Long-term clinical clerkship improves medical students' attitudes toward team collaboration.

Objectives: To examine the related factors associated with medical students' attitudes toward team collaboration. Methods: This cross-sectional study targeted medical students, residents, and doctors. A survey was conducted from 2016 to 2017 using the Japanese version of the Jefferson Scale of Attitudes Toward Interprofessional Collaboration (JeffSATIC-J), which evaluated "working relationship" and "accountability." We analyzed 2409 questionnaire responses with JeffSATIC-J items and the gender item. Analysis of variance was used for factors associated with the JeffSATIC-J score and Spearman's rank correlation coefficient for the relationship between educational intervention and the JeffSATIC-J score. Results: First-year students' scores were the highest (F(2, 2045) = 13.42 to 18.87, p < .001), and female students' scores were significantly higher than those of male students (F(1, 2045) = 21.16 to 31.10, p < .001). For residents' scores, the institution was not a significant variable. Female "accountability" scores were significantly higher than those of males (F (1,108) = 4.95, p = .03). Gender was not a significant variable for doctors' scores. Sixth-year students' scores were significantly correlated with the length of clinical clerkship (r(5)=.78 to .96, p<.05), with the exception of females' "working relationship" scores. The medical school with the highest JeffSATIC-J scores had the longest clinical clerkship in the community. Conclusions: These results indicate that long-term clinical clerkship in the community at higher grades is important in improving medical students' attitudes toward team collaboration. A qualitative study is required to confirm our findings.

Potential predictors of susceptibility to occupational stress in Japanese novice nurses - a pilot study.

BACKGROUND: Occupational stress is a known factor behind employee resignations; thus, early identification of individuals prone to such stress is important. Accordingly, in this pilot study we evaluated potential predictors of susceptibility to occupational stress in Japanese novice nurses. METHODS: Forty-two female novice nurses at Kagoshima University Hospital were recruited for the study population. Each underwent physical health and urinary examinations, and completed a lifestyle questionnaire at the time of job entry. Each also completed a Brief Job Stress Questionnaire (BJSQ), related to mental health status, at job entry and 5 months post-entry. Psychological stress, somatic symptoms, and combined BJSQ scores were determined for each time point. RESULTS: All three stress condition scores had significantly decreased at 5 months post-entry, suggesting occupational stress. Systolic blood pressure (r = -0.324, p < 0.05) and urinary sodium (r = -0.313, p < 0.05) were significantly negatively correlated with combined BJSQ score at 5 months post-entry. Post-entry stress condition scores were significantly low in subjects reporting substantial 1-year body weight change (≤ ± 3 kg) and short times between dinner and bedtimes (≤2 h), though baseline stress condition scores were not. Urinary sodium concentration, 1-year body weight change, and pre-sleep evening meals were then targeted for multivariate analysis, and confirmed as independent explanatory variables for post-entry stress condition scores. CONCLUSIONS: One-year body weight change, times between dinner and bedtimes, and urinary sodium concentration are promising potential predictors of susceptibility to occupational stress, and should be further investigated in future research. TRIAL REGISTRATION: ISRCTN ISRCTN17516023. Retrospectively registered 7 December 2016.

Antihypertensive therapy improves insulin resistance and serum levels of interleukin-6 and -10 in spontaneously hypertensive rats with steatohepatitis.

