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BACKGROUND Certain lipid-lowering drugs increase bile lithogenicity. Here we investigated whether long-term administration of ezetimibe, a new class of hypocholesterolemic agents designed to inhibit intestinal cholesterol absorption by inhibiting Niemann-Pick C1-like 1, alters bile lithogenicity in patients with hepatobiliary diseases. METHODS Eleven dyslipidemic patients with gallstones and/or fatty liver diseases were treated with ezetimibe (10 mg/day) for 12 months. Bile samples were collected by nasal endoscopy before and after 3 and 12 months of treatment. Serum and bile lipids and serum metabolic parameters were analyzed. RESULTS Serum levels of campesterol, total cholesterol, and low-density lipoprotein cholesterol were significantly decreased after 3 and 12 months of treatment. In contrast, serum lathosterol levels increased gradually. The lithogenic index of bile was unsaturated and unchanged in patients who were previously and concomitantly receiving ursodeoxycholic acid (UDCA). In patients who were not receiving UDCA, bile was initially supersaturated, but eventually was unsaturated. However, ezetimibe tended to elevate bile lithogenicity in cholecystectomy patients. CONCLUSIONS Long-term treatment with ezetimibe improves lipid metabolism without significantly altering the bile lithogenicity. Therefore, inhibiting intestinal cholesterol absorption in dyslipidemic patients with hepatobiliary diseases is a safe therapeutic strategy without worsening biliary physiology.

Jugular paraganlioma is a benign, slow-growing tumor originating from the paraganglion cells and it is associated with catecholamine secretion. Paragangliomas can secrete Interleukin-6 (IL-6) and present as a systemic inflammatory syndrome; these characteristics have not been previously associated with jugular paragangliomas. A 63-year-old man with a jugular tumor in the skull base was referred to our hospital for an evaluation of pyrexia, back pain, and acute inflammation. His serum IL-6 level was elevated on admission and it decreased after radiotherapy. This is the first known case of a jugular paraganglioma exhibiting systemic inflammatory syndrome.

Since acute abdomen requires accurate diagnosis and treatment within a particular time limit to prevent mortality, the Japanese Society for Abdominal Emergency Medicine, in collaboration with four other medical societies, launched the Practice Guidelines for Primary Care of Acute Abdomen that were the first English guidelines in the world for the management of acute abdomen. Here we provide the highlights of these guidelines (all clinical questions and recommendations were shown in supplementary information). A systematic and comprehensive evaluation of the evidence for epidemiology, diagnosis, differential diagnosis, and primary treatment for acute abdomen was performed to develop the Practice Guidelines for Primary Care of Acute Abdomen 2015. Because many types of pathophysiological events underlie acute abdomen, these guidelines cover the primary care of adult patients with nontraumatic acute abdomen. A total of 108 questions based on nine subject areas were used to compile 113 recommendations. The subject areas included definition, epidemiology, history taking, physical examination, laboratory test, imaging studies, differential diagnosis, initial treatment, and education. Japanese medical circumstances were considered for grading the recommendations to assure useful information. The two-step methods for the initial management of acute abdomen were proposed. Early use of transfusion and analgesia, particularly intravenous acetaminophen, were recommended. The Practice Guidelines for Primary Care of Acute Abdomen 2015 have been prepared as the first evidence-based guidelines for the management of acute abdomen. We hope that these guidelines contribute to clinical practice and improve the primary care and prognosis of patients with acute abdomen.

Background: Since acute abdomen requires accurate diagnosis and treatment within a particular time limit to prevent mortality, the Japanese Society for Abdominal Emergency Medicine in collaboration with four other medical societies launched the Practice Guidelines for Primary Care of Acute Abdomen that were the first English guidelines in the world for the management of acute abdomen. Here we provide the highlights of these guidelines (all CQ and recommendations were shown in supplementary information). Methods: A systematic and comprehensive evaluation of the evidence for epidemiology, diagnosis, differential diagnosis, and primary treatment for acute abdomen was performed to develop the Practice Guidelines for Primary Care of Acute Abdomen 2015. Because many types of pathophysiological events underlie acute abdomen, these guidelines cover the primary care of adult patients with nontraumatic acute abdomen. Results: A total of 108 questions based on 9 subject areas were used to compile 113 recommendations. The subject areas included definition, epidemiology, history taking, physical examination, laboratory test, imaging studies, differential diagnosis, initial treatment, and education. Japanese medical circumstances were considered for grading the recommendations to assure useful information. The two-step methods for the initial management of acute abdomen were proposed. Early use of transfusion and analgesia, particularly intravenous acetaminophen, were recommended. Conclusions: The Practice Guidelines for Primary Care of Acute Abdomen 2015 have been prepared as the first evidence-based guidelines for the management of acute abdomen. We hope that these guidelines contribute to clinical practice and improve the primary care and prognosis of patients with acute abdomen.

