Gastric mucosal precancerous lesions in Helicobacter pylori-infected pediatric patients in central China: A single-center, retrospective investigation.

BACKGROUND: Helicobacter pylori (H. pylori) infects about 50% of the world population and is the major cause of chronic gastritis, peptic ulcers, and gastric cancer. Chronic H. pylori infection induces gastric mucosal precancerous lesions mostly in adulthood, and it is debatable whether these pathological conditions can occur in childhood and adolescents as well. Since this is a critical issue to determine if intervention should be offered for this population group, we investigated the gastric mucosal precancerous lesions in pediatric patients in an area in central China with a high prevalence of H. pylori and gastric cancer. AIM: To investigate the relationship of H. pylori infection and gastric mucosal precancerous lesions in children and adolescents in central China. METHODS: We screened 4258 ward-admitted children and adolescent patients with upper gastrointestinal symptoms, and finally enrolled 1015 pediatric patients with H. pylori infection and endoscopic and histological data. H. pylori infection status was determined by rapid urease test and histopathological examination. Both clinical and pathological data were collected and analyzed retrospectively. Occurrence of gastric mucosal precancerous lesions, inflammatory activity and degree of inflammatory cell infiltration between H. pylori-positive and -negative groups were compared. RESULTS: Among the 1015 eligible children and adolescents, the overall H. pylori infection rate was 84.14% (854/1015). The infection rate increased with age. The incidence of gastric mucosal precancerous lesions in H. pylori-infected children was 4.33% (37/854), which included atrophic gastritis (17 cases), intestinal metaplasia (11 cases) and dysplasia (9 cases). In H. pylori-negative patients, only 1 atrophic gastritis case [0.62%, (1/161)] was found (P < 0.05). Active inflammation in H. pylori-infected patients was significantly higher than that in non-infected patients, and the H. pylori-infected group showed more severe lymphocyte and neutrophil granulocyte infiltration (P < 0.001). In addition, endoscopy revealed that the most common findings in H. pylori-positive patients were antral nodularity, but in H. pylori-negative patients only superficial gastritis was observed. CONCLUSION: In children and adolescents, gastric mucosal precancerous lesions occurred in 4.33% of H. pylori-infected patients in central China. These cases included atrophic gastritis, intestinal metaplasia, and dysplasia. The data revealed an obvious critical issue requiring future investigation and intervention for this population group.

Both family-based Helicobacter pylori infection control and management strategy and screen-and-treat strategy are cost-effective for gastric cancer prevention.

BACKGROUND: Helicobacter pylori (H. pylori) infection and its related diseases are substantial public health burden for highly infected areas. Recently, a novel family-based H. pylori infection control and management (FBCM) strategy is introduced for H. pylori infection prevention and control. However, its cost-effectiveness has not been evaluated. We conducted this health economic evaluation to investigate the cost-effectiveness of FBCM, screen-and-treat, and no-screen strategies in Chinese population. MATERIALS AND METHODS: Cost-effectiveness analysis was performed using decision tree and Markov model. Parameters required for the model were from published literatures and public databases, including health state utility, screening characteristics, treatment effectiveness, and medical costs for the three strategies. Outcomes were cost, quality-adjusted life year (QALY), incremental cost-effectiveness ratio (ICER). Uncertainty analysis was performed to verify the robustness of this model. RESULTS: To prevent gastric cancer in a cohort of 1 million asymptomatic Chinese families, FBCM and screen-and-treat strategies prevented 1010 and 1201 new gastric cancer cases, reduced 2809 and 3339 gastric cancer-related death, and saved 956,971 and 1,137,549 QALYs, respectively, when compared with no-screen strategy. Cost-effectiveness analysis showed that FBCM strategy cost $9.18/QALY, and screen-and-treat strategy cost $12.08/QALY for gastric cancer prevention when compared with no-screen strategy. One-way sensitivity analysis revealed that screening from younger age by both strategies are more cost-effective. When compared with FBCM strategy, screen-and-treat strategy saved 5.98% gastric cancer cases and 5.78% of gastric cancer deaths, but costed $9348 to reduce a gastric cancer case. Results are not sensitive to any variables, and probabilistic sensitivity analysis confirmed robustness of the results. CONCLUSIONS: Both FBCM and screen-and-treat strategies are cost-effective for gastric cancer prevention compared with no-screen strategy. Since FBCM is more practical and convenient, it may be an efficient and excellent cost-effective strategy for gastric cancer prevention in H. pylori and gastric cancer prevalent areas.