Metabolic syndrome based on insulin resistance (IR) and hypertension is a risk factor for advanced liver disease and cardiovascular disease in patients with nonalcoholic steatohepatitis (NASH). The present study investigated the effects of severe hypertension induced by a high­salt (HS) diet and antihypertensive therapy on the pathophysiological condition of spontaneously hypertensive rats (SHRs) with steatohepatitis. Steatohepatitis was induced using a choline-deficient, L-amino acid-defined diet (CDAA). Male SHRs (7­week­old) were randomly divided into five groups: Those receiving 6 weeks of standard chow with a normal salt concentration, followed by an additional 8 weeks of standard chow or CDAA with a normal salt concentration (control and CDAA groups, respectively); and those receiving 6 weeks of standard chow with HS, followed by CDAA with HS for an additional 8 weeks, with or without the antihypertensive agents, amlodipine (Aml) or hydralazine. In the CDAA and CDAA+HS groups, blood pressure was significantly correlated with serum levels of insulin, fasting blood glucose and homeostasis model assessment (HOMA)­IR. Antihypertensive therapy ameliorated the elevated glucose, insulin and HOMA­IR. Furthermore, the increased levels of serum interleukin (IL)­6 following the CDAA+HS diet were attenuated by antihypertensive therapy. The serum levels of IL­10 were increased by antihypertensive therapy, and the decrease in the proportion of splenic CD4+CD25+forkhead box P3+ T cells observed following the CDAA+HS diet tended to be restored by Aml. In conclusion, antihypertensive therapy improved glucose metabolism and imbalances in cytokine expression in the rat model of hypertension with steatohepatitis, suggesting that antihypertensive therapy acting through immunological factors may be beneficial for patients with metabolic syndrome-associated NASH.

Fecal Human Neutrophil Peptide Levels Correlate with Intestinal Inflammation in Ulcerative Colitis.

BACKGROUND/AIM: Fecal markers have recently been found to provide convenient and noninvasive assessment of intestinal inflammation in inflammatory bowel disease (IBD). In this study, we examined the clinical significance of fecal human neutrophil peptides (F-HNP) in the evaluation of IBD disease activity. METHODS: This study enrolled 70 patients with IBD, consisting of 45 patients with ulcerative colitis (UC), 25 patients with Crohn's disease (CD), and 11 non-IBD controls. Stools samples were evaluated for the association between F-HNP concentration and disease and endoscopic activity in each group and the correlation between F-HNP and fecal calprotectin (F-CP) concentrations. RESULTS: Median F-HNP levels were as follows: UC: 25.6 ng/ml; CD: 20.1 ng/ml; and non-IBD controls: 4.9 ng/ml. F-HNP levels were significantly higher in each IBD group, especially in the UC group, than in the control group. In the UC group, both F-HNP and F-CP levels were significantly higher during active disease compared to the remission phase. Both markers were significantly correlated with the Mayo endoscopic score, although the correlation was stronger for F-HNP than for F-CP (r = 0.66 vs. r = 0.54). CONCLUSION: F-HNP is a noninvasive marker that is useful for evaluating UC endoscopic activity.

Effect of endoscopic submucosal dissection for superficial esophageal neoplasms and risk factors for postoperative stricture.

Endoscopic submucosal dissection (ESD) enables wider tumor resection compared with endoscopic mucosal resection and en bloc resection of superficial esophageal neoplasms. However, ESD may cause difficult-to-treat stricture of the esophagus, and therefore, prediction of and measures against postoperative esophageal stricture are critical. The aim of this study was to evaluate the effect of ESD on superficial esophageal neoplasms and identify risk factors associated with esophageal stricture after ESD.This study included 165 lesions in 120 patients with superficial esophageal neoplasms, including cancer and neoplasia, who underwent ESD from 2009 to 2013.The complete resection rate of superficial esophageal neoplasms by ESD was 90.9%. After ESD, 22 subjects (18.3%) had symptomatic esophageal stricture, 12 (10.0%) had aspiration pneumonia of grade 2, and 7 (5.8%) had mediastinal emphysema of grade 2. Comparison of the 22 subjects with stricture with the 98 subjects without stricture showed significant differences in the rate of resection of >75% of the esophageal circumference, rate of whole circumference resection, and the required time for resection. The tumor size and the size of the resected tissue sample also differed between the 2 groups. The groups did not differ in age, sex, alcohol intake, and smoking; location, macroscopic, and histological tumor findings; chest pain; or use of anticoagulants for comorbidities. In multivariate analysis, tumor size and whole circumference resection were independent risk factors for stricture. Furthermore, in 45 subjects with resection of >75% of the esophageal circumference, whole resection of the esophagus was the only independent risk factor for stricture.This study suggests that ESD has a strong therapeutic effect on superficial esophageal neoplasms; however, a greater extent of resection of the esophagus increases the risk of postoperative esophageal stricture. Preventive measures against development of postoperative stricture require further study.

