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Objective To identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients. Design Multicentre prospective study. Setting Sixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan. Participants Patient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017. Intervention Japanese standard diagnostic examinations. Outcome measures Data collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive (CRP) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis. Results The most frequent age group was 65–79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in CRP level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified. Conclusions Age may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease. [ABSTRACT FROM AUTHOR]

Objectives This study examined the retention of regional quota graduates of Japanese medical schools and prefecture scholarship recipients within their designated prefectures where they are obliged or expected to work and revealed the personal and regional characteristics associated with their emigration to nondesignated prefectures. Regional quota and prefecture scholarship are two of the most ambitious policies ever conducted in Japan for recruiting physicians to practice in rural areas. Design Prospective cohort study. Setting Nationwide. Participants Regional quota graduates with prefecture scholarship, quota graduates without scholarship and nonquota graduates with scholarship of Japanese medical schools who obtained their physician license between 2014 and 2016. Primary outcome The emigration in 2016 of the participants from the designated prefectures. Results Total participants were 991 physicians, three of whom were excluded due to the missing values of crucial items, leaving 988 participants for analysis (quota with scholarship 387, quota alone 358 and scholarship alone 243). The percentage of those who emigrated was 11.9% (118/988). The mean (±SD) proportion of subjects who emigrated was 11.7% (±10.3) among all prefectures and the proportion varies widely among prefectures (0%-44.4%). Multilevel logistic regression analysis showed those who received prefecture scholarship (OR 0.23; 95% CI 0.08 to 0.67) and whose designated prefecture has an ordinance-designated city (ie, large city) were less likely to emigrate (OR 0.47; 95% CI 0.24 to 0.90). In contrast, graduates from a medical school outside the designated prefecture (OR 4.20; 95% CI 2.20 to 7.67) and who have a right to postpone their obligatory service (OR 3.42; 95% CI 1.52 to 7.67) were more likely to emigrate. Conclusions A substantial proportion of regional quota graduates and prefecture scholarship recipients emigrated to non-designated prefectures. Emigrations should be reduced by improving the potential facilitators for emigration such as discordance in location between medical school and designated prefecture. [ABSTRACT FROM AUTHOR]

Objectives Responding to the serious shortage of physicians in rural areas, the Japanese government has aggressively increased the number of entrants to medical schools since 2008, mostly as a chiikiwaku, entrants filling a regional quota. The quota has spread to most medical schools, and these entrants occupied 16% of all medical school seats in 2016. Most of these entrants were admitted to medical school with a scholarship with the understanding that after graduation they will practise in designated areas of their home prefectures for several years. The quota and scholarship programmes will be revised by the government starting in 2018. This study evaluates the intermediate outcomes of these programmes. Design Cross-sectional survey to all prefectural governments and medical schools every year from 2014 to 2017 to obtain data on medical graduates. Settings Nationwide. Participants All quota and non-quota graduates with prefecture scholarship in each prefecture, and all the quota graduates without scholarship in each medical school. Primary outcome measures Passing rate of the National License Examination for Physicians and the percentage of graduates who have not bought out the scholarship contract after graduation. Results Most prefectures and medical schools in Japan participated in this study (97.8%–100%). Quota graduates with scholarship were significantly more likely to pass the National License Examination for Physicians than the other medical graduates in Japan at all the years (97.9%, 96.7%, 97.4% and 94.7% vs 93.9%, 94.5%, 94.3% and 91.8%, respectively). The percentage of quota graduates with scholarship who remained in the scholarship contract 3 years after graduation was 92.2% and 89.9% for non-quota graduates with scholarship. Conclusions Quota entrants showed better academic performance than their peers. Most of the quota graduates remained in the contractual workforce. The imminent revision of the national policy regarding quota and scholarship programmes needs to be based on this evidence. [ABSTRACT FROM AUTHOR]

