Mesenchymal Stem Cell-Mediated Therapy of Peripheral Artery Disease Is Stimulated by a Lamin A-Progerin Binding Inhibitor

Objective@#Human adipose tissue-derived mesenchymal stem cells (ASCs) have been reported to promote angiogenesis and tissue repair. However, poor survival and engraftment efficiency of transplanted ASCs are the major bottlenecks for therapeutic application. The present study aims to improve the therapeutic efficacy of ASCs for peripheral artery diseases. @*Methods@#Hydrogen peroxide (H2O2) was used to induce apoptotic cell death in ASCs.To measure apoptosis, we used flow cytometry-based apoptosis analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. A murine hindlimb ischemia model was established to measure the ASC-mediated therapeutic angiogenesis and in vivo survival ability of ASCs. @*Results@#We identified that the inhibitor of lamin A-progerin binding, JH4, protects ASCs against H2O2-induced oxidative stress and apoptosis. Co-administration of ASCs with JH4 improved ASC-mediated blood reperfusion recovery and limb salvage compared to that of the control group in a mouse hind limb ischemia model. Immunofluorescence showed that JH4 treatment potentiated ASC-mediated vascular regeneration via reducing ASC apoptosis post transplantation. @*Conclusion@#JH4 exerts anti-apoptotic effects in ASCs in conditions of oxidative stress, and contributes to the repair of ischemic hind limb injury by improving cell survival.

Gender-specific Effect of Micronutrient on Non-erosive Reflux Disease and Erosive Esophagitis

BACKGROUND/AIMS: The effect of dietary micronutrients on non-erosive reflux disease (NERD) and reflux esophagitis is unclear. We aim to evaluate the gender-specific effect of micronutrient on erosive esophagitis and NERD. METHODS: A total of 11 690 participants underwent endoscopy and completed 3-day recordings for dietary intake and questionnaires for reflux symptoms from 2004 to 2008. To evaluate the effect of dietary micronutrients on NERD or erosive esophagitis, adjusted regression analysis with odds ratio (OR) and 95% confidence interval (CI) was used. In addition, we performed gender-specific analysis. RESULTS: Prevalence of NERD and erosive esophagitis was 6.8% and 11.2% in men and 9.1% and 2.4% in women. In adjusted analysis, high intake of vitamin A (OR, 0.78; 95% CI, 0.64–0.96), retinol (OR, 0.73; 95% CI, 0.59–0.90), vitamin B2 (OR, 0.68; 95% CI, 0.54–0.87), vitamin B6 (OR, 0.75; 95% CI, 0.58–0.96), folic acid (OR, 0.77; 95% CI, 0.62–0.96), calcium (OR, 0.66; 95% CI, 0.53–0.82), and iron (OR, 0.68; 95% CI, 0.53–0.87) had an inverse association with NERD. However, erosive esophagitis has no relationship with micronutrients except vitamin C (OR, 0.78; 95% CI, 0.62–0.98). High dietary intake of calcium reduced the risk of NERD in men and high dietary intake of many micronutrients reduced NERD in women. CONCLUSIONS: While many dietary micronutrients reduced NERD, they had no effect on erosive esophagitis. The effect of micronutrient on NERD was more prominent in women than men.

Quality of Bowel Preparation for Colonoscopy in Patients with a History of Abdomino-Pelvic Surgery: Retrospective Cohort Study