Hepatocyte growth factor stimulates the migration of gastric epithelial cells by altering the subcellular localization of the tight junction protein ZO-1.

BACKGROUND: Hepatocyte growth factor (HGF) is essential for epithelial restitution, a process in which epithelial cells rapidly migrate to cover desquamated epithelium after mucosal injury in the gastrointestinal tract. In this study, we aimed to elucidate the molecular mechanisms of the HGF-mediated reconstitution of gastric epithelial structures by analyzing the expression and subcellular dynamics of tight junction proteins. METHODS: We treated human gastric epithelial MKN74 cells with HGF, and examined the effects of HGF on cell migration and proliferation, and the expression and subcellular dynamics of tight junction proteins; as well, we investigated the effect of HGF on paracellular permeability to macromolecules (using fluorescein isothiocyanate [FITC]-dextran). RESULTS: HGF significantly stimulated the migration of MKN74 cells, but not their proliferation, in a dose-dependent manner. HGF did not affect the expression of tight junction proteins, including claudin-1, -3, -4 and -7; occludin; and zonula occludens (ZO)-1. However, fluorescence immunostaining revealed that, in the cell membrane, the levels of ZO-1, but not those of occludin or claudin-4, were transiently decreased 1 h after HGF treatment. The results were further confirmed by western blotting: HGF reduced the amount of ZO-1 protein in the cell membrane fraction concomitantly with an increase in cytoplasmic ZO-1. Furthermore, HGF reduced the interaction between ZO-1 and occludin, and induced the tyrosine phosphorylation of occludin, whereas the phosphorylation status of ZO-1 was not affected by exposure to HGF. Despite a decrease in the ZO-1/occludin interaction, HGF did not affect paracellular permeability to macromolecules. CONCLUSIONS: HGF alters the subcellular localization of ZO-1, probably through the tyrosine phosphorylation of occludin, which may induce cell dispersion during epithelial restitution.

Repeated enemas with hepatocyte growth factor selectively stimulate epithelial cell proliferation of injured mucosa in rats with experimental colitis.

AIMS: Hepatocyte growth factor (HGF) modulates intestinal epithelial cell proliferation and migration. We previously reported that systemic administration of recombinant human HGF (rh-HGF) ameliorated experimental colitis. However, an increase in serum HGF concentrations may induce undesired systemic effects, limiting the use of rh-HGF. To avoid possible side effects, we investigated the safety and efficacy of rectally administered rh-HGF as a treatment for experimental colitis. MAIN METHODS: We measured serum human HGF concentration following a single rectal enema of rh-HGF. Rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)- or dextran sulfate sodium (DSS)-induced colitis were treated with rectal enemas of rh-HGF once a day for seven days. The degree of mucosal injuries and the proliferative activity of the colon epithelium were examined. KEY FINDINGS: Rats administered a rectal enema of rh-HGF at a dose of 0.1 mg/ml or less had no detectable rh-HGF in the serum. Repeated enemas of rh-HGF at this dose significantly reduced mucosal injuries, both with respect to lesion size and inflammatory cell infiltration. This regimen also stimulated proliferation of epithelial cells surrounding injured mucosa; however, the cell proliferation of uninjured mucosa was not affected by this local treatment. SIGNIFICANCE: Rectally administered rh-HGF selectively accelerates the repair of injured mucosa in rat experimental colitis without systemic exposure to HGF. Rectal enemas of HGF are thus a potential novel and safe therapy for IBD.

Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety.