Objectives The aim of this study was to assess prevailing treatment of pancreatolithiasis in Japan. Methods We surveyed clinical data from 1834 patients (1479 men and 355 women) at 125 hospitals. Results Extracorporeal shock-wave lithotripsy (ESWL) was performed alone in 103 patients (5.6%), ESWL plus an endoscopic procedure in 446 (24.3%), endoscopic treatment alone in 261 (14.2%), and surgery in 167 (9.1%). Other treatments were given to 358 (19.5%), whereas 499 (27.2%) received no treatment. Symptoms were relieved in 85.7% after ESWL, 80.8% after endoscopic treatment alone, and 92.8% after surgery. Early complication rates within 3 months after ESWL, endoscopic treatment alone, and surgery were 8%, 4.5%, and 27.1%, respectively. Late complications after ESWL, endoscopic procedures alone, and surgery were 1.7%, 2.5%, and 8.2%, respectively. Symptom relief but also early and late complications were greater after surgery than after ESWL and endoscopic treatment. Among 417 patients undergoing ESWL, 61 (14.6%) required surgery, as did 32 (16%) of 200 patients treated endoscopically. Surgery was required less frequently following initial operative treatment (11/164 patients [6.7%]). Nonsurgical initial treatments were chosen more frequently. Conclusions First-line treatment of pancreatolithiasis should be ESWL with or without endoscopy because of minimal invasiveness and fewer complications.

Background Primary sclerosing cholangitis (PSC) is relatively rare disease and pathogenesis and methods of treatments were still not established. Then, we had conducted the making clinical guidelines to manage patients with PSC based on the literature review and expert opinions. These clinical guidelines were made for the medical doctors on the management of PSC, except child case of PSC. Methods We had employed modified Delphi method. The production committee decided guidelines, strength of recommendations and evidence level after reviewed literatures systematically, and The Expert panel evaluated those. The Scientific Committee of the Japan Biliary Association (JBA) evaluated revised guidelines, and the Public comments were collected on web site of JBA. Results We had made 16 guidelines about epidemiology/pathophysiology, diagnostics, therapy and prognosis. Also, we had made both diagnostic and therapeutic flow chart. Conclusions We hope that these guidelines will contribute to the improvement and development of the medical care of PSC.

Familial Mediterranean fever (FMF) is the most common genetic autoinflammatory disease, but it has been considered a rare disease in Japan. We herein describe five patients with FMF who were diagnosed both clinically and genetically at a single Japanese institute. A genetic investigation of Mediterranean fever (MEFV) detected heterozygosity for the compound mutations L110P/E148Q (n=2) and L110P/148Q/P369S/R406Q (n=1), and heterozygosity for M694I (n=1) and S503C (n=1). Colchicine prevented febrile attacks and accompanying symptoms in four patients. One patient with an S503C mutation showed resistance. Physicians should be aware of the characteristic symptoms, as well as the more unusual symptoms such as headache, when diagnosing FMF.

A 46-year-old man with severe back pain visited our hospital. Magnetic resonance imaging revealed extensive bone metastasis and rectal wall thickness. Colonoscopy revealed circumferential stenosis with edematous mucosa, suggesting colon cancer. However, histological findings of biopsy specimens revealed inflammatory cells but no malignant cells. The patient underwent endoscopic ultrasound, which demonstrated edematous wall thickness without destruction of the normal layer structure. After unsuccessful detection of neoplastic cells by boring biopsies, we performed endoscopic mucosal resection followed by boring biopsies that finally revealed signet ring cell carcinoma. Herein, we present a case and provide a review of the literature.

Background The disparity in the number of urban and rural physicians is a social problem in Japan. There may also be a disparity in the age of physicians. This study longitudinally examines both geographic and age distributions of physicians. Methods Individual data from the Survey of Physicians, Dentists and Pharmacists in 1994, 2004 and 2014 and municipality data from the National Population Census were used. The 2015 municipality border was applied to all years, and all municipalities were classified into equalsize quintiles based on population density. Both municipalities and physicians were longitudinally observed. Results Between 1994 and 2014, the number of physicians per 100,000 population increased by 31.8% in the most urban group of municipalities and 17.4% in the most rural group. The average age of physicians was highest in the most rural and lowest in the most urban group. The difference in average age between the urban and rural physicians widened from 2.1 years in 1994 to 6.0 years in 2014. This disparity is particularly pronounced among hospital physicians (from 1.5 years in 1994 to 7.6 years in 2014). In the most rural group, the number of hospital physicians younger than 40 years old has decreased by 59.4%, while the number of those 55±70 has grown by 153% and the number older than 70 years old by 41.0%. Between 1994 and 2004, only 23.0% of hospital physicians younger than 40 years old were retained in the most rural group; the retention rate fell to 19.3% between 2004 and 2014, while the rates increased in older physicians. Conclusions The uneven distribution of physicians is increasing in Japan, as is the aging of rural hospital physicians. Shortage of physicians in rural areas may be more serious than that shown as their headcount., This research was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number 16K09145 (http://www.jsps.go.jp/english/e-grants/index.html) (KI).

In addition to surgery, procedures for patients with pancreatolithiasis are developing; therefore, establishing practical guidelines for the management of pancreatolithiasis is required.Three committees (the professional committee for asking clinical questions (CQs) and statements by Japanese endoscopists, the expert panel committee for rating statements by the modified Delphi method, and the evaluating committee by moderators) were organized. Eight endoscopists and a surgeon for pancreatolithiasis made the CQs and statements from a total of 694 reports of published literature by PubMed search (from 1983 to 2012). The expert panelists individually rated these clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid.The professional committee made 3, 7, and 10 CQs and statements for the concept and pathogenesis, diagnosis, and treatment, respectively. The expert panelists regarded them as valid after a 2-round modified Delphi approach.After evaluation by the moderators, the Japanese clinical guidelines for pancreatolithiasis were established. Further discussions and studies for international guidelines are needed.

