Dietary intervention for adult survivors of cancers other than breast cancer: A systematic review.

INTRODUCTION: Healthy eating and weight control are recommended for cancer survivors; however, dietary interventions are not routinely offered to them. This study aimed to assess the effects of dietary interventions on survival, nutritional status, morbidity, dietary changes, health-related quality of life (QOL), and clinical measures in cancer survivors. METHODS: Searches were conducted from October 1, 2018 to November 21, 2011 in the Medline, EMBASE, CENTRAL, Emcare, and DARE electronic databases. We included randomized controlled trials (RCTs) that involved individuals diagnosed with cancer, excluding conference abstracts, case studies, other reviews, and meta-analyses, and screened the articles. RESULTS: Eight studies were included in this meta-analysis. We observed significant improvements in QOL and clinical data in 3 of 6 studies and in one study, respectively, significant weight loss on anthropometry in 2 of 5 studies, and dietary improvement in 4 of 5 studies of adult cancer survivors. However, we did not observe any benefits of dietary intervention for cancer survivors with undernutrition. DISCUSSION: Dietary interventions for adult cancer survivors might contribute to improving their nutritional status; however, further clarification requires a study that standardizes the intervention method. Furthermore, RCTs are required to determine the effects on cancer survivors with undernutrition.

Contributions of Japanese Hospitalists During the COVID-19 Pandemic and the Need for Infectious Disease Crisis Management Education for Hospitalists: An Online Cross-Sectional Study.

Introduction: Hospitalists in Japan have been at the forefront of the COVID-19 pandemic. However, contributions of Japanese hospitalists during the COVID-19 pandemic and hospitalists' awareness of crisis management education remain unclear. Material and Methods: We conducted a questionnaire survey to investigate the role of Japanese hospitalists during the COVID-19 pandemic. The questionnaire was conducted using email and Google Forms targeting the chairpersons of facilities certified by the Japanese Society of Hospital General Medicine (JSHGM). Members of the academic committee of the JSHGM and several hospitals conducted a narrative review and determined the questions for the survey in a discussion. Results: We conducted descriptive statistics based on the responses of 97 hospitals that agreed to participate in this survey. In total, 91.8% of general medicine departments in the included hospitals were involved in the medical care of COVID-19 patients. Furthermore, in 73.2% of hospitals, hospitalists were involved in infection control for COVID-19 inside or outside the hospital. Our survey revealed that Japanese hospitalists were responsible for COVID-19 treatment in over 60% of hospitals and contributed to hospital management, infection control, and vaccination. In total, 79.4% of hospitals answered that "training of personnel who can provide practical care for emerging infectious diseases is necessary", 78.4% indicated that "the establishment of an infection control system in advance to prepare emerging infectious diseases in the hospital is necessary", and 74.2% stated that "the establishment of an educational system for responding to emerging infectious diseases is necessary.". Conclusion: In conclusion, during the pandemic, in addition to inpatient care, Japanese hospitalists provided outpatient care for COVID-19, which is the role of primary care physicians in other countries. Furthermore, Japanese hospitalists who experienced the COVID-19 pandemic expressed the need for personnel development and education to prepare for future emerging infectious disease pandemics.

Roles considered important for hospitalist and non-hospitalist generalist practice in Japan: a survey study.

BACKGROUND: An increased focus on quality and patient safety has led to the evolution of hospitalists. The number of hospitalists covering ward and outpatient care is on the rise in Japan. However, it is unclear what roles hospital workers themselves consider important in their practice. Therefore, this study investigated what hospitalists and non-hospitalist generalists in Japan consider important for the practice of their specialty. METHODS: This was an observational study that included Japanese hospitalists (1) currently working in a general medicine (GM) or general internal medicine department and (2) working at a hospital. Using originally developed questionnaire items, we surveyed the items important to hospitalists and non-hospitalist generalists. RESULTS: There were 971 participants (733 hospitalists, 238 non-hospitalist) in the study. The response rate was 26.1%. Both hospitalists and non-hospitalists ranked evidence-based medicine as the most important for their practice. In addition, hospitalists ranked diagnostic reasoning and inpatient medical management as the second and third most important roles for their practice, while non-hospitalists ranked inpatient medical management and elderly care as second and third. CONCLUSIONS: This is the first study investigating the roles Japanese hospitalists consider important and comparing those to that of non-hospitalist generalists. Many of the items that hospitalists considered important were those that hospitalists in Japan are working on within and outside academic societies. We found that diagnostic medicine and quality and safety are areas that are likely to see further evolution as hospitalists specifically emphasized on them. In the future, we expect to see suggestions and research for further enhancing the items that hospital workers value and emphasise upon.

Long-standing diabetes mellitus increases concomitant pancreatic cancer risk in patients with intraductal papillary mucinous neoplasms.

BACKGROUND: When monitoring patients with an intraductal papillary mucinous neoplasm (IPMN), it is important to consider both IPMN-derived carcinoma and concomitant ductal adenocarcinoma (PDAC). The latter is thought to have a poorer prognosis. We retrospectively analyzed the risk factors for concomitant PDAC in IPMN. METHODS: In total, 547 patients with pancreatic cysts, including IPMNs inappropriate for surgery on initial diagnosis, encountered from April 2005 to June 2019, were reviewed. We performed surveillance by imaging examination once or twice a year. RESULTS: Five IPMNs with high-grade dysplasia and one IPMN associated with invasive carcinoma were encountered. In comparison, 14 concomitant PDACs were encountered. The prognosis was very poor for concomitant PDACs. All 14 PDAC patients had IPMNs. In patients with IPMNs, long-standing diabetes mellitus was the only significant risk factor for concomitant PDAC in both univariate and multivariate analyses (P < 0.001 and P < 0.01, respectively). Furthermore, patients with IPMNs and diabetes mellitus had a high frequency of concomitant PDACs (9.5%, 9/95) in a median 48-month surveillance period. CONCLUSIONS: When monitoring IPMNs, the development of not only IPMN-derived carcinomas but also concomitant PDACs should be considered. During this period, it may be prudent to concentrate on patients with other risk factors for PDAC, such as long-standing diabetes mellitus.