Rabeprazole plus amoxicillin dual therapy is equally effective to bismuth-containing quadruple therapy for Helicobacter pylori eradication in central China: A single-center, prospective, open-label, randomized-controlled trial.

BACKGROUND: Antibiotic resistance emerges as a major issue for Helicobacter pylori (H. pylori) treatment. High-dose dual therapy has recently shown encouraging results in H. pylori eradication, but it has yet to be validated in this H. pylori highly infected area; it is also not known if this concept can be extended to antibiotics other than amoxicillin, and factors that affect the eradication. We investigate if rabeprazole plus amoxicillin or furazolidone regimens could be a first-line therapy for H. pylori eradication, and factors that affect the curing rate. METHODS: This is a single-center, prospective, open-label, randomized-controlled trial. Naive patients (n=292) were randomly treated with bismuth-containing quadruple therapy (BQT), rabeprazole plus amoxicillin (RADT), or furazolidone (RFDT) groups. RADT and FADT use three times daily regimens. H. pylori diagnosis and eradication were determined and confirmed by 13 C-urea breath test. RESULTS: In per-protocol (PP) analysis, H. pylori eradication rate was 91.2% in BQT group, 89.6% in RADT, and 51.0% in RFDT group. In intention-to-treat (ITT) analysis, infection was eradicated in 86.7% of patients in BQT group, 85.8% in RADT, and 48.1% in RFDT groups, respectively. Noninferiority was confirmed between BQT and RADT groups. The incidence of side effects in BQT group was significantly higher than that in RADT group. Successful eradication was associated with lower body surface area (BSA) and low body mass index (BMI) in BQT group. Smoking and high BSA index reduced H. pylori eradication rate in RADT group. CONCLUSIONS: Rabeprazole-amoxicillin dual therapy is equally effective to the bismuth-containing quadruple therapy for H. pylori eradication with fewer side effects and saves use of one antibiotic per each treatment. Successful eradication is also associated with low BSA and non-smoking condition, which deserves future stratified analysis for refinement and optimization.

Whole family-based Helicobacter pylori eradication is a superior strategy to single-infected patient treatment approach: A systematic review and meta-analysis.

BACKGROUND: Two critical concerns during Helicobacter pylori (H. pylori) eradication are the successful eradication and recurrence. It is debatable whether whole family-based H. pylori treatment regimen might have any advantage over single-infected patient treatment approach in increasing eradication rate and reducing recurrence rate. We conduct systematic review and meta-analysis to compare the efficacy of these two treatment regimens in order to provide clinical practice a better option for H. pylori eradication. METHODS: Randomized controlled trials evaluating H. pylori eradication and recurrence in whole family-based treatment group (WFTG) versus single-infected patient treatment group (SPTG) were collected from published literature up to July 2020 from common databases. Pooled results were analyzed using either fixed-effect or random-effect model. Results were expressed as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 1751 relevant articles were identified, and 12 studies were eligible for analysis. Among them: (a) Eight articles including 1198 patients were selected to analyze H. pylori eradication rate, pooled result showed that eradication rate of WFTG was higher than that of SPTG (OR=2.93; 95% CI 1.68-5.13). Stratified analysis showed that H. pylori eradication rate in WFTG were higher over SPTG in children subgroup, but had no difference in spouse subgroup. (b) Six studies including 881 patients were analyzed for recurrence rate between the two groups, pooled analysis showed that the overall recurrence rate of WFTG was lower than that of SPTG (OR=0.3; 95% CI 0.19-0.48). Stratified analysis showed that the recurrence rate in WFTG was lower over SPTG at 6, 12, 18, and more than 24 months post-treatment subgroups. CONCLUSION: Whole family-based H. pylori treatment can partially increase eradication rate and reduce recurrence rate over single-infected patient treatment approach, the results provide clinical practice a novel notion for H. pylori eradication and infection prevention.

Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontaneous and acid-induced matriptase zymogen activation.

