Shiu Kum Lam

Second Asia–Pacific Consensus Guidelines for Helicobacter pylori infection

The Asia–Pacific Consensus Conference was convened to review and synthesize the most current information on Helicobacter pylori management so as to update the previously published regional guidelines. The group recognized that in addition to long‐established indications, such as peptic ulcer disease, early mucosa‐associated lymphoid tissue (MALT) type lymphoma and family history of gastric cancer, H. pylori eradication was also indicated for H. pylori infected patients with functional dyspepsia, in those receiving long‐term maintenance proton pump inhibitor (PPI) for gastroesophageal reflux disease, and in cases of unexplained iron deficiency anemia or idiopathic thrombocytopenic purpura. In addition, a population ‘test and treat’ strategy for H. pylori infection in communities with high incidence of gastric cancer was considered to be an effective strategy for gastric cancer prevention. It was recommended that H. pylori infection should be tested for and eradicated prior to long‐term aspirin or non‐steroidal anti‐inflammatory drug therapy in patients at high risk for ulcers and ulcer‐related complications. In Asia, the currently recommended first‐line therapy for H. pylori infection is PPI‐based triple therapy with amoxicillin/metronidazole and clarithromycin for 7 days, while bismuth‐based quadruple therapy is an effective alternative. There appears to be an increasing rate of resistance to clarithromycin and metronidazole in parts of Asia, leading to reduced efficacy of PPI‐based triple therapy. There are insufficient data to recommend sequential therapy as an alternative first‐line therapy in Asia. Salvage therapies that can be used include: (i) standard triple therapy that has not been previously used; (ii) bismuth‐based quadruple therapy; (iii) levofloxacin‐based triple therapy; and (iv) rifabutin‐based triple therapy. Both CYP2C19 genetic polymorphisms and cigarette smoking can influence future H. pylori eradication rates.

Asia-Pacific consensus guidelines on gastric cancer prevention

Background and Aim:  Gastric cancer is a major health burden in the Asia–Pacific region but consensus on prevention strategies has been lacking. We aimed to critically evaluate strategies for preventing gastric cancer.

Differences in Genotypes of Helicobacter pylori from Different Human Populations

DNA motifs at several informative loci in more than 500 strains of Helicobacter pylori from five continents were studied by PCR and sequencing to gain insights into the evolution of this gastric pathogen. Five types of deletion, insertion, and substitution motifs were found at the right end of the H. pylori cag pathogenicity island. Of the three most common motifs, type I predominated in Spaniards, native Peruvians, and Guatemalan Ladinos (mixed Amerindian-European ancestry) and also in native Africans and U.S. residents; type II predominated among Japanese and Chinese; and type III predominated in Indians from Calcutta. Sequences in the cagA gene and in vacAm1 type alleles of the vacuolating cytotoxin gene (vacA) of strains from native Peruvians were also more like those from Spaniards than those from Asians. These indications of relatedness of Latin American and Spanish strains, despite the closer genetic relatedness of Amerindian and Asian people themselves, lead us to suggest that H. pylori may have been brought to the New World by European conquerors and colonists about 500 years ago. This thinking, in turn, suggests that H. pylori infection might have become widespread in people quite recently in human evolution.

Functional p53 is required for triptolide-induced apoptosis and AP-1 and nuclear factor-κB activation in gastric cancer cells

Triptolide, a major component in the extract of Chinese herbal plant Tripterygium wilfordii Hook f (TWHf), has potential anti-neoplastic effect. In the present study we investigated the potential therapeutic effects and mechanisms of triptolide against human gastric cancer cells. Four gastric cancer cell lines with different p53 status, AGS and MKN-45 (wild type p53); MKN-28 and SGC-7901 (mutant p53) were observed as to cell growth inhibition and induction of apoptosis in response to triptolide treatment. We showed that triptolide inhibited cell growth, induced apoptosis and suppressed NK-κB and AP-1 transactivation in AGS cells with wild-type p53. Triptolide induced apoptosis by stimulating the expressions of p53, p21waf1/cip1, bax protein, and increased the activity of caspases. In addition, it caused cell cycle arrest in the G0/G1 phase. To examine the role of p53 in these functions, we showed that suppression of p53 level with antisense oligonucleotide abrogated triptolide-induced apoptosis and over-expression of dominant negative p53 abolished the inhibitory effect on NF-κB activation. Furthermore, we demonstrated that triptolide had differential effects on gastric cancer cells with different p53 status. We showed that triptolide also inhibited cell growth and induced apoptosis in MKN-45 with wild-type p53, whereas it had no significant growth-inhibition and apoptosis induction effects on the MKN-28 and SGC-7901 cells with mutant p53. Our data suggest that triptolide exhibits anti-tumor and anti-inflammatory effects by inhibiting cell proliferation, inducing apoptosis and inhibiting NF-κB and AP-1 transcriptional activity. However, a functional p53 is required for these proapoptotic, anti-inflammatory and anti-tumor effects.

