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Because non-bleeding visible vessels (NBVV) of gastric peptic ulcers have the potential to re-bleed, endoscopic hemostatic treatment may be necessary during the first emergency endoscopy. However, not all NBVV re-bleed, and endoscopic hemostasis sometimes causes fatal side-effects. Therefore, we have evaluated the risk of re-bleeding from various NBVV in gastric peptic ulcers to determine which types should be treated by endoscopy to prevent re-bleeding. A total of 227 NBVV in 202 patients with gastric peptic ulcers that were endoscopically followed without endoscopic hemostatic procedures were classified by the following factors: vessel color, form, location of the NBVV in the ulcer crater, and location of the ulcer in the stomach. The re-bleeding rate was then analyzed for each type of NBVV. Significantly high rates of re-bleeding were observed in cases with white, protruded and peripheral NBVV. In particular, white NBVV located in the peripheral zone of the ulcer crater were frequent re-bleeding sources. The location of the ulcer in the stomach was not a statistically significant factor in determining re-bleeding rates. We found that white, protruded and peripherally located NBVV in gastric ulcers have a higher chance of re-bleeding if preventive endoscopic hemostatic procedures are not performed. [ABSTRACT FROM AUTHOR]

Sarcopenia is a common skeletal muscle disease in older people. Lower limb muscle strength is a good predictive value for sarcopenia; however, little is known about its genetic components. Here, we conducted a genome-wide association study (GWAS) for knee extension strength in a total of 3452 Japanese aged 60 years or older from two independent cohorts. We identified a significant locus, rs10749438 which is an intronic variant in TACC2 (transforming acidic coiled-coil-containing 2) (P = 4.2 × 10 -8 ). TACC2, encoding a cytoskeleton-related protein, is highly expressed in skeletal muscle, and is reported as a target of myotonic dystrophy 1-associated splicing alterations. These suggest that changes in TACC2 expression are associated with variations in muscle strength in older people. The association was consistently observed in young and middle-aged subjects. Our findings would shed light on genetic components of lower limb muscle strength and indicate TACC2 as a potential therapeutic target for sarcopenia., (© 2024. The Author(s).)

Linear ubiquitin chains, which are generated specifically by the linear ubiquitin assembly complex (LUBAC) ubiquitin ligase, play crucial roles in immune signaling, including NF-κB activation. LUBAC comprises catalytic large isoform of heme-oxidized iron regulatory protein 2 ubiquitin ligase 1 (HOIL-1L) interacting protein (HOIP), accessory HOIL-1L, and SHANK-associated RH domain-interacting protein (SHARPIN). Deletion of the ubiquitin ligase activity of HOIL-1L, an accessory ligase of LUBAC, augments LUBAC functions by enhancing LUBAC-mediated linear ubiquitination, which is catalyzed by HOIP. Here, we show that HOIL-1L ΔRING1 mice, which exhibit augmented LUBAC functions upon loss of the HOIL-1L ligase, developed systemic lupus erythematosus (SLE) and Sjögren's syndrome in a female-dominant fashion. Augmented LUBAC activity led to hyperactivation of both lymphoid and myeloid cells. In line with the findings in mice, we sought to identify missense single nucleotide polymorphisms/variations of the RBCK1/HOIL-1L gene in humans that attenuate HOIL-1L ligase activity. We found that the R464H variant, which is encoded by rs774507518 within the RBCK1/HOIL-1L gene, attenuated HOIL-1L ligase activity and augmented LUBAC-mediated immune signaling, including that mediated by Toll-like receptors. We also found that rs774507518 was enriched significantly in patients with SLE, strongly suggesting that RBCK1/HOIL-1L is an SLE susceptibility gene and that augmented linear ubiquitin signaling generated specifically by LUBAC underlies the pathogenesis of this prototype systemic autoimmune disease.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations., (© 2024. The Author(s).)

Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10 -10 ). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa., (© 2023. Springer Nature Limited.)