PURPOSE: Prior abdomino-pelvic (AP) surgery makes colonoscopy difficult and can affect bowel preparation quality. However, bowel preparation quality has been found to vary according to prior AP surgery type. We examined the relationship of prior AP surgery type with bowel preparation quality in a large-scale retrospective cohort. MATERIALS AND METHODS: In the health screening cohort of the National Cancer Center, 12881 participants who underwent screening or surveillance colonoscopy between June 2007 and December 2014 were included. Personal data were collected by reviewing patient medical records. Bowel preparation quality was assessed using the Aronchick scale and was categorized as satisfactory for excellent to good bowel preparation or unsatisfactory for fair to inadequate bowel preparation. RESULTS: A total of 1557 (12.1%) participants had a history of AP surgery. The surgery types were colorectal surgery (n=44), gastric/small intestinal surgery (n=125), appendectomy/peritoneum/laparotomy (n=476), cesarean section (n=278), uterus/ovarian surgery (n=317), kidney/bladder/prostate surgery (n=19), or liver/pancreatobiliary surgery (n=96). The proportion of satisfactory bowel preparations was 70.7%. In multivariate analysis, unsatisfactory bowel preparation was related to gastric/small intestinal surgery (odds ratio=1.764, 95% confidence interval=1.230–2.532, p=0.002). However, the other surgery types did not affect bowel preparation quality. Current smoking, diabetes, and high body mass index were risk factors of unacceptable bowel preparation. CONCLUSION: Only gastric/small intestinal surgery was a potential risk factor for poor bowel preparation. Further research on patients with a history of gastric/small intestinal surgery to determine appropriate methods for adequate bowel preparation is mandatory.

Effect of Abdominal Visceral Fat Change on the Regression of Erosive Esophagitis: A Prospective Cohort Study

BACKGROUND/AIMS: Although abdominal visceral fat has been associated with erosive esophagitis in cross-sectional studies, there are few data on the longitudinal effect. We evaluated the effects of abdominal visceral fat change on the regression of erosive esophagitis in a prospective cohort study. METHODS: A total of 163 participants with erosive esophagitis at baseline were followed up at 34 months and underwent esophagogastroduodenoscopy and computed tomography at both baseline and follow-up. The longitudinal effects of abdominal visceral fat on the regression of erosive esophagitis were evaluated using relative risk (RR) and 95% confidence intervals (CIs). RESULTS: Regression was observed in approximately 49% of participants (n=80). The 3rd (RR, 0.13; 95% CI, 0.02 to 0.71) and 4th quartiles (RR, 0.07; 95% CI, 0.01 to 0.38) of visceral fat at follow-up were associated with decreased regression of erosive esophagitis. The highest quartile of visceral fat change reduced the probability of the regression of erosive esophagitis compared to the lowest quartile (RR, 0.10; 95% CI, 0.03 to 0.28). Each trend showed a dose-dependent pattern (p for trend < 0.001). The presence of baseline Helicobacter pylori increased the regression of erosive esophagitis (RR, 2.40; 95% CI, 1.05 to 5.48). CONCLUSIONS: Higher visceral fat at follow-up and a greater increase in visceral fat reduced the regression of erosive esophagitis in a dose-dependent manner.

Osteoporosis and Osteoporotic Fractures in Gastrointestinal Disease

Patients with gastrointestinal disease (GI) are at risk for osteopenia or osteoporosis, which can lead to fractures. Although these patients may be at risk from a young age, gastroenterologists often overlook this fact in practice. There are well-known GI diseases associated with osteopenia and osteoporosis, such as the post-gastrectomy state, inflammatory bowel disease (IBD), and celiac disease. As there is an increase in the prevalence of IBD patients, newly diagnosed celiac disease in adulthood, and gastric cancer survivors following gastrectomy, bone disease in these patients becomes an important issue. Here, we have discussed osteoporosis and fractures in GI disease, especially in the post-gastrectomy state, IBD, and celiac disease. Although the pathogenesis of bone loss in each disease has not been fully identified, we have confirmed that the prevalence of osteoporosis and fractures in each of these diseases is high. There are scarce studies comparing the prevalence of osteoporosis or osteoporotic fractures in GI disease patients with studies in postmenopausal women, and specific guidelines for their management in each disease have not been established. Intensive surveillance and management are needed to ensure that these patients attain peak bone mass for age and sex to prevent fractures.

Infection of human intestinal epithelial cells by invasive bacteria activates NF-κB and increases ICAM-1 expression through NOD1