Introduction: Given the shortage of physicians, particularly in rural areas, the Japanese government has rapidly expanded the number of medical school students by adding chiikiwaku (regional quotas) since 2008. Quota entrants now account for 17% of all medical school entrants. Quota entrants are usually local high school graduates who receive a scholarship from the prefecture government. In exchange, they temporarily practise in that prefecture, including its rural areas, after graduation. Many prefectures also have scholarship programmes for non-quota students in exchange for postgraduate in-prefecture practice. The objective of this cohort study, conducted by the Japanese Council for Community-based Medical Education, is to evaluate the outcomes of the quota admission system and prefecture scholarship programmes nationwide. Methods and analysis: There are 3 groups of study participants: quota without scholarship, quota with scholarship and non-quota with scholarship. Under the support of government ministries and the Association of Japan Medical Colleges, and participation of all prefectures and medical schools, passing rate of the National Physician License Examination, scholarship buy-out rate, geographic distribution and specialties distribution of each group are analysed. Participants who voluntarily participated are followed by linking their baseline information to data in the government's biennial Physician Census. Results to date have shown that, despite medical schools' concerns about academic quality, the passing rate of the National Physician License Examination in each group was higher than that of all medical school graduates. Ethics and dissemination: The Ethics Committee for Epidemiological Research of Hiroshima University and the Research Ethics Committee of Nagasaki University Graduate School of Biomedical Sciences permitted this study. No individually identifiable results will be presented in conferences or published in journals. The aggregated results will be reported to concerned government ministries, associations, prefectures and medical schools as data for future policy planning. [ABSTRACT FROM AUTHOR]

Background: Hepatolithiasis is a calculus disease of the liver with no known cause that is relatively uncommon, and is characterized by a refractory nature and high frequency of recurrence. Hepatolithiasis is one of the diseases listed by the Ministry of Health, Labour and Welfare of Japan under Research on Intractable Diseases, and it requires further research on the pathogenesis as well as the therapeutic strategy. It is also included in the clinical guidelines for cholelithiasis of the Japanese Society of Gastroenterology, which suggest guiding principles for the treatment of hepatolithiasis. Methods: we performed questionnaire surveys of hepatolithiasis twice in 2010 and in 2012. Verification of the evidence-based clinical practice guidelines a questionnaire survey of 22 facilities in 2010 and 25 facilities in 2012 across Japan that provided cooperation, which enabled us to assess 210 new cases over a two-year period. Conclusions: Comparison with two surveys that have been carried out previously revealed the main factor associated with hepatolithiasis was a history of biliary tract surgery, which was noted in the majority of cases. In addition, there was an increase of patients in whom balloon endoscopy was performed using transduodenal approach. This method is not included in the treatment options of the current clinical guidelines for cholelithiasis, so there may be a need to take it into consideration when the guidelines are revised. [ABSTRACT FROM AUTHOR]

Objective: To determine the incidence of fever among elderly persons under home medical management, diagnosis at fever onset and outcomes from a practical standpoint. Design: Prospective cohort study. Setting: 5 clinics in residential areas of Tokyo that process an average of 50–200 outpatients/day. Participants: Patients (n=419) aged ≥65 years who received home medical management from the five clinics between 1 October 2009 and 30 September 2010. Main outcome measures: Fever (≥37.5°C or ≥1.5°C above usual body temperature), diagnosis at onset and outcomes (cure at home, hospitalisation and death). Results: The incidence of fever was 2.5/1000 patient-days (95% CI 2.2 to 2.8). Fever occurred at least once (229 fever events) among one-third of the participants during the study period. Fever was more likely to arise in the wheelchair users or bedridden than in ambulatory individuals (HR 1.9 (95% CI 1.3 to 2.8; p<0.01); in patients with moderate-to-severe rather than those with none-to-mild cognitive impairment (HR, 1.7 (95% CI 1.1 to 2.6, p=0.01); and in those whose care-need levels were ≥3 rather than ≤2 (HR, 4.5 (95% CI 2.9 to 7.0; p<0.01). The causes of fever were pneumonia/bronchitis (n=103), skin and soft tissue infection (n=26), urinary tract infection (n=22) and the common cold (n=13). Fever was cured in 67% and 23% of patients at home and in hospital, respectively, and 5% of patients each died at home and in hospital. Antimicrobial agents treated 153 (67%) events in the home medical care setting. Conclusions: Fever was more likely to occur in those requiring higher care levels and the main cause of fever was pneumonia/bronchitis. Healthcare providers should consider the conditions of elderly residents with lower objective functional status. [ABSTRACT FROM AUTHOR]