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development., Competing Interests: YK, MT, MN, NO, HS, XL, TE, SI, KK, TK, SK, MK, HS, TT, TM, HI, TY, MK, HN, KA, YT, KT, SI, KT, KH, YI, YK, SM, HN, KM, AS, SF, TK, KW, TT, KK, SK, MT, KY, HT, HL, SN, KO, YM, AO, MM, NI, CT, SI No competing interests declared, YK Consulting fees from Medacta International, MY representatives of Japanese Organization of the Study for Ossification of Spinal Ligament, (© 2023, Koike, Takahata, Nakajima et al.)

Systemic lupus erythematosus (SLE) is a complex autoimmune disease involving multiple immune cells. To elucidate SLE pathogenesis, it is essential to understand the dysregulated gene expression pattern linked to various clinical statuses with a high cellular resolution. Here, we conducted a large-scale transcriptome study with 6,386 RNA sequencing data covering 27 immune cell types from 136 SLE and 89 healthy donors. We profiled two distinct cell-type-specific transcriptomic signatures: disease-state and disease-activity signatures, reflecting disease establishment and exacerbation, respectively. We then identified candidate biological processes unique to each signature. This study suggested the clinical value of disease-activity signatures, which were associated with organ involvement and therapeutic responses. However, disease-activity signatures were less enriched around SLE risk variants than disease-state signatures, suggesting that current genetic studies may not well capture clinically vital biology. Together, we identified comprehensive gene signatures of SLE, which will provide essential foundations for future genomic and genetic studies., Competing Interests: Declaration of interests M.O., Y.T., Y.N., and T.O. belong to the Social Cooperation Program, Department of Functional Genomics and Immunological Diseases, supported by Chugai Pharmaceutical. K.F. receives speaking fees, consulting honoraria, and research support from Chugai Pharmaceutical., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis., Methods: We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches., Results: TWAS identified 171 genes for SLE (p<1.0×10 -5 ); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10 -8 ). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 -9 ) around CD83 . For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1 , and that presence of the SLE risk allele decreased ACAP1 expression., Conclusions: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background/aims: Although risk factors of reflux esophagitis (RE) have been investigated in numerous cross-sectional studies, little is known about predictive factors associated with future onset of RE. We investigated time courses of clinical parameters before RE onset by a longitudinal case-control study using health checkup records., Methods: We used health checkup records between April 2004 and March 2014 at 9 institutions in Japan. A multivariate logistic regression analysis was performed to evaluate associations of baseline clinical parameters with RE. The time courses of the clinical parameters of RE subjects were compared with those of non-RE subjects by the mixed-effects models for repeated measures analysis or longitudinal multivariate logistic analysis., Results: Initial data were obtained from 230 056 individuals, and 2066 RE subjects and 4132 non-RE subjects were finally included in the analysis. Body mass index, alanine aminotransferase, smoking, acid reflux symptoms, hiatal hernia, and absence of atrophic gastritis at baseline were independently associated with RE. The time courses of body mass index, fasting blood sugar, triglyceride, aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, percentages of acid reflux symptoms, feeling of fullness, and hiatal hernia in the RE group were significantly worse than in the non-RE group., Conclusions: The RE group displayed a greater worsening of the clinical parameters associated with lifestyle diseases, including obesity, diabetes, hyperlipidemia, and fatty liver for 5 years before RE onset compared with the non-RE group. These results suggest that RE is a lifestyle disease and thus lifestyle guidance to at-risk person may help to prevent RE onset.