Gastro-oesophageal reflux disease in Asia

Gastro‐oesophageal reflux disease (GORD) occurs more frequently in Europe and North America than in Asia but its prevalence is now increasing in many Asian countries. Many reasons have been given for the lower prevalence of GORD in Asia. Low dietary fat and genetically determined factors, such as body mass index and maximal acid output, may be important. Other dietary factors appear to be less relevant. Increased intake of carbonated drinks or aggravating medicines may influence the increasing rates of GORD in some Asian countries but no strong evidence links other factors, such as the age of the population, smoking or alcohol consumption, to GORD. The management of GORD in Asia is similar to that in Europe and North America but the lower incidence of severe oesophagitis in Asia may alter the approach slightly. Also, because Asians tend to develop stomach cancer at an earlier age, endoscopy is used routinely at an earlier stage of investigation. Gastro‐oesophageal reflux disease is essentially a motility disorder, so short‐term management of the disease can usually be achieved using prokinetic agents (or histamine (H2)‐receptor antagonists). More severe and recurrent GORD may require proton pump inhibitors (PPI) or a combination of prokinetic agents and PPI. The choice of long‐term treatment may be influenced by the relative costs of prokinetic agents and PPI.

Pyogenic liver abscess: Retrospective analysis of 80 cases over a 10‐year period

Background: A total of 80 patients with pyogenic liver abscess managed at a single institution over a 10‐year period were studied.

Arsenic trioxide induces apoptosis in human gastric cancer cells through up‐regulation of P53 and activation of caspase‐3

Arsenic trioxide (As2O3) can induce clinical remission in patients suffering from acute promyelocytic leukemia, through induction of apoptosis and activation of caspases. We investigated the potential use of As2O3 in human gastric cancer and its possible mechanisms. Human gastric cancer cell lines AGS and MKN‐28 were treated with various concentrations (0.1 to 100 μM) of As2O3 for 24 to 72 hr. Apoptosis was determined by acridine orange staining, flow cytometry and DNA fragmentation. Protein levels of p53, p21waf1/cip1, c‐myc, bcl‐2 and bax were detected by Western blotting. Effects of As2O3 on caspase‐3 protease activity, its protein concentration and cleavage of poly(ADP)‐ribose polymerase (PARP) were also studied. As2O3 inhibited cell growth and induced apoptosis in both cell lines, though AGS cells were more sensitive. As2O3 induced apoptosis in AGS cells in a concentration‐ and time‐dependent manner. Treatment resulted in a marked increase in p53 protein levels as early as 4 hr. Co‐incubation with p53 anti‐sense oligo‐nucleotide suppressed As2O3‐induced intracellular p53 over‐expression and apoptosis. As2O3 increased the activity of caspase‐3, with appearance of its 17 kDa peptide fragment, and cleavage of PARP, with appearance of the 85 kDa cleavage product, both in parallel with the induction of apoptosis. Both the tripeptide caspase inhibitor zVAD‐fmk and the specific caspase‐3 inhibitor DEVD‐fmk partially suppressed As2O3‐induced caspase‐3 activation and apoptosis. As2O3 inhibits cell growth and induces apoptosis in gastric cancer cells, involving p53 over‐expression and activation of caspase‐3. The potential use of this compound in the treatment of gastric cancer is worth further investigation.