BACKGROUND: Hepatocyte growth factor (HGF) stimulates hepatocyte proliferation, and also acts as an anti-apoptotic factor. Therefore, HGF is a potential therapeutic agent for treatment of fatal liver diseases. We performed a translational medicine protocol with recombinant human HGF (rh-HGF), including a phase I/II study of patients with fulminant hepatitis (FH) or late-onset hepatic failure (LOHF), in order to examine the safety, pharmacokinetics, and clinical efficacy of this molecule. METHODS: Potential adverse effects identified through preclinical safety tests with rh-HGF include a decrease in blood pressure (BP) and an increase in urinary excretion of albumin. Therefore, we further investigated the effect of rh-HGF on circulatory status and renal toxicity in preclinical animal studies. In a clinical trial, 20 patients with FH or LOHF were evaluated for participation in this clinical trial, and four patients were enrolled. Subjects received rh-HGF (0.6 mg/m2/day) intravenously for 12 to 14 days. RESULTS: We established an infusion method to avoid rapid BP reduction in miniature swine, and confirmed reversibility of renal toxicity in rats. Although administration of rh-HGF moderately decreased BP in the participating subjects, this BP reduction did not require cessation of rh-HGF or any vasopressor therapy; BP returned to resting levels after the completion of rh-HGF infusion. Repeated doses of rh-HGF did not induce renal toxicity, and severe adverse events were not observed. Two patients survived, however, there was no evidence that rh-HGF was effective for the treatment of FH or LOHF. CONCLUSIONS: Intravenous rh-HGF at a dose of 0.6 mg/m2 was well tolerated in patients with FH or LOHF; therefore, it is desirable to conduct further investigations to determine the efficacy of rh-HGF at an increased dose.

Hepatocyte growth factor ameliorates mucosal injuries leading to inhibition of colon cancer development in mice.

Hepatocyte growth factor (HGF), which facilitates the repair of injured mucosa, has the potential to be a new therapeutic agent for inflammatory bowel disease (IBD). However, given that the incidence of colorectal cancer increases continuously with disease duration in patients with IBD, the fact that HGF is a potent mitogen for intestinal epithelial cells may further heighten the risk of bowel cancer in this patient population. In this study, we examined the effects of recombinant HGF on colorectal cancer development in mice with or without experimentally induced colitis. Although HGF stimulated proliferation of colonic epithelial cells in normal mucosa, the development of colorectal cancer induced by repeated injection of azoxymethane (AOM) was significantly inhibited by HGF treatment. In a mouse model of colitis-associated cancer, colorectal cancer frequently developed despite only a single injection of AOM prior to three cycles of dextran sulfate sodium administration. However, HGF treatment significantly facilitated the repair of injured mucosa, leading to inhibition of colorectal cancer development in a dose-dependent manner. Thus, HGF-induced repair of injured mucosa inhibits rather than accelerates the development of colorectal cancer, and these results also suggest the importance of blocking the cycles of mucosal injury and repair to prevent colitis-associated colorectal cancer.

Translational research on HGF: A phase I/II study of recombinant human HGF for the treatment of fulminant hepatic failure.

Hepatocyte growth factor (HGF) is a potential therapeutic agent for fatal liver diseases, including fulminant hepatic failure (FHF). After performing a number of preclinical tests with recombinant human HGF (rh-HGF), we started a phase I/II study in September 2005 of patients with FHF or late-onset hepatic failure (LOHF), to examine the safety and clinical efficacy of rh-HGF. We first administered rh-HGF (0.6 mg/m(2)/day) for 13 days to a 67-year-old Japanese man with FHF. All data from this patient were reviewed by the independent data monitoring committee, and the safety of rh-HGF was recognized. Finally, a clinical trial of rh-HGF was approved to be continued. As of August 2007, we have administered rh-HGF to four patients with FHF or LOHF. All patients showed a moderate decrease in systolic blood pressure during rh-HGF administration, while the urinary excretion of albumin did not increase in all cases. In the first and third patients, hepatic failure gradually progressed, and they died 66 and 29 days, respectively, after encephalopathy occurred. The second and fourth patients are presently still alive. In conclusion, we started a clinical trial that examined the effects of rh-HGF in patients with FHF or LOHF, and in the four patients with FHF or LOHF enrolled in this study, repeated doses of rh-HGF did not produce any severe side effects.