Objective: Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO. Design: A nationwide retrospective study. Setting: 17 hospitals affiliated with the Japanese Society of Hospital General Medicine. Participants: This study included patients =18 years diagnosed with 'classical fever of unknown origin' (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011. Results: A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19-94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients. Conclusions: With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO. [ABSTRACT FROM AUTHOR]

Abstract  To achieve more potent and long-lasting acid suppression, omeprazole was administered for 7 days in 5 regimens: 10, 20, and 40 mg once daily (od), and 10 and 20 mg twice daily (bid), in 7 healthy Helicobacter pylori-negative CYP2C19 homozygous extensive metabolizers, and intragastric pH was continuously measured. The median intragastric pH and percent time pH > 4.0 for 24 hours increased dose dependently with 10, 20, and 40 mg od. Ten and 20 mg bid wre comparable to 20 and 40 mg od, respectively. Concerning percent time pH > 4.0 in the nighttime (20:00–8:00 hours), 20 mg bid was significantly superior to 40 mg od (P  [ABSTRACT FROM AUTHOR]

Abstract??Low-dose omeprazole is superior to full-dose famotidine in maintenance therapy for gastroesophageal reflux disease, whereas ?on-demand? famotidine is more effective for relief of episodes of heartburn. To explain this apparent discrepancy, intragastric pH was measured for 24-hr seven times in eight JapaneseHelicobacter pylori-negative cytochrome P450 2C19 extensive metabolizers; on Days 1, 8, and 15 of repeated administration of 10?mg of omeprazole once daily and of 20?mg of famotidine twice daily and before medication. During repeated administration of omeprazole, mean intragastric pH and % time that intragastric pH > 4.0 were significantly higher and became greater. With famotidine, although these parameters were significantly higher, the degrees became smaller. Consequently, acid-suppressive effect was in the order; omeprazole?famotidine on Day 15. This discrepancy possibly results from the ?potentiation? of acid-suppressive effect of omeprazole and the ?tolerance? phenomenon in respect to famotidine. [ABSTRACT FROM AUTHOR]

Lafutidine, a newly developed histamine H2-receptor antagonist, inhibits daytime (i.e., postprandial) as well as nighttime gastric acid secretion in clinical studies. It also has gastroprotective activity that particularly affects mucosal blood flow in rats. This study focused on the efficacy of lafutidine on plasma concentrations of gastrointestinal peptides in humans. Six healthy male volunteers aged 23–32 years without Helicobacter pylori infection were orally administered either 10 mg lafutidine, 20 mg famotidine, or water only (control) 30 min after a standard meal (650 kcal). Plasma concentrations of lafutidine and famotidine were highest from 90 to 150 min after administration. Intragastric pH was elevated after both lafutidine and famotidine compared with the control. Plasma concentrations of calcitonin gene-related peptide (CGRP) and somatostatin were significantly increased after lafutidine at 60 and 90 min. We concluded that lafutidine increases plasma concentrations of CGRP and somatostatin in humans, which may result in inhibition of postprandial acid secretion and gastroprotective activity. [ABSTRACT FROM AUTHOR]

Abstract We studied the roles of hepatitis C virus (HCV) core protein in hepatic steatosis and changes in hepatic lipid metabolism. HCV core protein expression plasmid was transfected in HepG2 . Triacylglyceride (TG) and mRNA level associated with lipid metabolism were measured. Male C57BL/6 mice were infected with HCV core recombinant adenovirus and used for lipids and mRNA studies. In HCV core protein-expressing cells, peroxisome proliferator-activated receptor (PPAR)α, multidrug resistance protein (MDR) 3, and microsomal triglyceride transfer protein (MTP) were down-regulated 48 hr after transfection. In HCV core protein-expressing mice, hepatic TG content and hepatic thiobarbituric acid-reactive substances increased. PPARα, MDR2, acyl-CoA oxidase (AOX), and carnitine palmitoyl transferase-1 (CPT-1) were down-regulated. HCV core protein down-regulated lipid metabolism-associated gene expression, Mdr2, CPT, and AOX, accompanied by down-regulation of PPARα. There findings may contribute to the understanding of HCV-related steatosis, induction of reactive oxygen species, and carcinogenesis. [ABSTRACT FROM AUTHOR]