Background: Atopic dermatitis (AD) is the most common allergic disease in the world. While genetic components play critical roles in its pathophysiology, a large proportion of its genetic background is still unexplored., Objectives: This study sought to illuminate the genetic associations with AD using genome-wide association study (GWAS) and its downstream analyses., Methods: This study conducted a GWAS for AD comprising 2,639 cases and 115,648 controls in the Japanese population, followed by a trans-ethnic meta-analysis with UK Biobank data and downstream analyses including partitioning heritability analysis by linkage disequilibrium score regression., Results: This study identified 17 significant susceptibility loci, among which 4 loci-AFF1, ITGB8, EHMT1, and EGR2-were novel in the Japanese GWAS. The trans-ethnic meta-analysis revealed 4 additional novel loci, namely-ZBTB38,LOC105755953/LOC101928272, TRAF3, andIQGAP1. This study found a missense variant (R243W) with a deleterious functional effect in NLRP10 and a variant altering expression of CCDC80 via enhancer expression as highly likely causal variants. These 2 regions were Asian-specific, and these population-specific associations could be explained by the frequency of causal variants. The gene-based test showed SMAD4 as an additional novel significant locus. Downstream analyses revealed substantial overlap of GWAS significant signals in enhancers of skin cells and immune cells, especially CD4 T cells. A highly shared polygenic architecture of AD between Europeans and Asians was also found., Conclusions: This study identified Japanese-specific loci and novel significant loci shared by different populations. Two putative causal variants were illuminated in Japanese-specific loci. Trans-ethnic analyses revealed strong heritability enrichment in immune-related pathways, and relevant cell types shared among populations., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Objective: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations., Methods: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations., Results: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10 -8 ). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r g =-0.242) and non-albumin protein (r g =0.238)., Conclusion: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The breakage of an epidural catheter is an extremely rare complication. We describe a unique case where a retained epidural catheter fragment after epidural anesthesia was treated by surgery. The epidural catheter broke during its removal, requiring surgery to remove the retained catheter. Intraoperatively, the removal of the catheter was attempted by simple traction, but was impossible because of the adhesion. The adhesion of the dura mater surface was carefully exfoliated and the successful removal of the catheter was accomplished. Conventionally, it was said that this follow-up was enough for the retained catheter. However, if a catheter is retained within the spinal canal, surgical removal should thus be considered before the adhesion advances.

A 59-year-old woman was hospitalized in June 2012 for Stage IV bilateral breast cancer, axillary lymph-node metastasis, metastatic lung tumor, metastatic bone tumor, right carcinomatous pleuritis, and right-eye choroidal metastasis. Treatment for improvement of symptoms included steroids, continuous subcutaneous infusion of morphine hydrochloride, and thoracic drainage. Chemotherapy with zoledronic acid+TC therapy was administered, with only a small residual primary lesion of the right breast. Interstitial pneumonia caused by the chemotherapy occurred and the volume occupied, it was continued treatment is difficult. In October 2013, she experienced right axillary lymph node metastases, and progress of the right breast cancer, with pain and bleeding from the right breast tumor. Therefore, for the purpose of improving quality of life, Bt+Ax was administered in October 2013, but since the resected part of the right breast included an approximately 10 cm dermal infiltration, a preserved subcutaneous vascular network (PSVN) skin graft was performed using healthy skin. The patient recovered well, the pain and bleeding disappeared, and the patient was discharged following surgery. PSVN skin graft for the purpose of local control was useful in this case.

Objective: Quality of life (QOL) impairment of patients who visit an outpatient clinic for abdominal symptoms has not been clarified. We investigated symptom-related QOL impairment that led patients to seek medical care., Patients and Methods: Abdominal symptom-related QOL was determined using the Izumo scale instrument in 172 patients who visited a clinic for their abdominal symptoms and in 961 healthy subjects who attended an annual health check., Results: QOL was more strongly impaired in the patients with abdominal symptoms than in subjects who attended health checks. Patients with heartburn consulted physicians even when QOL impairment was minimal, while those with epigastric fullness tended to consult a physician only when QOL impairment was significant., Conclusion: Abdominal symptom-related QOL impairment is considered to lead patients to seek medical care, though different symptoms have varying levels of influence.

A 24-year-old female Japanese patient presented with remarkably long roots of retained deciduous anterior teeth and permanent anterior teeth in the upper and lower jaw. Four lower anterior teeth were extracted for esthetic reasons. The patient had no apparent clinical syndrome related to the teeth or jaw, nor did there appear to be a family history of this condition. The extracted teeth and their lengths were as follows: the lower right deciduous lateral incisor was 25.55 mm long (root length, 18.95 mm); the lower left deciduous lateral incisor was 22.10 mm long (root length, 17.25 mm); the lower right deciduous canine was 27.95 mm long (root length, 20.60 mm); and the lower left deciduous canine was 23.90 mm long (root length, 17.65 mm).

