infused slowly, and SO manometry was repeated after five minutes. Continuous infusion of somatostatin 250 µg/h was given for 12 hours after SO manometry. Serum amylase, lipase, glucose, and C reactive protein (CRP) levels were examined before and after somatostatin infusion.
RESULTS—SO manometry was unsuccessful in six patients due to contracted sphincter. In the remaining 14 patients, high SO basal pressure (SOBP >40 mm Hg) was found in seven patients. After somatostatin infusion, mean SOBP decreased from 48.8 (29) to 31.9 (22) mm Hg (p<0.01). One patient had a paradoxical reaction to somatostatin (SOBP increased from 30 to 50 mm Hg) while the other 13 patients had a fall in SOBP after somatostatin. One patient developed abdominal pain with a serum amylase level of 2516 IU/l after SO manometry. No other side effects or changes in amylase, lipase, glucose, or CRP levels were observed in the other 19 patients after SO manometry and somatostatin infusion.
DISCUSSION—Sphincter of Oddi dysfunction is common in patients with acute non-biliary pancreatitis and in most cases somatostatin can relax the sphincter.


Keywords: acute alcoholic pancreatitis; sphincter of Oddi; somatostatin
doi:10.1136/gut.49.6.843
PMCID: PMC1728542  PMID: 11709520
23.  Transforming growth factor-β1 expression in dilated cardiomyopathy 
Heart  2001;86(6):701-708.
doi:10.1136/heart.86.6.701
PMCID: PMC1729995  PMID: 11711472
24.  Soluble E-cadherin is a valid prognostic marker in gastric carcinoma 
Chan, A | Lam, S | Chu, K | Lam, C | Kwok, E | Leung, S | Yuen, S | Law, S | Hui, W | Lai, K | Wong, C | Hu, H | Lai, C | Wong, J
Gut  2001;48(6):808-811.
BACKGROUND—Gastric cancer remains a major cause of cancer mortality globally but no good prognostic tumour marker is available. Soluble fragment of E-cadherin protein has been reported to increase in the sera of patients with cancer and recently was found to be elevated in 67% of patients with gastric cancer.
AIMS—To investigate if serum soluble E-cadherin is a valid prognostic marker in gastric cancer.
METHODS—Concentrations of soluble E-cadherin from 116 patients with histologically confirmed gastric adenocarinoma and 40 healthy subjects were measured using an immunoenzymometric method with a commercially available sandwich ELISA kit based on monoclonal antibodies.
RESULTS—The logarithm of the means of soluble E-cadherin concentration was significantly higher in patients with gastric cancers (mean 3.85 (SD 0.28)) than in healthy subjects (3.71 (0.18)) (p=0.001), and in palliative/conservatively treated cancers (3.91 (0.35)) than in operable cancers (3.78 (0.19)) (p=0.015). The logarithm of the concentrations correlated with tumour size (p=0.032) and carcinoembryonic antigen concentrations (p=0.001). The cut off value calculated from discriminant analysis on operability and inoperability/palliative treatment was 7025 ng/ml. Soluble E-cadherin concentrations higher than this cut off value predicted tumour (T4) depth invasion (p=0.020, confidence interval (CI) 1.008-1.668) and palliative/conservative treatment (p=0.023, CI 1.038-2.514). In contrast, the relative risks for lymph node (N2) metastasis, distant metastasis, and stage III/IV disease were 1.41, 1.33, and 1.55 respectively, despite not reaching statistical significance.
CONCLUSION—Serum soluble E-cadherin is a potential valid prognostic marker for gastric cancer. A high concentration predicts palliative/conservative treatment and T4 invasion.


Keywords: E-cadherin; gastric cancer; tumour marker
doi:10.1136/gut.48.6.808
PMCID: PMC1728335  PMID: 11358900
25.  Mucociliary function of eustachian tube in atrophic rhinitis 
Atrophic rhinitis is a chronic inflammatory disease characterized by progressive atrophy of nasal mucosa and underlying turbinate bones. Atrophie changes may extend to the nasopharynx and subsequently Eustachian tube and middle ear system may also get involved. Mucociliary function of the Eustachian tube In cases of atrophie rhinitis has been measured by saccharine tut and 17.46% of cases showed a delayed clearance time. All these cases had prolonged duration of symptoms with advanced stage of the disease.
doi:10.1007/BF02993754
PMCID: PMC3450464  PMID: 23119922
Mucoeiliary function; Eustachian tube; Atrophie rhinitis

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