Pathophysiology and pathogenesis of acute gastric mucosal lesions after hypothermic restraint stress in rats

The interrelationships of core body temperature, blood viscosity, gastric mucosal blood flow, surface pH of the corpus mucosa, and acute gastric mucosal lesions in rats after up to 3 h of hypothermic stress were investigated. Three groups of rats were studied: (a) control rats restrained at room temperature, (b) conscious rats under restraint and varying degrees of hypothermia, and (c) anesthetized rats under hypothermia. Under hypothermic stress both restrained and anesthetized rats manifested a sharp decline in core temperature, a marked increase in blood viscosity with a mirror-image decrease in gastric mucosal blood flow, a significant decline in gastric mucosal surface pH, and similar frequencies and severities of acute gastric mucosal lesions. In the control group, neither mucosal lesions nor changes in physiologic measurements were observed, except for a decline in mucosal surface pH. An increase in blood viscosity identical to that in rats subjected to hypothermia was observed in vitro when blood temperature was lowered in the viscometer. These findings indicate that hypothermia but not restraint led to an increase in blood viscosity, which in turn resulted in a decrease in mucosal blood flow and the development of gastric mucosal lesions. Also, hyperacidity was found to be a permissive factor in the pathogenesis of mucosal lesions.

A retrospective and prospective study on the safety of discharging selected patients with duodenal ulcer bleeding on the same day as endoscopy

BACKGROUND Low risk of rebleeding has been observed in patients with gastrointestinal bleeding due to peptic ulcer without high-risk stigmata of recent hemorrhage. We aimed to evaluate the safety and acceptability of an aggressive early discharge policy in those patients admitted with upper gastrointestinal bleeding due to duodenal ulcers without high-risk stigmata of recent hemorrhage. METHOD Retrospective analysis was carried out in bleeding ulcer patients less than 60 years of age with stable vital signs and no stigmata or only flat spots on endoscopy. A prospective study was then performed that included only duodenal ulcer patients less than 60 years of age with stable vital signs, no concomitant serious medical illness, and no stigmata of recent hemorrhage. These patients were discharged on the same day that endoscopy was performed. RESULTS During a period of 18 months, 72 patients satisfied the criteria in the retrospective study. The mean hospital stay was 1.4 days (range, 1 to 5). There were no episodes of rebleeding nor significant drops in hemoglobin level 2 weeks after discharge (10.8 gm/dL +/- 1.4 vs 11.0 gm/dL +/- 1.5). Seventy-five patients were recruited into the prospective study. None of them had rebleeding nor significant drops in hemoglobin 1 week after discharge (12.1 gm/dL +/- 1.8 vs 11.7 gm/dL +/- 2.5). CONCLUSION We conclude that patients with gastrointestinal bleeding who have clean-based duodenal ulcers and are stable on admission can be safely discharged on the same day as endoscopy.

Novel target for induction of apoptosis by cyclo-oxygenase-2 inhibitor SC-236 through a protein kinase C-β 1 -dependent pathway

Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of gastrointestinal cancers. Recently, a similar protective effect has been demonstrated by the specific cyclo-oxygenase-2 (COX-2) inhibitors. However, the exact mechanism that accounts for the anti-proliferative effect of specific COX-2 inhibitors is still not fully understood, and it is still controversial whether these protective effects are predominantly mediated through the inhibition of COX-2 activity and prostaglandin synthesis. Identification of molecular targets regulated by COX-2 inhibitors could lead to a better understanding of their pro-apoptotic and anti-neoplastic activities. In the present study, we investigated the effect and the possible molecular target of a COX-2-specific inhibitor SC-236 on gastric cancer. We showed that SC-236 induced apoptosis in gastric cancer cells. However, this effect was not dependent on COX-2 inhibition. SC-236 down-regulated the protein expression and kinase activity of PKC-β1, increased the expression of PKCδ and PKCη, but did not alter the expression of other PKC isoforms in AGS cells. Moreover, exogenous prostaglandins or PGE2 receptor antagonists could not reverse the inhibition effect on PKCβ1 by SC-236, which suggested that this effect occurred through a mechanism independent of cyclo-oxygenase activity and prostaglandin synthesis. Overexpression of PKCβ1 attenuated the apoptotic response of AGS cells to SC-236 and was associated with overexpression of p21waf1/cip1. Inhibition of PKCβ1-mediated overexpression of p21waf1/cip1 partially reduced the anti-apoptotic effect of PKCβ1. The down-regulation of PKCβ1 provides an explanation for COX-independent apoptotic effects of specific COX-2 inhibitor in cultured gastric cancer cells. We also suggest that PKCβ1 act as survival mediator in gastric cancer, and its down-regulation by COX-2 inhibitor SC-236 may provide new target for future treatment of gastric cancer.