Background and Aim: Endoscopic retrograde cholangiopancreatography (ERCP) is a useful diagnostic and therapeutic procedure; however, ERCP occasionally causes post-ERCP pancreatitis. The administration of gabexate mesilate has been reported to be effective for the prevention for post-ERCP pancreatitis when given during and after the procedure. The aim of the present study was to investigate the preventive effect of the novel protease inhibitor ulinastatin on post-ERCP pancreatitis., Methods: One hundred and thirty-nine patients who underwent the ERCP procedure were studied. These patients were randomly divided into three groups based on the agent and dose given during and following the ERCP procedure: gabexate mesilate (900 mg), high-dose ulinastatin (450 000 units) and low-dose ulinastatin (150 000 units). Serum amylase, interleukin (IL)-6 and IL-8 levels and plasma polymorphonuclear leukocyte elastase (PMN-E) activity were measured after ERCP. In addition, post-ERCP hyperamylasemia and post-ERCP pancreatitis were recorded., Results: There were no significant differences in serum amylase, IL-6 and IL-8 levels and PMN-E activity after ERCP procedure between the three groups. Post-ERCP pancreatitis was observed in two (4.3%), three (6.5%) and four (8.5%) cases in the gabexate mesilate, high-dose ulinastatin and low-dose ulinastatin groups, respectively. Multiple logistic regression analysis showed that the addition of endoscopic sphincterotomy during the ERCP procedure was the only significant risk factor for the development of post-ERCP hyperamylasemia and post-ERCP pancreatitis (P = 0.03 and P = 0.04, respectively), but there was no significant difference in the occurrence of post-ERCP hyperamylasemia and post-ERCP pancreatitis between the three groups receiving different preventative treatments., Conclusion: The administration of low- and high-dose ulinastatin has similar effects to high-dose gabexate in the prevention of post-ERCP pancreatitis.

Background: The therapeutic effect of combined administration of prokinetics and histamine H2 receptor antagonists (H2RA) in gastroesophageal reflux disease is reported to be superior to that of monotherapy with H2RA alone. In addition to its acid-suppressing effect, the H2RA nizatidine also has a prokinetic action by suppressing acetylcholine esterase. The present multicenter, randomized controlled study was performed to investigate whether nizatidine is superior to famotidine, which does not suppress acetylcholine esterase activity, in maintenance therapy for erosive esophagitis. In addition, the question as to whether the grade of erosive esophagitis affects the non-recurrence rate during the maintenance therapy with H2RA was also investigated., Methods: Seventy-two patients with endoscopically healed erosive esophagitis after 8 weeks of initial treatment with proton pump inhibitors were randomly divided into two groups. Patients in the nizatidine group were treated with 150 mg nizatidine twice a day (b.i.d.), while patients in the famotidine group were treated with 20 mg famotidine b.i.d. for 6 months. At the end of therapy, and at the time when patients complained of symptoms, endoscopic investigations were repeated to find out whether the esophagitis had recurred., Results: Nizatidine produced a significantly higher non-recurrence rate than famotidine (P = 0.049 in intention-to-treat [ITT] analysis). This difference of remission rate between nizatidine and famotidine was observed mainly in grade B esophagitis (P = 0.016 in ITT analysis)., Conclusion: Nizatidine is a more effective H2RA than famotidine in the maintenance therapy of patients with reflux esophagitis., ((c) 2004 Blackwell Publishing Asia Pty Ltd.)

