[Show abstract][Hide abstract] ABSTRACT: Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn's disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of "chronic enteropathy associated with SLCO2A1 gene" (CEAS).
[Show abstract][Hide abstract] ABSTRACT: Objectives
We aimed to evaluate a long-term risk of cancer in the rectal remnant in patients with familial adenomatous polyposis after ileorectal anastomosis.Methods
Cumulative incidence and clinicopathological characteristics of cancer in the rectal remnant were retrospectively investigated in 27 patients with familial adenomatous polyposis who had undergone ileorectal anastomosis.ResultsDuring the follow-up period ranging from 3.0 to 35.0 years (median, 21.1 years), cancer in the rectal remnant developed in 10 patients. The cumulative risk of cancer in the rectal remnant 30 years after surgery was 57%. Five patients had metastases and 3 patients died of cancer in the rectal remnant after proctectomy. There was a trend towards higher incidence of cancer in the rectal remnant in patients with small-intestinal adenoma and congenital hypertrophy of the retinal pigment epithelium. Multivariate analysis revealed that the ocular lesion was an independent risk factor associated with cancer in the rectal remnant.Conclusions
Subtotal colectomy with ileorectal anastomosis does not seem to be an appropriate prophylactic surgery in patients with familial adenomatous polyposis.
[Show abstract][Hide abstract] ABSTRACT: Objectives
Double-balloon endoscopy has enabled direct, detailed examination of the entire small bowel with interventional capabilities. Although its usefulness is recognized, efficacy and safety have not been extensively evaluated by prospective multicenter studies. To evaluate the efficacy and safety of double-balloon endoscopy performed by expert and non-expert endoscopists, a prospective, multicenter study was conducted in five university hospitals and a general hospital in Japan.MethodsA total of 120 patients, who underwent 179 procedures were enrolled to the study. Experts performed 129 procedures and non-experts performed 50 procedures. The primary end point was the rate of achievement of the procedural objectives, namely, identification of a new lesion, detailed examination to establish a therapeutic strategy, or exclusion of significant lesions by total enteroscopy. The secondary end points were the rate of successful examination of the entire small bowel, and evaluation of safety.ResultsThe overall rate of achievement of the procedural objectives was 82.5% (99/120). The overall success rate for examination of the entire small bowel was 70.8% (34/48). The incidence of adverse events was 1.1% (a mucosal injury and an episode of pyrexia in two of 179 examinations). No severe adverse events were encountered. There were no significant differences in any of the outcome measures comparing expert and non-expert operators.Conclusions
Double-balloon endoscopy is effective and safe for patients with suspected small bowel diseases, and can be safely performed even by a non-expert under the supervision of an expert, following a simple training program.
[Show abstract][Hide abstract] ABSTRACT: Many studies have demonstrated that increased carotid intima-media thickness (IMT) is related to future cardiovascular events and is influenced by cardiovascular risk factors such as sex, hypertension, diabetes, and hypercholesterolemia. Although aging is a well-known risk factor for an increase in carotid IMT, few studies have investigated which factors influence carotid IMT in the very elderly. In the present study, we investigated the relationship of pulse pressure (PP), blood pressure (BP), and its variability (six consecutive visits) with carotid IMT among 240 high-risk elderly in whom risk factors were managed clinically (average age was 79 ± 5 years). In the simple correlation, mean systolic BP (SBP) had a positive correlation with IMT and max IMT (P = .012 and P = .045), as did PP (P = .018 and P = .004), but did not diastolic BP or standard deviation of BP and coefficient of variation of BP. In multiple regression analyses, mean SBP and mean PP were each determinants of both IMT and max IMT, when each parameter was added separately to the regression model. We concluded that high SBP and wide PP still have an influence on increased carotid IMT in the very elderly Japanese patients.
[Show abstract][Hide abstract] ABSTRACT: An 80-year-old Japanese woman suffered multiple brain infarctions of unknown etiology during maintenance therapy of prednisolone and azathioprine for ulcerative colitis. Although a small cavity in the left lung spontaneously regressed, the patient suddenly died of massive brain hemorrhage due to disseminated aspergillosis, which was not identified until autopsy.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 04/2013; 110(4):648-54.