The 3(rd) English edition of the Japanese classification of biliary tract cancers was released approximately 10 years after the 5(th) Japanese edition and the 2(nd) English edition. Since the first Japanese edition was published in 1981, the Japanese classification has been in extensive use, particularly among Japanese surgeons and pathologists, because the cancer status and clinical outcomes in surgically resected cases have been the main objects of interest. However, recent advances in the diagnosis, management and research of the disease prompted the revision of the classification that can be used by not only surgeons and pathologists but also by all clinicians and researchers, for the evaluation of current disease status, the determination of current appropriate treatment, and the future development of medical practice for biliary tract cancers. Furthermore, during the past 10 years, globalization has advanced rapidly, and therefore, internationalization of the classification was an important issue to revise the Japanese original staging system, which would facilitate to compare the disease information among institutions worldwide. In order to achieve these objectives, the new Japanese classification of the biliary tract cancers principally adopted the 7(th) edition of staging system developed by the International Union Against Cancer (UICC) and the American Joint Committee on Cancer (AJCC). However, because there are some points pending in these systems, several distinctive points were also included for the purpose of collection of information for the future optimization of the staging system. Free mobile application of the new Japanese classification of the biliary tract cancers is available via http://www.jshbps.jp/en/classification/cbt15.html.

Background In the reform of specialist training by Japanese Medical Specialty Board, general practice is expected to be one of 19 core specialties. University departments of general practice can play a central role in training board‐certified generalists, but whether they are actually preparing to do so is unknown. Method We sent a questionnaire to 79 universities and requested to forward it to the general practice department. Fifty‐six departments of general practice (37 public and 19 private universities) completed the questionnaire (response rate 71%). Results Fifty‐one (91.9%) universities planned to be the base institutes of certified programs. The annual seats per program ranged from 2 to 20 (median 5). In these 51 university‐based programs, 33 (64.7%) departments provide the general practice II element. Twenty‐eight (54.9%) require the program trainees to belong to the departments (do nyukyoku) and 11 (21.6%) recommend that they do so. Forty‐seven (92.2%) programs had affiliated institutions in rural areas. Thirty‐nine (76.5%) were willing to accept graduates of regional quota (chiikiwaku). Twenty‐nine (56.9%) program directors took into account the obligatory service of regional quota when making the programs. Programs that accept regional quota graduates were more likely to be affiliated with rural institutions (P=.002) and conscious of the obligatory service in making the program than other programs (P

Aim Ezetimibe inhibits cholesterol absorption by blocking Niemann–Pick C1-like 1 proteins (NPC1L1) expressed in the small intestine. Because NPC1L1 is also expressed in human liver, ezetimibe conceivably alters biliary lipid compositions. Here, we performed a clinical trial investigating the effect of ezetimibe on biliary lipids using transnasal endoscopy for bile collection. Methods Eight patients with dyslipidemia enrolled in this study completed blood and bile sampling before and at 3 months after ezetimibe treatment (10 mg/day), and the samples are analyzed. Results Endoscopic bile sampling was performed safely and painlessly. Serum sterol-based biomarkers declared decreased cholesterol absorption and increased synthesis. On analysis of biliary lipids, four of the eight patients showed relative decrease of cholesterol and increase of bile acids with improved lithogenicity while the remainder exhibited the symmetrical changes. Conclusion Our data suggests that biliary lithogenicity is not worsened by ezetimibe. The regulation of biliary cholesterol is presumably multifactorial such as body cholesterol pool size and biliary cholesterol reabsorption by NPC1L1 in the liver.

Key Clinical Message Salicylate‐induced acute respiratory syndrome (ARDS) is a well‐known entity occurring in 35% of salicylate‐intoxicated patient. Careful history taking, physical examination, arterial blood gas analysis, and measurement of serum salicylate concentration will lead to early recognition to initiate appropriate treatment.

ObjectivesThis 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 non-designated 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.DesignProspective cohort study.SettingNationwide.ParticipantsRegional quota graduates with prefecture scholarship, quota graduates without scholarship and non-quota graduates with scholarship of Japanese medical schools who obtained their physician license between 2014 and 2016.Primary outcomeThe emigration in 2016 of the participants from the designated prefectures.ResultsTotal 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.ConclusionsA 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.

Nutritional factors play a key role in the pathogenesis of biliary diseases such as gallstones and pancreaticobiliary maljunction. Gallstones are primarily classified into cholesterol stone and pigment stone according to the major composition. Cholesterol gallstone formation is very likely based upon supersaturated bile formation, and pigment stones are formed in bile rich in bilirubin. Thus, defects of hepatic metabolism of lipids and organic anions lead to biliary stones. Here, the recent understanding of cholesterol gallstone pathogenesis is elaborated. On the other hand, there is another important link of biliary lipid degradation to serious biliary disease, namely pancreaticobiliary maljunction. Lysophosphatidylcholine (lysoPC), a derivative of phosphatidylcholine hydrolysis by phospholipase A2, is a highly abundant bioactive lipid mediator present in circulation as well as in bile. Increases in bile of lysoPC and phospholipase A2 have been reported in pancreaticobiliary maljunction and considered to be the major risk factor for biliary tract cancers. Further, oxidized fatty acids have been established as a potent ligand for G2A, a member of G protein-coupled receptor family that mediates a diverse array of biological processes including cell growth and apoptosis. Thus, both of lysoPC and free fatty acids are supposed to play an important role through G2A in biliary inflammation and carcinogenesis of pancreaticobiliary maljunction. Taken together, nutritional factors, especially lipid compounds, are seemingly crucial in the pathogenesis of biliary diseases, and such a causal relationship is reviewed by mainly authors' previous publications.