BACKGROUND/AIMS@#Nucleotide-binding oligomerization domain 1 (NOD1) is required for primary intestinal epithelial cells (IECs) to respond to natural mucopeptides secreted by gram-negative bacteria. Infection of human IECs with invasive bacteria up-regulates intercellular adhesion molecule-1 (ICAM-1) expression. However, the role of NOD family members in host defense has been largely unknown. The aim of this study was to determine whether there is a functional role for NOD1 in the up-regulation of ICAM-1 expression in invasive bacteria-infected IECs.@*METHODS@#ICAM-1 mRNA expression was compared between controls, Caco-2 or HT29 cells transfected with an empty vector, and IECs stably transfected with a dominant-negative (DN) NOD1. Expression was compared using qualitative reverse transcription polymerase chain reaction (RT-PCR), real-time RT-PCR, and flow cytometry after infection with enteroinvasive Escherichia coli O29:NM or Shigella flexneri. Nuclear factor kB (NF-κB) activation was determined by electrophoretic mobility shift assays.@*RESULTS@#DN NOD1 significantly inhibited the up-regulation of ICAM-1 expression in response to an enteroinvasive bacterial infection. The Caco-2 cells transfected with DN NOD1 manifested marked inhibition of NF-kB activation in response to E. coli O29:NM infection.@*CONCLUSIONS@#Signaling through NOD1 may play an essential role in neutrophil trafficking following infection with enteroinvasive bacteria.

Effect of Helicobacter pylori eradication on the regression of gastric polyps in National Cancer Screening Program

BACKGROUND/AIMS: Western guidelines recommend Helicobacter pylori eradication in H. pylori-associated gastric polyps; however, there is no standard guideline in Korea. The aim of this study is to assess the effect of H. pylori eradication on the regression of gastric hyperplastic polyps in National Cancer Screening Cohort, representative of general population. METHODS: Among participants in National Cancer Screening Program, subjects who had H. pylori positive gastric hyperplastic polyps less than 10 mm and underwent follow-up endoscopy and H. pylori testing were enrolled. The effect of H. pylori eradication on hyperplastic gastric polyps was estimated using odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: A total of 183 H. pylori infected subjects with hyperplastic polyp at baseline underwent follow-up endoscopy and H. pylori test after mean of 2.2 years. Successful H. pylori eradication markedly induced the disappearance of hyperplastic polyps comparing to non-eradication group (83.7% vs. 34.1%, p = 0.001). Successful eradication increased the possibility of disappearance of hyperplastic polyps (adjusted OR, 5.56; 95% CI, 2.63 to 11.11). Polyp size was inversely related with the disappearance of hyperplastic polyps (adjusted OR, 59; 95% CI, 0.48 to 0.71). CONCLUSIONS: Eradication of H. pylori infection may induce disappearance of gastric hyperplastic polyps in National Cancer Screening Cohort.

The Effect of Abdominal Visceral Fat, Circulating Inflammatory Cytokines, and Leptin Levels on Reflux Esophagitis

BACKGROUND/AIMS: Although adipocytes secrete inflammatory cytokines and adipokines, their role in reflux esophagitis is controversial. We investigated the association between visceral fat and inflammatory cytokines or adipokines in reflux esophagitis. METHODS: Abdominal visceral fat and cytokines were measured in 66 individuals with reflux esophagitis and 66 age- and sex-matched controls. The mean values for visceral fat and cytokines were compared in cases and controls. Second, correlations between visceral fat and inflammatory cytokines were measured. Finally, multiple logistic regression models for odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the effects of visceral fat and cytokines on reflux esophagitis. RESULTS: Visceral fat, leptin, interleukin (IL)-6, and IL-1beta were higher in reflux esophagitis compared to controls. Visceral fat showed a strong positive correlation with IL-6 (r = 0.523, P < 0.001), IL-8 (r = 0.395, P < 0.001), and IL-1beta (r = 0.557, P < 0.001), and a negative correlation with adiponectin (r = -0.466, P < 0.001). With adjusted analysis, visceral fat/100 (OR, 4.32; 95% CI, 2.18-8.58; P < 0.001) and leptin (OR, 1.36; 95% CI, 1.10-1.69; P = 0.005) independently increased the risk of reflux esophagitis, but the effects of other cytokines were abolished. CONCLUSIONS: Visceral fat may increase the risk of reflux esophagitis by increasing the levels of inflammatory cytokines. Leptin showed a positive association with reflux esophagitis that was independent of visceral fat.