[Show abstract][Hide abstract] ABSTRACT: Background & aims:
Crohn's disease is an inflammatory bowel disease induced by multiple genetic and environmental factors. Genome-wide association studies have identified genetic factors that affect the risk for Crohn's disease in European populations, but information from other ethnic groups is scarce. We therefore investigated genetic factors associated with Crohn's disease in the Japanese population.
We performed a genome-wide association study with 372 individuals with Crohn's disease (cases) and 3389 controls, all from the Japanese population. To confirm identified associations, we performed a replication study with an independent panel of 1151 Crohn's disease cases and 15,800 controls. We also performed an association analysis using genome-wide genotype imputation in the discovery cohort.
We confirmed associations of Crohn's disease with variants in MHC (rs7765379, P = 2.11 × 10(-59)), TNFSF15 (rs6478106, P = 3.87 × 10(-45)), and STAT3 (rs9891119, P = 2.24 × 10(-14)). We identified 2 new susceptibility loci: on chromosome 4p14 (rs1487630, P = 2.40 × 10(-11); odds ratio, 1.33), and in the SLC25A15-ELF1-WBP4 region on 13q14 (rs7329174 in ELF1, P = 5.12 × 10(-9); odds ratio, 1.27).
In a genome-wide association study, we identified 2 new susceptibility loci for Crohn's disease in a Japanese population. These findings could increase our understanding of the pathogenesis of Crohn's disease.
[Show abstract][Hide abstract] ABSTRACT: Serum pepsinogen (sPG) levels have been established as a good marker of chronic atrophic gastritis and the sequential occurrence of gastric cancer. However, there have been few prospective investigations which investigated the predictive performance of sPG for future gastric cancer incidence.
We prospectively followed-up a total of 2446 community-dwelling Japanese aged ≥ 40 years for 10 years and used the Youden's index to determine the cutoff values of the pepsinogen I level and pepsinogen I/II ratio to accurately discriminate gastric cancer events. Predictive performance of sPG was assessed by ROC curve.
During the follow-up, 69 subjects developed gastric cancer. The most predictive sPG test criteria were determined to be a pepsinogen I level ≤ 59 ng/ml and pepsinogen I/II ratio ≤ 3.9. The sensitivity and specificity of these criteria to discriminate the actual occurrence of gastric cancer were 71.0% and 69.2%, respectively. The area under the ROC curve for gastric cancer occurrence increased significantly by adding the sPG test to the model that included the status of Helicobater pylori infection and other potential risk factors (from 0.742 to 0.809; p for difference in the area < 0.001).
This study determined the optimal sPG test criteria for predicting gastric cancer occurrence over 10 years in a general Japanese population. These criteria would be effective to screen for individuals at high risk of this disease.
[Show abstract][Hide abstract] ABSTRACT: The authors examined the association between white blood cell (WBC) count and the development of gastric cancer in a 19-year follow-up study of 2,558 Japanese subjects aged ≥40 years (1988-2007). The subjects were stratified into 4 groups according to baseline WBC quartile (≤4.4, 4.5-5.2, 5.3-6.3, or ≥6.4 × 10(3) cells/μL). During follow-up, 128 subjects developed gastric cancer. The age- and sex-adjusted incidence of gastric cancer increased linearly with higher WBC level: 1.7, 2.6, 3.9, and 5.4 per 1,000 person-years, respectively, for the 4 quartile groups (P for trend < 0.01). The risk of gastric cancer was 2.22-fold (95% confidence interval: 1.19, 4.14) higher in the highest WBC quartile group than in the lowest group after adjustment for confounding factors. With respect to Helicobacter pylori infection status, H. pylori-seropositive subjects in the highest WBC quartile group showed a significantly greater risk of gastric cancer than those in the lower 3 quartile groups, whereas such an association was not observed in H. pylori-seronegative subjects. There was no evidence of heterogeneity in the association (P for heterogeneity = 0.65). The study findings suggest that higher WBC levels are a risk factor for gastric cancer, especially in subjects with H. pylori infection.