Background We previously conducted nationwide surveys for primary sclerosing cholangitis (PSC) in Japan, and demonstrated several characteristic features of Japanese PSC patients, yet patients with IgG4-related sclerosing cholangitis (IgG4-SC) might be misdiagnosed as PSC. Since the clinical diagnostic criteria of IgG4-SC were established in 2012, we again conducted a nationwide survey to investigate the characteristics of PSC and IgG4-SC lacking pancreatic involvement. Methods The design was a questionnaire-based, multi-center retrospective study. The enrolled subjects were patients with PSC and IgG4-SC without pancreatic involvement diagnosed after 2005. Results We enrolled 197 PSC and 43 IgG4-SC patients without pancreatic lesions. The male dominance was significantly evident in IgG4-SC (P = 0.006). In patients with PSC, two peaks in age distribution were clearly observed. IgG4-SC was not detected in any patient younger than 45 years of age. At presentation, serum albumin and IgM were significantly higher in PSC, while serum IgG and IgG4 were significantly elevated in IgG4-SC. Inflammatory bowel disease (IBD) was detected in only 68/197 PSC patients (34%). The prognosis of IgG4-SC was considerably better than that of PSC. Conclusion We confirmed several interesting clinical details of PSC in Japanese patients: two peaks in the age distribution and lower prevalence of IBD.

OBJECTIVES A Japanese multicenter study of pancreatolithiasis was performed to investigate its clinical features and determine treatment strategies for pancreatolithiasis. METHODS A retrospective study was performed on 916 patients managed in 34 institutions for a period of more than 5 years. RESULTS The treatment methods were extracorporeal shock wave lithotripsy (ESWL) in 479 patients, surgery in 133, and endoscopy alone in 68. Fragmentation of stones after ESWL was achieved in 92.4% of the patients. However, complete stone clearance was achieved in 49.4% of the patients after ESWL alone. The complete stone clearance rate was lower after ESWL than after endoscopy (87.9%). The incidence of early complications was significantly higher after surgery (13.3%) than after ESWL (6.1%). The frequencies of total stone recurrence after ESWL (22.5%) and endoscopy (12.0%) were significantly higher than that after surgery (1.5%). After ESWL (17.6%), abdominal pain recurred significantly more frequently than after surgery (2.2%). Stones and abdominal pain most often recurred within 3 years after ESWL and endoscopy. CONCLUSIONS First-line treatment of pancreatic stones should be ESWL alone or with endoscopy because of its minimal invasiveness and low incidence of early complications. Surgery should be performed on patients in whom ESWL and endoscopy failed.

Aim In Japan, many elderly patients are managed at home, and fever is a common problem. This study examined the incidence of fever events in elderly patients on home medical management, and underlying disorders from the pragmatic standpoint. This study also investigated whether the care-need level determined at the start of home care predicts fever onset. Methods The participants were patients aged ≥65 years who received home medical management from one clinic from 1 July 2008 to 30 June 2009. End-points were onset of fever, diagnosis at time of fever onset and outcome. The incidence of fever was determined using the Kaplan–Meier method and compared using the log–rank test. To evaluate the effect of care-need level on fever, Cox's proportional hazards model was used to adjust for confounding variables. Results A total 105 patients were included, with 100% follow up. The median observation period was 364 days. There were 64 fever events, for a fever incidence of 2.3/1000 patient-days (95% CI 1.8–2.9); fever occurred at least once in 42.6% of participants. Fever was significantly more likely to occur in care-need level 5 than in ≤4, with a risk ratio of 2.4. The most common diagnosis for all fever events was pneumonia/bronchitis, followed by urinary tract infection, and skin and soft tissue infection. Nearly 80% of cases were cured at home. Conclusions Fever occurred in approximately half of the participants over 1 year, and was more likely in patients requiring the highest care level; nearly 80% of cases were cured at home. Geriatr Gerontol Int 2013; 13: 887–893.

Cholelithiasis is one of the commonest diseases in gastroenterology. Remarkable improvements in therapeutic modalities for cholelithiasis and its complications are evident. The Japanese Society of Gastroenterology has revised the evidence-based clinical practice guidelines for cholelithiasis. Forty-three clinical questions, for four categories—epidemiology and pathogenesis, diagnosis, treatments, and prognosis and complications—were selected, and a literature search was performed for the clinical questions with use of the MEDLINE, Cochrane, and Igaku Chuo Zasshi databases for the period between 1983 and June 2012. The guidelines were developed with use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. This article preferentially describes the clinical management of cholelithiasis and its complications. Following description of the diagnosis performed stepwise through imaging modalities, treatments of cholecystolithiasis, choledocholithiasis, and hepatolithiasis are introduced along with a flowchart. Since there have been remarkable improvements in endoscopic treatments and surgical techniques, the guidelines ensure flexibility in choices according to the actual clinical environment. The revised clinical practice guidelines are appropriate for use by clinicians in their daily practice.

