Evaluation of duodenal hypersensitivity induced by duodenal acidification using transnasal endoscopy

Background and Aim: Although duodenal hypersensitivity has been suggested as one of the causes of functional dyspepsia (FD), a practical method to clarify this has not yet been established. The aim of this study was to evaluate whether patients with FD have duodenal hypersensitivity to acid, using transnasal endoscopy. Methods: In all, 44 patients with FD and 16 healthy volunteers were enrolled, and all the subjects received transnasal endoscopy in the morning after overnight fasting. After ordinary transnasal endoscopy, an infusion tube was introduced into the duodenal bulb by transnasal endoscopy and acid (20 mL, 0.1 N HCl, 20 mL/min, 36.5°C) was injected via the infusion tube. The severity of 12 symptoms was assessed by each subject using a 100‐mm visual analogue scale. The maximum severity scale was defined as the maximum score of the symptom severity scale. The total score was defined as the aggregate score of the maximum severity scale of the 12 symptoms. The maximum severity scales and the total scores between patients with FD and healthy volunteers were evaluated. Results: The maximum severity scales of nine symptoms increased significantly more after acid infusion in patients with FD than in healthy volunteers (P < 0.05). There were significant differences in the total scores (patients with FD vs healthy volunteers 233.8 ± 37.8 vs 63.9 ± 14.6, mean ± standard error of the mean, P < 0.001). Conclusions: Duodenal acidification using transnasal endoscopy enabled the evaluation of duodenal hypersensitivity to acid in healthy volunteers and patients with FD.     

New therapeutic approach for impaired arteriogenesis in diabetic mouse hindlimb ischemia.

BACKGROUND: The combined treatment of sustained-release basic fibroblast growth factor (Sr-bFGF) and a 5-hydroxytryptamine(2A) blocker, sarpogrelate, was evaluated to see whether it reversed the impaired collateral circulation in diabetic (DM) mouse hindlimb ischemia. METHOD AND RESULTS: Diabetic and normal mice with ischemic hindlimb were randomly assigned to 1 of 5 experimental groups (no treatment, sarpogrelate 50 mg . kg(-1) . day(-1), 20 microg or 50 microg Sr-bFGF and a combined treatment of 20 microg Sr-bFGF and sarpogrelate), and treated for 4 weeks. Tissue blood perfusion (TBP), vascular density (angiogenesis) and the number of mature vessels (arteriogenesis) were checked by the use of standard methods. Although angiogenesis was comparable (161+/-14 vs 154+/-12 vessels/mm(2)), the laser Doppler perfusion image index (LDPII) (0.43+/-0.11 (SD) vs 0.63+/-0.08, p<0.05) and arteriogenesis (8+/-3 vs 12+/-4 vessels/mm(2), p<0.05) were significantly lower in DM mice than those in normal mice. The dose of Sr-bFGF for the sufficient number of mature vessels (>or=45 vessels/mm(2)) and LDPII (>or=0.9) was 20 microg for the normal mice, and 50 microg for the DM mice, which was reduced with the aid of sarpogrelate. Conclusions A combined therapy of Sr-bFGF and sarpogrelate is effective for neovascularization to reverse the impaired arteriogenesis and TBP in DM mice.     

Clinical factors that impair health-related quality of life in ulcerative colitis patients vary with the disease duration

BACKGROUND AND AIM: The health-related quality of life (HRQOL) of patients with ulcerative colitis (UC) can be impaired because of the chronic symptoms. Although UC patients suffer from such symptoms over the long term, there have been few reports on the changes of HRQOL with disease duration. The aim of this study was to clarify these changes. METHODS: The HRQOL of 331 Japanese UC patients was examined using the validated Japanese version of the Inflammatory Bowel Disease Questionnaire (J-IBDQ). HRQOL and factors affecting HRQOL identified using multiple linear regression analysis were stratified by disease duration. RESULTS: Of the 15 clinical factors examined, the clinical activity index score was the strongest determinant (P<0.0001) of all the scores of IBDQ regardless of disease duration. HRQOL did not differ significantly among patients with different disease durations. The factors, however, that affected HRQOL varied according to disease duration. In patients with disease duration of less than 5 years, the clinical activity index score was the predominant factor affecting HRQOL. Being 'on sick leave or hospitalized' was a significant factor impairing HRQOL in patients with disease duration of 5-9 years. Moreover, complications due to corticosteroids significantly impaired all of the IBDQ scores in patients with disease duration of 10 years or more. CONCLUSION: Factors that affected the HRQOL of UC patients varied according to the patients' disease duration. Our findings should assist in the development of a long-term strategy for the treatment of UC patients.     