American journal of epidemiology 02/2012; 175(6):504-10. DOI:10.1093/aje/kwr345 · 5.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular calcification is closely related to cardiovascular morbidity and mortality. Accumulating data indicate that oxidative stress is associated with dysfunction of various organs, including cardiovascular diseases in chronic kidney disease (CKD). However, it remains undetermined if oxidative stress induced by uremia promotes arterial medial calcification. The present study investigated the role of oxidative stress in the pathogenesis of arterial medial calcification in uremic rats. Rats with uremia induced by adenine-rich diet progressively developed arterial medial calcification, which was accompanied by time-dependent increases in both aortic and systemic oxidative stress. Immunohistochemical and biochemical analyses showed that the arterial medial calcification progressed in a time-dependent manner that is parallel to the osteogenic transdifferentiation of vascular smooth muscle cells. Accumulation of oxidative stress was also identified in the calcified regions. Time-course studies indicated that both oxidative stress and hyperphosphatemia correlated with arterial medial calcification. Tempol, an antioxidant, ameliorated osteogenic transdifferentiation of vascular smooth muscle cells and arterial medial calcification in uremic rats, together with reduction in aortic and systemic oxidative stress levels, without affecting serum biochemical parameters. Our data suggest that oxidative stress induced by uremia can play a role in the pathogenesis of vascular calcification in CKD, and that antioxidants such as tempol are potentially useful in preventing the progression of vascular calcification in CKD.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2012; 27(2):474-85. DOI:10.1002/jbmr.539 · 6.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To clarify the efficacy of medication versus carotid endarterectomy (CEA), we investigated cardiovascular events and outcomes in Japanese patients with moderate carotid stenosis. We consecutively registered patients with significant carotid stenosis (50%-79%) measured by digital subtraction angiography (DSA) over 10 years and compared the incidences of stroke, myocardial infarction, and death between treatment groups (surgical group vs medical group). Of 406 registered patients, 163 (108 treated surgically and 55 treated medically) with moderate carotid stenosis were analyzed. Complete follow-up data (mean, 4.2 years) were available for 105 patients in the surgical group (97.2%) and 54 patients in the medical group (98.2%). Surgical treatment was associated with lower incidences of any stroke, myocardial infarction, and death compared with medication. Although the incidence rates differed significantly between CEA and medication in the 66 symptomatic patients, there were no significant differences in the 93 asymptomatic patients. The results of this single-center study in Japanese patients suggest that CEA is an acceptable treatment for patients with symptomatic moderate carotid stenosis, but that CEA for asymptomatic moderate carotid stenosis seems to be less effective in Japanese patients.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 01/2012; 21(1):24-9. DOI:10.1016/j.jstrokecerebrovasdis.2010.03.016 · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic nonspecific multiple ulcer of the small intestine is a recently proposed enteropathy characterized by persistent blood and protein loss from the small-bowel. We examined possible segregation of the disease in family pedigrees.
All cases of the disease diagnosed at our institution were reviewed with respect to particular focuses on the presence of close consanguinity in the families, the enteroscopic findings and the long-term clinical course. The diagnosis was based on persistent occult gastrointestinal bleeding and hypoproteinemia for more than 5 years, and irregularly shaped shallow ulcers in the ileum.
During a 45-year-period, 13 patients were diagnosed as having the disease. There were 11 females and 2 males, with ages ranging from 8 to 37 years at the time of the initial presentation and with those from 13 to 38 years at the diagnosis. Enteroscopy performed in 11 patients with a time duration ranging from 0.5 to 44 years after the diagnosis revealed active ileal ulcers in 10 patients. Parents' consanguineous marriage was verified in 6 patients, two of whom also had siblings with the enteropathy. Another patient without consanguinity had a sibling with protein-losing enteropathy.
Chronic nonspecific multiple ulcer of the small intestine seems to segregate in offspring from consanguineous marriage.
Journal of Crohn s and Colitis 12/2011; 5(6):559-65. DOI:10.1016/j.crohns.2011.05.008 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both ulcerative colitis (UC) and Crohn's disease (CD) have a complex etiology involving multiple genetic and environmental factors. Many genome-wide association studies (GWAS) and subsequent replication studies revealed that both diseases share some of the susceptibility loci; however, common genetic factors for both diseases are not fully elucidated. This study is aimed to identify the common genetic factors for CD and UC by a meta-analysis of published studies.