Background & Aims Immunoglobulin G4 sclerosing cholangitis (IgG4-SC) is a biliary tract manifestation of IgG4-related systemic disease. We investigated the demographics, clinical features at presentation, treatment response, and outcomes of IgG4-SC using data from a large-scale survey in Japan. Methods We performed a retrospective cohort study of 527 patients with IgG4-SC (436 female; median age, 66.2 years; range, 23–89 years) in Japan from 2000 to 2015. Data on patient demographics, presentation, treatment response, and outcomes were collected from questionnaires given to patients at 211 referral centers in Japan in 2015. Patients were diagnosed with IgG4-SC based on the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Patients were followed for a median of 4.1 ± 3.1 years. Survival was assessed using the Kaplan-Meier curve and log-rank test. Results Symptoms at presentation included jaundice (35% of patients) and pruritus (13% of patients); 28% of patients were asymptomatic. It was extremely rare for patients with IgG4-SC to present with symptoms of decompensated cirrhosis. At presentation, serum levels of IgG4 were increased (>135 mg/dL) in 84% of patients. Response to prednisolone was excellent in 90% of patients. No patients received liver transplants, and cholangiocarcinoma was found in only 4 patients (0.7%). Restenosis of bile ducts was observed in 19% of patients but did not affect overall survival. Conclusions In a retrospective cohort study of 527 patients with IgG4-SC in Japan, we found the disease to be benign. Most patients (90%) respond to treatment with prednisolone and few develop decompensated cirrhosis or cholangiocarcinoma.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown cause that is characterized pathologically by an inflammatory and fibrotic process centered on the epithelium, leading to diffuse biliary stenosis and increased wall thickness throughout the intra- and extra-hepatic biliary trees. A nationwide survey in Japan revealed several differences in the clinical aspects of PSC between Japan and Western countries. PSC was recently designated an intractable hepatobiliary disease in Japan. The aim of this study was to establish Japanese diagnostic criteria for PSC according to the current Japanese conditions. The Intractable Hepato-Biliary Diseases Study Group in Japan of the Committee of Research on Measures for Intractable Diseases established a working group consisting of researchers specializing in PSC and proposed the 2016 Japanese diagnostic criteria for PSC. The diagnostic criteria consisted of the major and minor items. Major items are directly related to bile duct changes based on biliary tract imaging and an increased alkaline phosphatase level. Minor items consist of an association with inflammatory bowel disease and liver histology. The diagnostic criteria for PSC are useful for general physicians in practice.

Aim The present study examined whether social support, informal socializing and social participation are associated with glycemic control in older people. Methods Data for this population-based cross-sectional study was obtained from the Japan Gerontological Evaluation Study (JAGES) 2010 linked to the annual health check-up data in Japan. We analyzed 9,554 individuals aged ≥65 years without the certification of needed long-term care. Multivariate logistic regression models were used to assess the effect of social support, informal socializing and social participations on glycemic control. The outcome measure was HbA1c ≥8.4%. Results 1.3% of the participants had a level of HbA1c over 8.4%. Better glycemic control was significantly associated with meeting with friends one to four times per month (odds ratio [OR] 0.51, 95% confidence interval [CI]0.30-0.89, compared to meeting with friends a few times per year or less) and participation in sports groups (OR 0.50, 95% CI 0.26-0.97) even after adjusting for other variables. Meeting with friends more than twice per week, receiving social support, and being married were not associated with better control of diabetes. Conclusions Meeting with friends occasionally is associated with better glycemic control among older people.

Measuring the learning effectiveness of Kampo Medicine (KM) education is challenging. The aim of this study was to develop a web-based test to measure the learning effectiveness of KM education among medical students (MSs). We used an open-source Moodle platform to test 30 multiple-choice questions classified into 8-type fields (eight basic concepts of KM) including “qi-blood-fluid” and “five-element” theories, on 117 fourth-year MSs. The mean (±standard deviation [SD]) score on the web-based test was30.2±11.9(/100). The correct answer rate ranged from 17% to 36%. A pattern-based portfolio enabled these rates to be individualized in terms of KM proficiency. MSs with scores higher (n=19) or lower (n=14) than mean ± 1SD were defined as high or low achievers, respectively. Cluster analysis using the correct answer rates for the 8-type field questions revealed clear divisions between high and low achievers. Interestingly, each high achiever had a different proficiency pattern. In contrast, three major clusters were evident among low achievers, all of whom responded with a low percentage of or no correct answers. In addition, a combination of three questions accurately classified high and low achievers. These findings suggest that our web-based test allows individual quantitative assessment of the learning effectiveness of KM education among MSs.

The Japan Primary Care Association has certified family physicians to play a key role in emergency care. During the family medicine program, family physicians train how to treat mild to moderate emergency symptoms for at least three months at a hospital in which more than one thousand patients are transported by ambulance a year. After the three-year program, they can provide not only emergency care for citizens but also emergency care education for trainee doctors. There will be a greater need for certified family physicians because they have a vital mission to protect the health of local communities by associating with several departments, including the emergency department.