The pathophysiological functions of matriptase, a type 2 transmembrane serine protease, rely primarily on its enzymatic activity, which is under tight control through multiple mechanisms. Among those regulatory mechanisms, the control of zymogen activation is arguably the most important. Matriptase zymogen activation not only generates the mature active enzyme but also initiates suppressive mechanisms, such as rapid inhibition by HAI-1, and matriptase shedding. These tightly coupled events allow the potent matriptase tryptic activity to fulfill its biological functions at the same time as limiting undesired hazards. Matriptase is converted to the active enzyme via a process of autoactivation, in which the activational cleavage is thought to rely on the interactions of matriptase zymogen molecules and other as yet identified proteins. Matriptase autoactivation can occur spontaneously and is rapidly followed by the formation and then shedding of matriptase-HAI-1 complexes, resulting in the presence of relatively low levels of the complex on cells. Activation can also be induced by several non-protease factors, such as the exposure of cells to a mildly acidic buffer, which rapidly causes high-level matriptase zymogen activation in almost all cell lines tested. In the current study, the structural requirements for this acid-induced zymogen activation are compared with those required for spontaneous activation through a systematic analysis of the impact of 18 different mutations in various structural domains and motifs on matriptase zymogen activation. Our study reveals that both acid-induced matriptase activation and spontaneous activation depend on the maintenance of the structural integrity of the serine protease domain, non-catalytic domains, and posttranslational modifications. The common requirements of both modes of activation suggest that acid-induced matriptase activation may function as a physiological mechanism to induce pericellular proteolysis by accelerating matriptase autoactivation.

The intracellular seven amino acid motif EEGEVFL is required for matriptase vesicle sorting and translocation to the basolateral plasma membrane.

Matriptase plays important roles in epithelial integrity and function, which depend on its sorting to the basolateral surface of cells, where matriptase zymogen is converted to an active enzyme in order to act on its substrates. After activation, matriptase undergoes HAI-1-mediated inhibition, internalization, transcytosis, and secretion from the apical surface into the lumen. Matriptase is a mosaic protein with several distinct protein domains and motifs, which are a reflection of matriptase's complex cellular itinerary, life cycle, and the tight control of its enzymatic activity. While the molecular determinants for various matriptase regulatory events have been identified, the motif(s) required for translocation of human matriptase to the basolateral plasma membrane is unknown. The motif previously identified in rat matriptase is not conserved between the rodent and the primate. We, here, revisit the question for human matriptase through the use of a fusion protein containing a green fluorescent protein linked to the matriptase N-terminal fragment ending at Gly-149. A conserved seven amino acid motif EEGEVFL, which is similar to the monoleucine C-terminal to an acidic cluster motif involved in the basolateral targeting for some growth factors, has been shown to be required for matriptase translocation to the basolateral plasma membrane of polarized MDCK cells. Furthermore, time-lapse video microscopy showed that the motif appears to be required for entry into the correct transport vesicles, by which matriptase can undergo rapid trafficking and translocate to the plasma membrane. Our study reveals that the EEGEVFL motif is necessary, but may not be sufficient, for matriptase basolateral membrane targeting and serves as the basis for further research on its pathophysiological roles.

Aberrant regulation favours matriptase proteolysis in neoplastic B-cells that co-express HAI-2.

Matriptase is ectopically expressed in neoplastic B-cells, in which matriptase activity is enhanced by negligible expression of its endogenous inhibitor, hepatocyte growth factor activator inhibitor (HAI)-1. HAI-1, however, is also involved in matriptase synthesis and intracellular trafficking. The lack of HAI-1 indicates that other related inhibitor, such as HAI-2, might be expressed. Here, we show that HAI-2 is commonly co-expressed in matriptase-expressing neoplastic B-cells. The level of active matriptase shed after induction of matriptase zymogen activation in 7 different neoplastic B-cells was next determined and characterised. Our data reveal that active matriptase can only be generated and shed by those cells able to activate matriptase and in a rough correlation with the levels of matriptase protein. While HAI-2 can potently inhibit matriptase, the levels of active matriptase are not proportionally suppressed in those cells with high HAI-2. Our survey suggests that matriptase proteolysis might aberrantly remain high in neoplastic B-cells regardless of the levels of HAI-2.

Matriptase shedding is closely coupled with matriptase zymogen activation and requires de novo proteolytic cleavage likely involving its own activity.

The type 2 transmembrane serine protease matriptase is involved in many pathophysiological processes probably via its enzymatic activity, which depends on the dynamic relationship between zymogen activation and protease inhibition. Matriptase shedding can prolong the life of enzymatically active matriptase and increase accessibility to substrates. We show here that matriptase shedding occurs via a de novo proteolytic cleavage at sites located between the SEA domain and the CUB domain. Point or combined mutations at the four positively charged amino acid residues in the region following the SEA domain allowed Arg-186 to be identified as the primary cleavage site responsible for matriptase shedding. Kinetic studies further demonstrate that matriptase shedding is temporally coupled with matriptase zymogen activation. The onset of matriptase shedding lags one minute behind matriptase zymogen activation. Studies with active site triad Ser-805 point mutated matriptase, which no longer undergoes zymogen activation or shedding, further suggests that matriptase shedding depends on matriptase zymogen activation, and that matriptase proteolytic activity may be involved in its own shedding. Our studies uncover an autonomous mechanism coupling matriptase zymogen activation, proteolytic activity, and shedding such that a proportion of newly generated active matriptase escapes HAI-1-mediated rapid inhibition by shedding into the extracellular milieu.