We first reviewed the 10 GWAS for CD to select candidate single nucleotide polymorphisms (SNPs). Next, we performed a PubMed literature search up to June 30, 2010 and carried out a systemic review of published studies that examined the association of CD susceptibility loci in UC patients. Meta-analysis was carried out using the inverse variance-weighted method or the DerSimonian-Laird method after estimating the heterogeneity among the studies. The data for highly linked SNPs were combined. Finally, we performed a meta-analysis of 43 published studies in 45 SNPs located at 33 loci by using a total of 4852 to 31,125 subjects.
We confirmed the association of 17 reported common susceptibility loci. Moreover, we found associations at eight additional loci: GCKR, ATG16L1, CDKAL1, ZNF365, LRRK2-MUC19, C13orf31, PTPN2, and SBNO2. The genetic risk of each locus was modest (odds ratios ranged from 1.05-1.22) except IL23R.
These results indicate that CD and UC share many susceptibility loci with small genetic effect. Our data provide further understanding of the common pathogenesis between CD and UC.
[Show abstract][Hide abstract] ABSTRACT: The effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab.
Cytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6 weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6 weeks after infliximab infusion.
At baseline, serum levels of IL-23 (p<0.05), IL-17A (p<0.01), IFN-γ (p<0.05), and IL-6 (p<0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p<0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter.
Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.
Journal of Crohn s and Colitis 11/2011; 6(5):529-35. DOI:10.1016/j.crohns.2011.10.010 · 6.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The results of prospective studies examining the association between dietary vitamin A intake and the risk of gastric cancer have often been conflicting. The objective of this study was to investigate this issue in a general Japanese population.
A total of 2,467 community-dwelling Japanese subjects aged 40 years or older were followed up prospectively for 14 years. Dietary vitamin A intake was estimated using a semiquantitative food frequency method.
During the follow-up period, gastric cancer developed in 93 subjects. The age- and sex-adjusted incidence of gastric cancer rose progressively with increasing levels of dietary vitamin A intake: at 2.2, 3.0, 3.8, and 4.5 per 1,000 person-years for quartile groups defined by dietary vitamin A intake levels of <639, 639-837, 838-1,061, and >1,061 μg retinol equivalents (RE)/day, respectively (P for trend <0.01). The risk of gastric cancer was significantly higher in the fourth quartile than in the first one even after multivariate adjustment [hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 0.70-3.09, P = 0.30 for the second quartile; HR = 1.85, 95% CI = 0.82-4.18, P = 0.14 for the third quartile; HR = 2.96, 95% CI = 1.12-7.80, P = 0.03 for the fourth quartile]. Comparable effects of vitamin A intake were observed irrespective of the location or histological type of gastric cancer. The HR for gastric cancer increased significantly only in subjects with a combination of high vitamin A intake (>1,061 μg RE/day) and Helicobacter pylori infection.
Our findings suggest that dietary vitamin A intake is clearly associated with the risk of gastric cancer in the general Japanese population.
Gastric Cancer 09/2011; 15(2):162-9. DOI:10.1007/s10120-011-0092-7 · 3.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Activation-induced cytidine deaminase (AID) is a DNA/RNA-editing enzyme that is essential for hypermutation and class-switch recombination in immunoglobulin genes. The aim of this study was to investigate the expression of AID and its association with p53 mutation in ulcerative colitis (UC)-associated carcinogenesis.
The expression of AID was examined in 25 patients with UC-associated neoplasia, 20 UC patients without neoplasia, 18 patients with non-inflamed colorectal mucosa unaffected by UC, and 19 patients with sporadic colorectal cancer, by immunohistochemistry and quantitative reverse transcription polymerase chain reaction analysis. Mutational analysis and immunohistochemistry for p53 were also performed. The degree of AID expression was not different between UC-associated neoplasia and sporadic colorectal cancer. However, AID was expressed in both UC-associated neoplasia and UC without neoplasia. Whereas AID expression in UC-associated neoplasia was not correlated with the grade of dysplasia, expression in non-neoplastic mucosa of UC was correlated with the histological grade of inflammation. In UC-associated neoplasia, there was no significant correlation between AID expression and p53 mutation.