Periostin is a matricellular protein that serves as a ligand for integrins and is required for tissue remodeling and fibrosis. We investigated the role of periostin in hepatic fibrosis and the mechanisms involved.Primary hepatic stellate cells (HSCs) and the HSC-immortalized cell line LX2 were used to study the profibrotic property of periostin and the interaction of periostin with integrins. Wild-type and periostin-deficient (periostinPeriostin expression in HSCs and LX2 cells increased in association with their activation. Gene silencing of periostin resulted in a significant reduction in the levels of profibrotic markers. In addition to enhanced cell migration in response to periostin, LX2 cells incubated on periostin showed significant induction of α-smooth muscle actin and collagen, indicating a profibrotic property. An antibody targeting αPeriostin exerts potent profibrotic activity mediated by α

IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases. The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012. The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC. These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

Aim: Non-alcoholic fatty liver disease (NAFLD) that encompasses a spectrum of liver disorders characterized by simple steatosis, non-alcoholic steatohepatitis (NASH) through cirrhosis, is becoming an important chronic liver disease in Japan. Currently, there is no proven therapy for NASH. In this study, we assessed the efficacy of statin therapy in NASH patients with dyslipidemia. Methods: Twenty patients with biopsy-proven NASH with dyslipidemia who agreed to participate in this multicentric prospective study were enrolled. The patients were treated for 12 months with pitavastatin 2 mg/day. Clinical and histological alterations were comparatively evaluated before and after treatment. Standard weight loss counseling was continued during the treatment period. Follow-up liver biopsy was performed in 13 patients. Results: Twenty-five percent of patients had hyperlipoproteinemia type IIa and 75% had hyperlipoproteinemia type IIb at baseline. The levels of alanine aminotransferase, γ-glutamyl transpeptidase and lipid profiles were significantly improved by the treatment with pitavastatin for 12 months. Especially, these improvements were prominent in NASH patients with hyperlipoproteinemia type IIb. While non-alcoholic fatty liver disease activity score and fibrosis stage did not change significantly in all patients, they did improve in 54% and 42% in individual patients, respectively. Conclusion: NASH-related metabolic parameters improved with therapy including histology in some patients. However, three of 13 patients had progression of fibrosis during the treatment. Our pilot study demonstrated the efficacy of pitavastatin for the treatment of NASH with dyslipidemia, especially with hyperlipoproteinemia type IIb and controlled trials are needed in the future.

Background We previously reported a model of non-alcoholic fatty liver disease (NAFLD) using spontaneously hypertensive rats (SHRs), fed a choline-deficient (CD) diet for 5 weeks, that hepatic steatosis but not fibrosis is developed through oxidative stress. To determine the relationship between hypertension and hepatic fibrosis in NAFLD, we examined whether long-term CD diet leads to hepatic fibrosis through oxidative stress. Methods Eight-week-old male SHR and normotensive Wistar Kyoto rats (WKYs) were fed a CD diet for 5 or 20 weeks, then liver histology and hepatic expression of genes related to lipid metabolism, fibrosis, and oxidative stress were assessed. Oxidative stress was assessed by hepatic thiobarbituric acid reactive substance (TBARS) levels. Results After 5 weeks on CD diet, prominent hepatic steatosis and decrease in expression of genes for lipid metabolism were observed in SHRs as compared with WKYs. SHRs on a CD diet demonstrated a downregulated expression of genes for antioxidants, along with significant increases in hepatic TBARS. After 20 weeks on CD diet, SHRs demonstrated severe liver fibrosis and upregulated expressions of genes for fibrosis when compared with WKY. Conclusion Hypertension precipitated hepatic steatosis, and further, acts as an enhancer in NAFLD progression to liver fibrosis through oxidative stress.

AIM Patients with non-alcoholic steatohepatitis (NASH) frequently have many co-morbidities including essential hypertension, which is reported to increase vascular production of reactive oxygen species (ROS) and alter the hepatic anti-oxidant defense system. Since ROS play a role in the pathogenesis of NASH, it is hypothesized that hypertension modulates the hepatic oxidative status and influences the development of NASH. The aim of this study was to investigate the potential effects of hypertension on the progression of NASH. METHODS Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats as normotensive controls were fed choline-deficient (CD) diet for 5 weeks. Histological changes, messenger RNA (mRNA) expression and thiobarbituric acid reactive substances (TBARS) levels in the liver were assessed in each group. RESULTS Choline-deficient diet led to pronounced hepatic steatosis in SHR with an 8-fold increase of the hepatic triglyceride content, while there was no significant increase in WKY. These changes in SHR were associated with significant reduction in the expression of mRNA for peroxisome proliferator activated receptor α, acyl-CoA oxidase, microsomal triglyceride transfer protein, and apolipoprotein B100. Consistent with the significant reduction of hepatic superoxide dismutase activity and marked downregulation of the gene expression of hepatic antioxidant enzymes, the hepatic TBARS level and the plasma level of alanine aminotransferase were only increased in SHR on CD diet. CONCLUSIONS Spontaneously hypertensive rats receiving CD diet showed severe hepatic steatosis associated with reduction of hepatic anti-oxidant capacity, leading to increased hepatic oxidative stress and tissue damage. Accordingly, hypertension might have a potential effect on the progression of NASH.