Selective Inhibition of Prostasin in Human Enterocytes by the Integral Membrane Kunitz-Type Serine Protease Inhibitor HAI-2.

Mutations of hepatocyte growth factor activator inhibitor (HAI)-2 in humans cause sodium loss in the gastrointestinal (GI) tract in patients with syndromic congenital sodium diarrhea (SCSD). Aberrant regulation of HAI-2 target protease(s) was proposed as the cause of the disease. Here functional linkage of HAI-2 with two membrane-associated serine proteases, matriptase and prostasin was analyzed in Caco-2 cells and the human GI tract. Immunodepletion-immunoblot analysis showed that significant proportion of HAI-2 is in complex with activated prostasin but not matriptase. Unexpectedly, prostasin is expressed predominantly in activated forms and was also detected in complex with HAI-1, a Kunitz inhibitor highly related to HAI-2. Immunohistochemistry showed a similar tissue distribution of prostasin and HAI-2 immunoreactivity with the most intense labeling near the brush borders of villus epithelial cells. In contrast, matriptase was detected primarily at the lateral plasma membrane, where HAI-1 was also detected. The tissue distribution profiles of immunoreactivity against these proteins, when paired with the species detected suggests that prostasin is under tight control by both HAI-1 and HAI-2 and matriptase by HAI-1 in human enterocytes. Furthermore, HAI-1 is a general inhibitor of prostasin in a variety of epithelial cells. In contrast, HAI-2 was not found to be a significant inhibitor for prostasin in mammary epithelial cells or keratinocytes. The high levels of constitutive prostasin zymogen activation and the selective prostasin inhibition by HAI-2 in enterocytes suggest that dysregulated prostasin proteolysis may be particularly important in the GI tract when HAI-2 function is lost and/or dysregulated.

Efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea and anxiety.

AIM: To investigate the efficacy of tandospirone in patients with irritable bowel syndrome-diarrhea (IBS-D) and anxiety in a prospective, randomized, controlled study. METHODS: Two hundred patients with IBS-D and moderate anxiety were randomized to receive pinaverium and tandospirone (arm A) or pinaverium and placebo (arm B). Tandospirone or placebo was given thrice daily at a fixed dose of 10 mg and pinaverium was given thrice daily at a fixed dose of 50 mg. The duration of treatment was 8 wk. Patients were assessed for abdominal pain and diarrhea. Anxiety was evaluated using the Hamilton Rating Scale for Anxiety (HAM-A). The primary study endpoints were response rates for abdominal pain and diarrhea. The secondary study endpoints were response rates for anxiety. Adverse events were also evaluated. RESULTS: One hundred and seventy of 200 patients (82 patients in arm A and 88 patients in arm B) completed the study. Demographic and baseline characteristics of the 200 participants were comparable in the two arms. At week 8, the overall response rate for abdominal pain and diarrhea was 52.0% for arm A and 37.0% for arm B (P < 0.05). The HAM-A score showed that the response rate was 61.0% for arm A and 21.0% for arm B (P < 0.01). The treatments were well tolerated and no significant adverse events were reported. CONCLUSION: Tandospirone is effective and can be combined with pinaverium in IBS-D patients with anxiety.

[Preliminary study on the effects of an artificial liver support system in the treatment of medicamentous liver insufficiency].

OBJECTIVES: To study the effectiveness of an artificial liver support system. METHODS: Thirty-two patients with medicamentous liver insufficiency were treated with an artificial liver support system in addition to the routine medicinal therapy. Thirty patients treated with routine medicinal therapy only served as controls. RESULTS: The clinical symptoms (e.g. hepatic encephalopathy) and the laboratory indices (serum total bilirubin and prothrombin time) of the treatment group patients were obviously improved compared with those of the control group patients (P < 0.05). The cure rate and hospitalization days were 90.6% (26/32) and 47 days respectively in the treatment group, and 43.3% (13/30) and 72 days in the control group (P < 0.05). CONCLUSION: Using an artificial liver support system combined with routine medicinal therapy is more effective than using medication alone.