Irritable Bowel Syndrome Is Associated With Gastroesophageal Reflux Symptom but Not Erosive Esophagitis

BACKGROUND/AIMS: Although several studies have suggested overlaps between gastroesophageal reflux symptom and irritable bowel syndrome (IBS), the studies for the association between erosive esophagitis and IBS are rare. The aim of this study was to evaluate the association among IBS, non-erosive reflux disease (NERD), and erosive esophagitis. METHODS: A total of 2,769 participants completed questionnaires and underwent esophagogastroduodenoscopy and colonoscopy. IBS was diagnosed by Rome III; NERD was defined as heartburn or acid regurgitation occurring at least once per week without erosive esophagitis. Erosive esophagitis was defined by Los Angeles classification. Psychological distress was evaluated with modified 4 dimensions from revised Hopkins symptom checklist 90. RESULTS: Psychological distress was associated with both IBS and NERD, but not with erosive esophagitis. IBS was associated with somatization (adjusted OR, 2.88; 95% CI, 1.55-5.36; P < 0.001), anxiety (adjusted OR, 2.82; 95% CI, 1.36-5.88; P = 0.005), and hostility (adjusted OR, 2.06; 95% CI, 1.10-3.87; P = 0.024) and NERD was associated with somatization (adjusted OR, 5.65; 95% CI, 2.92-10.98; P < 0.001) and anxiety (adjusted OR, 3.29; 95% CI, 1.47-7.34; P = 0.004). Erosive esophagitis was associated with somatization (adjusted OR, 2.69; 95% CI, 1.26-7.91; P < 0.001). Hiatal hernia and male sex were related with erosive esophagitis but not with IBS or NERD. H. pylori had an inverse relationship with erosive esophagitis, but had no association with IBS. Whereas IBS was positively associated with NERD (adjusted OR, 2.72; 95% CI, 1.84-4.03; P < 0.001), it had no association with erosive esophagitis. CONCLUSIONS: IBS shared many risk factors with NERD but not with erosive esophagitis. It partially explains why IBS was associated with NERD, but not with erosive esophagitis.

Prevalence and Risk Factors of Irritable Bowel Syndrome in Healthy Screenee Undergoing Colonoscopy and Laboratory Tests

INTRODUCTION: The prevalence of irritable bowel syndrome (IBS) after excluding organic disease has not been reported in Korea. METHODS: Of 5,605 participants in a health screening program, inclusion criteria were persons who underwent colonoscopy and completed questionnaires. Exclusion criteria were persons diagnosed with colon cancer, inflammatory bowel disease, previous colectomy, and abnormal results of thyroid function tests. IBS was defined by Rome III criteria. Physical and psychological stress was evaluated with visual analogue scales, ranging from 0 to 10. Risk factors for IBS were estimated with odds ratios (OR) and 95% confidence intervals (CI) using logistic regression analysis. RESULTS: The prevalence of IBS was 8.2% (5,605) in the total population and 9.1% (393/4,296) in the final study sample. IBS had a positive association with female sex (adjusted OR, 1.33; 95% CI, 1.00-1.79; p = 0.05) and current smoking (adjusted OR, 1.31; 95% CI, 1.00-1.71; p = 0.05). The prevalence of IBS increased with increased psychological stress (adjusted p for trend = 0.005) and decreased with increasing age (adjusted p for trend <0.001), with adjusted OR of 0.95 (95% CI, 0.68-1.33) for age of 40.0 to 49.9 years; 0.79 (95% CI, 0.54-1.15) for age of 50.0 to 59.9 years; and 0.51 (95% CI, 0.30-0.86) for age of 60 years or more, compared with age less than 40 years. Drinking status, body mass index, hypertension, diabetes, and use of sedatives had no association with IBS. CONCLUSIONS: The prevalence of IBS increased with decreasing age and increasing psychological stress, and was positively associated with female sex and current smoking.