Aim: We conducted a multicenter trial to evaluate the efficacy and safety of i.v. doripenem (DRPM), a new class of carbapenem, in patients with moderate to severe biliary tract infection based on severity assessment using the Guidelines for the Management of Acute Cholangitis and Cholecystitis (1st Edition). Methods: One hundred and nineteen patients with moderate to severe acute cholangitis and/or cholecystitis were subjected to this study. After the initial collection of bile, patients were administrated DRPM 0.5 g three times daily by i.v. drip infusion. Results: The characteristics of the 119 patients were well balanced, including 60 with cholangitis, 44 with cholecystitis and 15 with cholangitis complicated by cholecystitis; there were 88.2% (105/119) moderate cases and 11.8% (14/119) severe. Based upon the assumption of the use of bile drainage, the rate of response to DRPM was 92.4% (110/119) in the group of all patients. The clinical response rates were 95.0% (57/60) for cholangitis, 93.2% (41/44) for cholecystitis and 80% (12/15) for cholangitis complicated by cholecystitis. Also, the clinical response rate was 80% (8/10) in 10 patients without drainage. In contrast, bacteriological efficacy was assessed in 50 patients, and the response rates were 87.0% (20/23) in patients with cholangitis, 100% (20/20) in patients with cholecystitis and 85.7% (6/7) in patients with cholangitis complicated by cholecystitis. Adverse events were found in six patients (5.0%), but were not serious and disappeared after treatment. Conclusion: These findings suggest that DPRM is useful as a new option for moderate to severe biliary tract infection.

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., This study is funded by the Ministry of Education, Culture, Sports, Science and Technology KAKENHI Grant-in-Aid for Scientific Research (C), Grant Number (25460803).

Background/Aims: A distinct subgroup of angiotensin II type I receptor (AT1R) blockers (ARBs) have been reported to suppress the development of hepatic steatosis. These effects were generally explained by selective peroxisome proliferator-activated receptor (PPAR) gamma modulating properties of ARBs, independent of their AT1R blocking actions. Here, we provide genetic evidence of the direct role for AT1R in hepatic steatosis. Methods: The effect of AT1R deletion on steatohepatitis was investigated in AT1a(-/-) mice. Furthermore, the influence of AT1R inhibition by telmisartan as well as gene silencing of AT1R by siRNA was assessed in an in vitro experiment using HepG2 cells. Results: Compared to wild-type (WT), A T1a(-/-) mice fed methionine-choline deficient (MCD) diet resulted in negligible lipid accumulation in the liver with marked induction of PPAR alpha mRNA. In vitro experiments also demonstrated reduced cellular lipid accumulation by telmisartan and AT1R knockdown following exposure of long chain fatty acids. This is pre-sumably explained by the observation that the expression of PPAR alpha and its target genes were significantly up-regulated in specific siRNA treated HepG2 cells. Conclusions: Our data indicate, in addition to pharmacological effect of ARBs on PPAR gamma activation, a key biological role for AT1R in the regulation of hepatic lipid metabolism.

Generic drugs contain the same active ingredient as an original drug and have their bioequivalence proved by pharmacokinetic tests. However, few studies have been reported on whether these bioequivalence studies infer pharmacodynamic equivalence. In this study, in eight healthy Helicobacter pylori-negative CYP2C19 extensive metabolizers, we compared the acid-suppressive effects of repeated administration of 15 mg of three brands of generic lansoprazole, Taiproton, Tapizol, and Lansoral, with those of the original lansoprazole, Takepron. Median intragastric pH value for 24-h and % pH4 for daytime (08:00-20:00 h) and night-time were significantly higher with any lansoprazole formulation, compared with the control (P0.05, Wilcoxon signed-rank test). However, during the daytime, % pH4 with Tapizol was significantly lower than the original (P0.05). Compared with the original, no significantly larger, but no small range of inter-subject variations were observed in these two parameters for each of the three brands of generic lansoprazole (Bartlett test). Pharmacokinetic bioequivalence tests do not necessarily guarantee pharmacodynamic equivalence.

Nonalcoholic steatohepatitis (NASH) is the hepatic manifestation of the metabolic syndrome. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the efficacy of atorvastatin in the treatment of NASH associated with hyperlipidemia. This prospective study included 31 patients with biopsy-proven NASH with hyperlipidemia. Body mass index, serum lipids, liver function tests, fibrosis markers, and adipocytokines (adiponectin, leptin, tumor necrosis factor-alpha) were measured periodically during an open-label study of atorvastatin (10 mg daily) for 24 months. Standard weight-loss counseling was continued during the treatment period. Oral glucose tolerance test and liver density assessed by computerized tomography were performed before and after treatment. Follow-up liver biopsy was performed in 17 patients. All 31 patients had high cholesterol levels at baseline, and 20 also presented high triglyceride levels. The body mass index and serum glucose levels did not change during the treatment. After treatment, 23 patients (74.2%) presented normal transaminase levels. Adiponectin levels were significantly increased, and the levels of tumor necrosis factor-alpha were significantly decreased. However, leptin levels were not changed significantly. The concentration of long-chain fatty acids was decreased; and significant decreases were observed in C18:2,n-6 (linoleic acid, -21%) and C20:4,n-6 (arachidonic acid, -22%). Liver steatosis and nonalcoholic fatty liver disease activity score were significantly improved, whereas 4 patients had increased fibrosis stage. The NASH-related metabolic parameters improved with therapy, including fibrosis in some patients. However, 4 of 17 patients had progression of fibrosis over the 2-year period, with 3 of them progressing to stage 3. It is unclear whether this divergent response represents sampling error, heterogeneity in the population, or untreated postprandial hyperglyceridemia. Controlled trials are needed to further investigate and resolve this.