Background and Aim: Rabeprazole has a faster onset of antisecretory activity than omeprazole and lansoprazole. The aim of the present study was to clarify whether there is any difference in the speed of symptom relief in patients with reflux esophagitis following the administration of these three proton pump inhibitors (PPI)., Methods: Eighty-five patients with erosive reflux esophagitis were randomized to receive 8 weeks of 20 mg of omeprazole (n = 30), 30 mg of lansoprazole (n = 25), or 20 mg of rabeprazole (n = 30) once a morning. Daily changes in heartburn and acid reflux symptoms in the first 7 days of administration were assessed using a six-point scale (0: none, 1: mild, 2: mild-moderate, 3: moderate, 4: moderate-severe, 5: severe)., Results: The mean heartburn score in patients administered rabeprazole decreased more rapidly than those given the other PPI. Complete heartburn remission also occurred more rapidly in patients administered rabeprazole (compared with omeprazole: P = 0.035, compared with lansoprazole: P = 0.038 by log-rank test). No differences were seen in the rate of endoscopic healing of reflux esophagitis at 8 weeks between the three treatment regimens., Conclusion: Rabeprazole may be more effective than omeprazole and lansoprazole for the rapid relief of heartburn symptoms in patients with reflux esophagitis.

The location of calcitonin gene-related peptide (CGRP) receptors in the rat stomach has not been elucidated. It was recently reported that the CGRP receptor is formed when a calcitonin-receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP) 1 are co-expressed on the cell membrane. The aim of this study was to determine the location and the role of CGRP receptors in the rat gastric mucosa. Gene expressions of CRLR and RAMP1 were investigated by Northern blot analysis, reverse transcription-polymerase chain reaction (RT-PCR), and in situ hybridization. Immunohistochemical stainings for CGRP, somatostatin, gastrin, and chromogranin A were performed. Gastric endocrine cells were collected by counterflow-elutriation and their responses to CGRP were studied. CRLR and RAMP1 mRNA was expressed mainly in small gastric epithelial cells in the pyloric glands. The mRNA expression had a similar distribution to that of D cells. In cultured gastric endocrine cells, CGRP enhanced somatostatin production, while it inhibited the secretion of histamine and gastrin. Our results suggest that CGRP receptors are expressed in D cells in the rat gastric mucosa and control production and secretion of somatostatin.

Background: Helicobacter pylori infection induces T helper-1 immune responses in inflamed mucosa. However, the role of T cell-mediated cytotoxicity in the induction of epithelial apoptosis is still unclear. The aim of this study was to investigate the involvement of the Fas/Fas ligand (Fas/Fas-L) system in the H. pylori-infected gastric corpus., Materials and Methods: Gastric fundic biopsy specimens were taken from patients with and without H. pylori infection. The expression of Fas and Fas-L was examined by immunohistochemistry and RT-PCR. Subsets of gastric infiltrating T cells in the biopsy specimens were studied by immunohistochemistry and flow cytometry. In histological sections, apoptosis was detected by the TUNEL method. We studied the in vitro expression of Fas-L in peripheral T cells after stimulation with H. pylori antigen and interferon-gamma (IFN-gamma). The Fas-mediated in vitro cytotoxicity of activated T cells was assessed by flow cytometry., Results: The numbers of CD4+ and CD8+ T cells were greater in H. pylori-infected subjects. Fas expression was abundantly increased on fundic gland epithelium, and Fas-L was detected on lamina propria mononuclear cells in H. pylori-infected mucosa. TUNEL-positive epithelial cells were also increased in H. pylori-infected subjects. H. pylori antigen and IFN-gamma induced Fas-L mRNA expression in both CD4+ and CD8+ T cells. In cytotoxic assay, activated T cells induced apoptosis in AGS cells, which could be significantly inhibited by neutralizing Fas-L antibody., Conclusions: T cell-mediated cytotoxicity via Fas/Fas-L signaling may contribute to the induction of apoptosis in gastric epithelial cells during H. pylori infection.