Hepatocyte growth factor gene transfer with naked plasmid DNA ameliorates dimethylnitrosamine-induced liver fibrosis in rats

Aim: Hepatocyte growth factor (HGF) has various biological properties, including antifibrogenic activity. In the present study, we tested the efficacy of HGF gene therapy using naked plasmid DNA in dimethylnitrosamine (DMN)-induced liver fibrosis in a rat model. Methods: Naked plasmid DNA encoding human HGF was injected once, together with a hypertonic solution, into the hepatic artery after DMN treatment on three consecutive days per week for 3 weeks. Naked plasmid DNA encoding beta-galactosidase was injected similarly in the DMN-treated control rats. DMN treatment was continued once weekly after gene transfer for additional 3 weeks. Results: The human HGF protein expression was detected in livers transfected with human HGF naked plasmid DNA, gradually decreasing by day 21. The expression of the endogenous rat HGF protein was also upregulated after human HGF gene transfer. Phosphorylation of c-Met, a HGF receptor, was detected only in livers transfected with human HGF plasmid DNA. Fibrosis was attenuated significantly in livers transfected with the human HGF plasmid. Attenuation wasaccompanied by decreased expression of alpha-smooth muscle actin. Increased portal vein pressure after treatment with DMN was suppressed significantly by HGF gene transfer. The upregulated hepatic protein expression of transforming growth factor-beta (TGF-beta) in response to DMN was markedly attenuated by HGF gene transfer accompanied by the increased protein expression for matrix metalloproteinases (MMP)-3 and -13. Conclusion: The hepatic arterial injection of human naked plasmid HGF DNA was effective in suppressing liver fibrosis induced in rats by DMN. The mechanisms by which HGF expression attenuated liver fibrosis may include the suppression of hepatic TGF-beta expression and the induction of MMP expression.     

Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration: role in preventing lung injury and fibrosis in bleomycin-challenged mice

BACKGROUND AND OBJECTIVE: Although the pathogenesis of interstitial pneumonia and pulmonary fibrosis are not well understood, it has been reported that inflammatory cells, especially neutrophils, and the injurious substances produced by them play important roles in the progression of interstitial pneumonia and subsequent fibrosis. Erythromycin and other 14-membered ring macrolides (14-MRMLs) have been reported to improve the survival of patients with diffuse panbronchiolitis by antineutrophil and several other anti-inflammatory mechanisms. The present study was undertaken to investigate the effects of 14-MRMLs on an experimental model of bleomycin-induced acute lung injury and subsequent fibrosis in mice. METHODS: Bleomycin was administered IV to ICR mice. At 28 days after bleomycin injection, fibrotic foci were histologically observed in left lung tissues, and hydroxyproline content in right lung tissues was chemically analyzed. The inhibitory effects of 14-MRMLs were assessed by overall comparison between control (normal saline solution [NS] alone), untreated (bleomycin alone), and treated (bleomycin plus 14-MRMLs) groups. For evaluation of early-phase inflammation, cell populations in BAL fluid and induction of messenger RNA (mRNA) of adhesion molecules (E-selectin, P-selectin, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) in lung tissues were examined at 0 to 13 days after bleomycin treatment. These parameters were also compared with those for the control (NS alone), 14-MRML untreated (bleomycin alone), and 14-MRML pretreated (bleomycin plus 14-MRML pretreated) groups. RESULTS: Bleomycin-induced pulmonary fibrosis was inhibited by erythromycin and other 14-MRMLs on day 28 after bleomycin injection in ICR mice, especially those pretreated with 14-MRMLs. Hydroxyproline content in lung tissues was also decreased in the 14-MRML-pretreated groups. The number of neutrophils in BAL fluid significantly increased, with two peaks at 1 day and 9 days (from 6 to 11 days) after bleomycin administration. 14-MRMLs significantly inhibited both peaks of neutrophil infiltration into the airspace. Changes in mRNA expression of adhesion molecules (E-selectin, P-selectin, ICAM-1, VCAM-1) were associated with leukocyte migration into the airspace. 14-MRMLs clearly inhibited the induction of VCAM-1 mRNA, and tended to attenuate that of ICAM-1 mRNA, but inhibited the induction of neither E-selectin mRNA nor P-selectin mRNA. CONCLUSION: These findings indicate that attenuation of inflammatory cell migration into the airspace by 14-MRMLs, especially of neutrophils and macrophages, resulted in inhibition of lung injury and subsequent fibrosis. 14-MRMLs clearly attenuated the expression of VCAM-1 mRNA during the early phase of bleomycin-induced lung injury, and this might be one mechanism of inhibition of neutrophil and macrophage migration into the airspace by 14-MRMLs. This may be one mechanism of the anti-inflammatory and antifibrotic effects of 14-MRMLs. These findings suggest that prophylactic administration of 14-MRMLs may be clinically efficacious in preventing acute exacerbation of interstitial pneumonia and acute lung injury.     

Risk factors of thrombotic recurrence and major bleeding in patients with intermediate-risk for recurrence of venous thromboembolism

Journal of Thrombosis and Thrombolysis - Prolonged anticoagulation therapy is recommended for patients with intermediate-risk for recurrence of venous thromboembolism (VTE). The current study aimed...