Background and Aim: Advanced glycation end products (AGE), senescent macroprotein derivatives formed at an accelerated rate in diabetes, play important roles in the pathogenesis of diabetic vascular complications. Recently, AGE have also been found to be involved in insulin resistance. Although non-alcoholic steatohepatitis (NASH) is generally considered a hepatic manifestation of insulin resistance, there are no reports showing the link of AGE to NASH. The aim of this study was to evaluate the clinical significance of AGE in patients with NASH. Methods: Glyceraldehyde-derived AGE levels were assayed from serum obtained from 106 patients: 66 with NASH, 10 with simple steatosis, and 30 controls. Results: Serum glyceraldehyde-derived AGE levels (U/mL) were significantly elevated in NASH patients (9.78 ± 3.73) compared with simple steatosis (7.17 ± 2.28, P = 0.018) or healthy controls (6.96 ± 2.36, P = 0.003). Moreover, these were inversely correlated with adiponectin, an adipocytokine with insulin-sensitizing and anti-inflammatory properties. In addition, immunohistochemistry of glyceraldehyde-derived AGE showed intense staining in the livers of NASH patients. Conclusion: The present data suggest that the sustained increase of glyceraldehyde-derived AGE could at least in part contribute to the pathogenesis of NASH. The serum glyceraldehyde-derived AGE level may be a useful biomarker for discriminating NASH from simple steatosis.

Lafutidine, a histamine H(2)-receptor antagonist, inhibits gastric acid secretion during the daytime, however, the relationship between the plasma concentration and the drug response remains unclear. The aim of this study was to compare the pharmacokinetic and pharmacodynamic properties of lafutidine and famotidine following postprandial oral administration. After a lafutidine tablet (10 mg), famotidine tablet (20 mg), or water only (control) was administered, blood samples were taken and intragastric pH was measured. The plasma concentrations of lafutidine and famotidine were determined by HPLC, and the median intragastric pH values per 30 min were used as the degrees of gastric acid suppression. Data were analyzed based on a one-compartment pharmacokinetic model and a sigmoid E(max) pharmacodynamic model. Lafutidine plasma concentrations rapidly increased after administration; famotidine required some time to increase the plasma concentrations, requiring an absorption lag time in the pharmacokinetic model. Between the plasma concentration and DeltapH (the difference in intragastric pH by the drug vs. control), lafutidine showed an anticlockwise hysteresis loop which indicated equilibration delay between the plasma concentration and effect site, requiring an effect site compartment in the pharmacodynamic model; famotidine showed more parallel relationship. These results indicated that the pharmacokinetic and pharmacodynamic properties of lafutidine after postprandial oral administration were different from those of famotidine at least 4.5 h after dosing.

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 Japanese Helicobacter 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 pH4.0 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; omeprazolefamotidine on Day 1, omeprazole approximately famotidine on Day 8, and omeprazolefamotidine on Day 15. This discrepancy possibly results from the "potentiation" of acid-suppressive effect of omeprazole and the "tolerance" phenomenon in respect to famotidine.

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.

Although inflammatory markers, such as the white blood cell (WBC) count, erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and procalcitonin, are widely used to differentiate causes of fever of unknown origin (FUO), little is known about the usefulness of this approach. We evaluated relationships between the causes of classical FUO and the levels of inflammatory markers.A nationwide retrospective study including 17 hospitals affiliated with the Japanese Society of Hospital General Medicine was conducted.This study included 121 patients ≥18 years old diagnosed with "classical FUO" (axillary temperature ≥38.0°C at least twice over a ≥3-week period without elucidation of the cause on three outpatient visits or during three days of hospitalization) between January and December 2011.The causative disease was infectious diseases in 28 patients (23.1%), non-infectious inflammatory disease (NIID) in 37 patients (30.6%), malignancy in 13 patients (10.7%), other in 15 patients (12.4%) and unknown in 28 patients (23.1%). The rate of malignancy was significantly higher for a WBC count of4,000/μL than for a WBC count of 4,000-8,000/μL (p=0.015). Among the patients with a higher WBC count, the rate of FUO due to NIID tended to be higher and the number of unknown cases tended to be lower. All FUO patients with malignancy showed an ESR of40 mm/h. A normal ESR appeared to constitute powerful evidence for excluding a diagnosis of malignancy. In contrast, the concentrations of both serum CRP and procalcitonin appeared to be unrelated to the causative disease.The present study identified inflammatory markers that should be considered in the differential diagnosis of classical FUO, providing useful information for future diagnosis.

Human bile salt export pump ( BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep−/−mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related (“coupled”) to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep−/−mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep−/−mice. We infused Bsep−/−and Bsep+/+(control) mice with TβMCA in stepwise increasing dosages (150–600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep−/−and control mice. TβMCA infusion increased BS secretion in both Bsep−/−and control mice. The secreted PL or CH amount per BS, i.e., the “coupling,” was continuously two- to threefold higher in Bsep−/−mice ( P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45–55% higher in Bsep−/−mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep−/−mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep−/−mice is based on increased expression of the responsible canalicular transporter proteins.