Background and Aim: Helicobacter pylori (H. pylori) infection is known to affect the gastric microcirculation, and cetraxate is reported to accelerate gastric ulcer healing, possibly by augmenting gastric mucosal blood flow (MBF). The aim of this study is to clarify the effect of H. pylori infection and cetraxate on MBF during gastric ulcer healing., Methods: Forty-two patients who had undergone endoscopic mucosal resection (EMR) were studied. Mucosal blood flow was measured by the use of a laser Doppler flowmeter in the surrounding mucosa and at the ulcer margin, before, 1 day, 1 week and 4 weeks after EMR. Helicobacter pylori infection was confirmed by the use of bacterial culture and histology. After EMR, patients were randomly assigned to receive 30 mg lansoprazole (u.i.d; L-regimen) or 30 mg lansoprazole (u.i.d.) with 200 mg cetraxate (q.i.d; LC-regimen) for 4 weeks., Results: The MBF ratio (MBF at ulcer margin/MBF in surrounding mucosa) 1 week after EMR was significantly lower than that before or 4 weeks after EMR only in H. pylori-positive patients treated with the L-regimen. No such decrease in MBF was observed after 1 week in H. pylori-positive patients treated with the LC-regimen or in H. pylori-negative patients., Conclusion: A transient decrease in MBF was detected at the ulcer margin during healing of EMR-induced ulcers in H. pylori-infected patients. Cetraxate seemed to prevent this decrease in MBF.

Background & Aims: Regenerating (Reg) protein has a trophic effect on gastric mucosal cells. We have shown that Reg gene expression is increased in enterochromaffin-like (ECL) cells during the healing of damaged gastric mucosa around mucosal erosion. This study was designed to explore the stimulants of Reg expression during the healing of gastric mucosal damage., Methods: Time course changes of the expression of genes for various proinflammatory cytokines and Reg were investigated after induction of gastric mucosal lesions in rats. The direct effect of proinflammatory cytokines on Reg gene expression and Reg protein production were investigated in vitro using counterflow elutriation-enriched rat ECL cells. CXC receptor 2 (CXCR-2) expression was investigated in ECL cells by reverse-transcription polymerase chain reaction. Reg gene expression was also investigated in rats treated by the neutralizing antibody of cytokine-induced neutrophil chemoattractant (CINC-2 beta)., Results: During healing, the gene expression of several proinflammatory cytokines and Reg was markedly augmented. Among the proinflammatory cytokines, CINC-2 beta is the only cytokine in which augmented expression preceded the increase of Reg gene expression. In rats treated with CINC-2 beta neutralizing antibody, the augmentation of Reg gene expression was significantly inhibited. When ECL cells were incubated with these proinflammatory cytokines, CINC-2 beta dose-dependently increased Reg messenger RNA and Reg protein in ECL cells. CXCR-2 was identified in isolated ECL cells., Conclusions: CINC-2 beta, expressed in damaged gastric mucosa, stimulates the production of Reg protein in ECL cells via CXCR-2 and may be involved in the accelerated healing of injured gastric mucosa.

Transforming growth factor (TGF) beta1 has an antitumorigenic role in the gastrointestinal tract and may be associated with the development of colon neoplasia. In the present study we investigated whether TGF-beta1 production in mucosa is lower in the distal colon, which is where clinical evidence shows that the incidence of colon neoplasia is higher, and whether TGF-beta1 levels were lower in the mucosa of patients with colon adenoma. Production of colon mucosa TGF-beta1 was investigated by means of a 24-hour organ culture with biopsy specimens taken from different segments of the colon of 58 normal subjects by using an enzyme immunoassay. TGF-beta1 production in colon mucosa from locations near the site of sporadic adenoma was also investigated in 46 patients. TGF-beta1 production gradually increased from the rectum to the ascending colon in a statistically significant manner in both normal (r = 0.77, P < .0001) and adenoma-bearing (r = 0.8, P < .0001) mucosa. When TGF-beta1 production was compared between normal and adenoma-bearing mucosa, levels were lower in the latter, although statistically significant results were seen only in the transverse colon (P < .05). TGF-beta1 production has clear site dependency, being lowest in the rectum and highest in the ascending colon. Furthermore, low levels of TGF-beta1 are associated with the development of adenoma. Our results suggest the possibility that this site dependency is associated with the higher epidemiologic incidence of colon neoplasia in the distal colon.