Rescue therapies for Helicobacter pylori infection after failure of proton pump inhibitor-based standard triple therapy / 대한내과학회지

BACKGROUND/AIMS: Proton pump inhibitor (PPI)-based standard triple therapy for Helicobacter pylori infection is widely used, but it has a considerable failure rate. The aim of this study was to evaluate the efficacy and tolerability of rescue therapies with a quadruple regimen and a rifabutin-based regimen for patients who experienced failure with PPI-based standard triple therapy. METHODS: From July 2004 through October 2006, 52 patients for whom first line triple therapy (PPI, amoxicillin and clarithromycin) had failed were included in this study. They were treated with a quadruple regimen for 7 days (PPI, bismuth, tetracycline and metronidazole) as a second line therapy. For third line therapy, a rifabutin-based regimen (PPI, rifabutin and amoxicillin) was prescribed for 14 days. The H. pylori status was determined before and at least 4 weeks after therapy by the 13C urea breath test or by endoscopy with antral and corpus biopsies for a rapid urease test, histological examination and culture. RESULTS: The mean age was 52.6 years. Thirteen patients (25%) of the 52 patients were dropped. The eradication rate of the quadruple therapy was 84.6% (33/39). Three patients of the 6 failures with quadruple therapy were then treated with the rifabutin-based regimen. The eradication rate of the rifabutin-based therapy was 100% (3/3). Adverse effects (10.2%) were reported in 4 patients who were treated with quadruple regimen. CONCLUSIONS: The quadruple regimen is still an effective second-line therapy for Korean patients who experience failure with PPI-based standard triple therapy. The rifabutin-based regimen could be used as a third-line rescue therapy in Korea.

Clinicopathologic Study of Colorectal Polyps and Obesity in Korean Adults / 대한소화기학회지

BACKGROUD/AIMS: Obesity is a rising problem in industrialized countries. Numerous epidemiologic studies have shown a positive association between obesity and colorectal polyps. There are few studies investigating the association between colorectal adenomatous polyps and body fat composition in Korea. We tried to examine the relationship between body fatness and colorectal adenomatous polyps in health check-up subjects in Korea. METHODS: Six thousand seven hundred and six routine health check-up subjects, who visited our hospital between March 2002 and April 2005 and underwent distal colon examimation with sigmoidoscopy, were enrolled in this study. Among them, colonoscopy was done in 860 patients to evaluate the entire colon. We tried to reveal the relationship between body mass index (BMI) and size, location, number and histopathological type of polyps. BMI was used as an indicator of obesity. RESULTS: The mean value of BMI in total polyp-free group (23.8+/-2.9) was not different from that of the polyp group (24.5+/-2.8, p=0.09). The frequency of rectosigmoid polyps in obese patients (20.4%) was higher than that in non-obese patients (16.0%, p or =4) correlated well with obesity. Moreover, age and triglyceride level in patients with colonic adenoma were significantly higher than in patients without colonic adenom. CONCLUSIONS: This study shows that obesity is not associated with colonic adenomatous polyp in Korean population. However, we observed that obesity may be associated with rectosigmoid colon polyps. Furthermore, age and triglyceride level might be the risk factors of colonic adenomatous polyps in Korean population.

Correlation of Helicobacter pylori Serology Titer with Endoscopic and Histologic Findings / 대한소화기내시경학회지

BACKGROUND/AIMS: In clinical practice, among the technique to detected Helicobacter pylori (H. pylori) infection, IgG serological test is noninvasive, safe, quick, widely available, and inexpensive. We studied that whether the titers of anti-H. pylori IgG antibody were correlated with endoscopic finding, and the degree of microscopic gastric damage and H. pylori density in dyspeptic patients. METHODS: Gastric biopsy specimens were obtained in 109 patients with H. pylori infection undergoing upper gastric endoscopy. The titers of serum IgG antibodies to H. pylori were measured by enzyme immunoassay. Macroscopic gastric damages and histologic grades were scored by the Sydney system. RESULTS: Endoscopic findings showed no significant association with H. pylori antibody titers (p=0.111). There was significant correlation between H. pylori antibody titers and lymphocyte infiltration (p=0.002), neutrophil infiltration (p=0.002), H. pylori density (p=0.0001), respectively. There was no significant correlation between H. pylori antibody titers and atropy (p=0.142), intestinal metaplasia (p=0.368), respectively. CONCLUSIONS: H. pylori antibody titer has significant association with the H. pylori density, neutrophil and lymphocyte infiltration. The serological test using EIA method is a useful in detecting H. pylori infection and it may be used as a predictor for the H. pylori density and degree of inflammation.