AID is associated with inflammation in UC, whereas it may not specifically contribute to carcinogenesis in UC.
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence suggests that mineralocorticoid receptor (MR) blockade effectively reduces proteinuria in diabetic nephropathy although the renin-angiotensin-aldosterone system is generally suppressed in diabetes. The present study was designed to confirm the antiproteinuric effect of MR blockade in diabetic rats and elucidate its mechanism.
The present study investigated whether MR blockade inhibits hyperglycemia-induced podocyte injury, focusing on the involvement of reactive oxygen species (ROS) production, in diabetic rats and cultured podocytes. Sprague-Dawley rats were divided into three groups: control, streptozotocin (STZ; 75 mg/kg)-injected diabetic and STZ treated with spironolactone (SPL; 50 mg/kg/day) and sacrificed after 8, 16 and 24 weeks.
Rats gradually developed proteinuria from 8 weeks after induction of diabetes. Immunostaining for Wilms' tumor-1 (WT1) and synaptopodin, markers of podocytes, was attenuated, whereas immunostaining for desmin, a marker of podocyte damage, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, was up-regulated in the glomeruli of diabetic rats. Diabetic rats showed hypoaldosteronemia compared to the control, whereas SPL decreased proteinuria, ROS production and podocyte damage. To elucidate the paradox between hypoaldosteronemia and effect of SPL under hyperglycemia, the role of high glucose in MR activation and podocyte injury was explored. In cultured MR-expressing podocytes, high glucose significantly enhanced Sgk1 expression, activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and ROS production and induced podocyte apoptosis. All these effects were inhibited by SPL.
We conclude that hyperglycemia in diabetes, independent of plasma aldosterone concentration, induces podocyte injury through MR-mediated ROS production and leads to proteinuria. SPL inhibits hyperglycemia-induced podocyte injury by attenuating ROS production.
[Show abstract][Hide abstract] ABSTRACT: Nonsteroidal anti-inflammatory drugs (NSAIDs) induce a broad spectrum of toxicologic manifestations throughout the gastrointestinal tract, including the large intestine. Even though several studies indicated that NSAIDs can cause perforation and bleeding of diverticula or they exacerbate inflammatory bowel disease, NSAIDs possibly damage the normal large intestine; such involvement has been characterized by ulceration, stricture and colitis. And NSAIDs might be an etiological factor in collagenous colitis. While severe stricture, which has been referred to as "diaphragm-like stricture", has been known to be the most characteristic phenotype of the colonic involvement, NSAIDs-induced colonic ulceration should be regarded as a preceding stage for the stricture formation. Further epidemiological studies and therapeutic trials are warranted to clarify NSAIDs-induced colopathy.
Nippon rinsho. Japanese journal of clinical medicine 06/2011; 69(6):1098-103.
[Show abstract][Hide abstract] ABSTRACT: Evaluating small bowel patency is recommended for capsule endoscopy in patients suspected of nonsteroidal anti-inflammatory drug-induced (NSAID) enteropathy.
The aim of this investigation was to examine whether radiography is a candidate of patency tool in NSAID enteropathy.
We reviewed double-contrast barium enteroclysis in 21 patients with NSAID enteropathy diagnosed either by capsule endoscopy or balloon-assisted endoscopy. The endoscopic findings were classified into circular ulcers, linear ulcers and small mucosal defects. The radiographic signs of the corresponding endoscopic findings were retrieved and the depiction rate was calculated.
Of the 21 patients, endoscopy detected circular ulcers, linear ulcers, and small ulcers in 12, 3 and 12 patients, respectively. Small bowel radiography depicted circular narrowing as pseudo-folds in 10 patients (83%) and linear ulcers as eccentric rigidity in 2 patients (67%). However, radiography was able to depict small mucosal defects in only 3 patients (17%). Two of 5 patients with pseudo-folds experienced retention of the capsule.
"Pseudo-folds" is a sign corresponding to circular ulcer in NSAID enteropathy, which may be predictive of capsule retention.