Abstract Rabeprazole achieves more potent acid suppression than other proton pump inhibitors. Therefore it is administered at reduced as well as high dosages in eradication therapy for Helicobacter pylori; however, there is incomplete assessment of the efficacy of a reduced dosage of rabeprazole as might be employed in therapy. [ABSTRACT FROM AUTHOR]

Abstract In this study, we assessed the hypothesis that angiotensin (Ang) II could modulate inflammatory cell recruitment into the liver through hepatic expression of monocyte chemoattractant protein (MCP)-1 during liver injury. For in vivo study, Ang II type 1a knockout (AT1a KO) mice and wild-type (WT) mice were treated with CCl4 for 4 weeks. After CCl4 treatment, AT1a KO mice showed lower expression of MCP-1 and fewer CD68-positive cells in the liver compared with WT mice. For in vitro study, Ang II was added to LI90 cells. Ang II enhanced MCP-1 mRNA together with RhoA mRNA and also induced secretion of MCP-1 into the culture medium. This change was strongly blocked by Y-27632, a specific Rho-kinase inhibitor. These results suggest that Ang II modulates hepatic inflammation via production of MCP-1 by hepatic stellate cells, and the effect of Ang II on MCP-1 production is, at least partly, mediated by the Rho/Rho-kinase pathway. [ABSTRACT FROM AUTHOR]

Abstract Bile acids are considered to be involved in the development of biliary tract carcinoma, although the underlying mechanisms are yet to be established. The aims of this study were (1) to investigate the carcinogenic role of bile acids in the biliary system based on the arachidonate–prostanoid pathway and (2) to clarify the therapeutic role of a farnesoid X receptor (FXR) ligand that modifies bile acid metabolism. Immortalized mouse cholangiocytes were incubated with glycochenodeoxycholate (GCDC), taurocholate, taurochenodeoxycholate, taurodeoxycholate, and tauroursodeoxycholate. GCDC induced cyclooxygenase 2 (COX-2) expression (Western blotting, 1.7-fold; RT-PCR, 2.3-fold) and prostaglandin (PG) production (PGE2, 6.3-fold; PGF2a, 8.5-fold), whereas cytosolic phospholipase A2 (cPLA2) expression and activity were reduced. In contrast, no marked changes were induced by the other bile acids. When the same experiment was performed in the presence of a synthetic FXR ligand (GW4064), cPLA2 expression and activity were reduced, although COX-2 expression was unchanged. GW4064 also suppressed PG generation by 40%. In conclusion, the present findings suggest a carcinogenic potential of GCDC. A synthetic FXR ligand (GW4064) inhibited the induction of COX-2 activity (detected as PG production) by GCDC, suggesting its anticarcinogenic potential. This effect seemed to be due to down-regulation of cPLA2. FXR ligands may have therapeutic potential against biliary carcinogenesis, but a delivery system for these agents is still to be developed. [ABSTRACT FROM AUTHOR]

In the pathogenesis of gastroesophageal reflux disease (GERD), gastric acid is considered to be one of the most important factors, but little is known about the degree of gastric acid secretion in GERD patients. In this study, we evaluated it in GERD patients and control subjects by 24-h intragastric pH, and serological and histological investigations, in relation to Helicobacter pylori (H. pylori) status. In H. pylori-negative GERD patients gastric acid secretion was similar to that in H. pylori-negative control subjects. In H. pylori-positive GERD patients, in particular, mild GERD patients, it decreased significantly compared to that in H. pylori-negative control subjects, but the degree of decrease was smaller than in H. pylori-positive control subjects. Results of serological and histological evaluation were supportive. In conclusion, in some GERD patients, gastric acid secretion was significantly decreased. Increased or maintained gastric acid secretion was not essential in the pathogenesis of mild GERD. [ABSTRACT FROM AUTHOR]