A Case of Death Due to Spontaneous Intraperitoneal Bleeding in P-ANCA Positive Small Vessel Vasculitis / 대한신장학회잡지

P-ANCA small vessel vasculitis is multisystemic disease, especially frequently involving the kidney. Diagnosis is delayed because it's non-specific clinical manifestation. Recently ANCA becomes available tools for diagnosis of vasculitis. Infection and gastrointestinal complications are relatively common in vasculitis. But spontaneous rupture of gastrointestinal artery is a rare complication. A 61-year-old housewife was admitted due to poor oral intake, weight loss and microscopic hematuria. Renal biopsy showed an extensive necrotizing glomerulonephritis, consistent with Wegener's granulomatosis or microscopic polyangitis. Serum test showed positive for P-ANCA. Despite steroid therapy, she expired due to spontaneous rupture of right gastroepiploic artery.

A Case of Chronic Inflammatory Demyelinating Polyneuropathy in Lupas Nephritis / 대한신장학회잡지

Systemic lupus erythematosus(SLE) is a multisys-temic disease. Peripheral neuropathy occurs in about 10% of patients with SLE. Chronic inflammatory demyelinating polyneurpathy has been reported rarely in SLE. We experienced a case of chronic inflammatory polyneuropathy in lupus nephritis. 32-year-old housewife presented to chronic progressive muscle weakness and heavy proteinuria. Kidney biopsy showed compatible with lupus nephritis (WHO Class V, membranous nephropathy). Nerve conduction studies showed reduction in conduction velocity and sural nerve biopsy revealed demyeli-nating polyneuropathy. Steroid therapy led to improvement in clinical symptoms and proteinuria.

Two Cases of Acute Interstitial Nephritis Associated with Acute Hepatitis A / 대한신장학회잡지

Although acute renal failure is common in patients with fulminant hepatitis, it has been recognized as a rare complication of non-fulrninant acute hepatitis A. So far about 30 patients have been described in the literature who had acute hepatitis A associated with acute renal failure. Variable renal biopsy findings have been described in previous reports, including mostly acute tubular necrosis, mesangial proliferative glomerulonephritis, and interstitial nephritis. But the exact mechanism by which hepatitis A causes acute renal damage is still obscure. We describe two cases with acute hepatitis A, proven by IgM anti-hepatitis A antibodies compli- cated by acute renal failure. One patient required hemodialysis. Kidney biopsy findings showed interstitial nephritis with no evidence of glomerular involvement. Our review of these cases and the relevant literature suggests that there is strong evidence to implicate hepatitis A virus as a cause of acute renal failure. It remains to be elucidated why the histologic features are variable in the cases of hepatitis A virus induced acute renal failure and which factors predispose a patients to have immunologic involvement versus interstitial and tubular involvement.

TGF-beta1 inhibition of apoptosis through the transcriptional up-regulation of Bcl-X(L) in human monocytic leukemia U937 cells

To characterize the TGF-beta1 response of monocytic leukemia cells, we analyzed the effects of TGF-beta1 on cell proliferation, differentiation, and apoptosis of human monoblastic U937 cells. Treatment of cells with TGF-beta1 in the absence of growth factors significantly enhanced cell viability. Flow cytometric analysis of DNA content and CD14 expression revealed that TGF-beta1 does not affect cell proliferation and differentiation. Consistent with these results was the finding that no transcriptional induction of Cdk inhibitors such as p21Waf1, p15Ink4b, and p27Kip1 was detected following TGF-beta1 treatment. Interestingly, however, pretreatment of TGF-beta1 significantly inhibited Fas-, DNA damage-, and growth factor deprivation-induced apoptosis. This antiapoptotic effect was totally abrogated by anti-TGF-beta1 antibody. Quantitative RT-PCR analysis demonstrated a dose- and time-dependent transcriptional up-regulation of Bcl-X(L), suggesting its implication in the TGF-1-mediated antiapoptotic pathway. We also observed elevated expression of c-Fos and PTEN/MMAC1. But, no detectable change was recognized in expression of c-Jun, Fas, Fadd, Fap-1, Bcl-2, and Bax. Taken together, our study shows that TGF-beta1 enhancement of cellular viability is associated with its antiapoptotic effect, which may result from the transcriptional up-regulation of Bcl-X(L).