Ursodeoxycholic acid is associated with improved long-term outcome in patients with primary sclerosing cholangitis.

BACKGROUND: It remains unclear whether ursodeoxycholic acid (UDCA) treatment improves long-term outcomes in patients with primary sclerosing cholangitis (PSC). In this study, we investigated whether UDCA treatment is associated with improved liver transplantation (LT)-free survival in a cohort of Japanese patients with PSC.Journal instruction requires a city and country for affiliations; however, these are missing in affiliation [6]. Please verify if the provided city and country are correct and amend if necessary.'Tokyo, Japan' is correct. METHODS: We used retrospective data from the Japanese PSC registry that included 435 patients with PSC. In this study, we enrolled patients with a complete dataset at diagnosis, along with the diagnosis year, treatment protocol, follow-up period, and outcome data. The association between UDCA treatment and all-cause death or LT was analyzed using Cox regression and inverse probability of UDCA treatment weighting (IPTW)-adjusted Cox regression models adjusted for covariates. RESULTS: Among 435 patients with PSC, 110 were excluded due to insufficient or missing data, and the remaining 325 patients (male, 187 (58%); mean age at diagnosis, 45.8 years) were enrolled. The mean follow-up period was 5.1 years, and 57 deaths and 24 LTs occurred during observation. UDCA was administered to 278 patients (86%). The Cox regression model demonstrated that UDCA treatment was associated with an improvement in LT-free survival [adjusted hazard ratio (aHR) 0.47, 95% confidence interval (CI) 0.28-0.78, p = 0.003]. In addition, the IPTW-adjusted model indicated a significant association between UDCA and LT-free survival (aHR 0.43, 95% CI 0.25-0.75, p = 0.020). Sensitivity analysis excluding patients treated with bezafibrate indicated a similarly significant association between UDCA treatment and LT-free survival. CONCLUSION: In this Japanese PSC cohort, UDCA treatment was significantly associated with improved LT-free survival.

Depletion of hepatic stellate cells inhibits hepatic steatosis in mice.

BACKGROUND AND AIM: Hepatic stellate cells (HSCs), the main source of extracellular matrix in hepatic fibrogenesis, produce various cytokines, growth factors, and morphogenetic proteins. Among these, several factors are known to promote hepatocyte lipid accumulation, suggesting that HSCs can be efficient therapeutic targets for non-alcoholic steatohepatitis (NASH). This study aimed to investigate the effects of HSC depletion on the development of hepatic steatosis and fibrosis in a murine NASH model. METHODS: C57BL/6 mice were treated with gliotoxin (GTX), an apoptosis inducer of activated HSCs under the feeding of a choline-deficient l-amino acid-defined high-fat diet for 4 weeks. For in vitro study, Hc3716 cells, immortalized human hepatocytes, were treated with fatty acids in the presence or absence of LX2, immortalized HSCs. RESULTS: Choline-deficient l-amino acid-defined high-fat diet increased pronounced hepatic steatosis, which was attenuated by GTX treatment, together with a reduction in the number of activated HSCs. This change was associated with the downregulation of the peroxisome proliferator-activated receptor gamma (PPARγ) and its downstream genes, including adipocyte protein 2, cluster of differentiation 36 (CD36), and fatty acid transport protein 1, all of which increase the fatty acid uptake into hepatocytes. As expected, GTX treatment improved hepatic fibrosis. Co-culture of hepatocytes with HSCs enhanced intracellular lipid accumulation, together with the upregulation of PPARγ and CD36 protein expressions. CONCLUSIONS: In addition to the improvement in hepatic fibrogenesis, depletion of HSCs had a favorable effect on hepatic lipid metabolism in a mouse NASH model, suggesting that HSCs are potentially efficient targets for the treatment of NASH.

Clinical utility of computed tomography-based evaluation of trunk muscles in primary sclerosing cholangitis.

PURPOSE: Sarcopenia is well recognized as a prognostic factor of chronic liver diseases. However, its impact on the clinical course of primary sclerosing cholangitis (PSC) is unclear. This study aimed to clarify the importance of trunk muscles evaluated by computed tomography (CT) in the pathophysiology of patients with PSC. MATERIALS AND METHODS: 22 PSC patients (12 men, mean age 42.8 years) were enrolled in this study. Patients who died of hepatic failure or had to receive liver transplantation were defined as event group. 44 age- and gender-matched individuals without hepatic disorder were served as controls. At the level of third lumbar vertebrae, the area of psoas muscle and trunk muscle as well as the CT values of multifidus muscle and subcutaneous fat were evaluated. Based on these, skeletal muscle index (SMI), psoas muscle mass index (PMI) and intramuscular adipose tissue content (IMAC) were calculated. Then we analyzed the relationship between these parameters and laboratory data, Fibrosis-4 index, MELD score and Mayo risk score. RESULTS: At baseline evaluation, SMI and PMI were statistically lower in male PSC patients compared with those in controls (P < 0.05). In male PSC, regarding the laboratory data, PMI was associated with total bilirubin, ALT, ALP, and platelet count (P < 0.05). We found close relationship between PMI and MELD score (R2 = 0.42, P = 0.02). PMI also decreased statistically in male Event group than in non-event group (4.85 vs 7.20, P = 0.01). CONCLUSION: Skeletal muscle mass evaluated by CT scan can be suitable for evaluating clinical and prognostic marker in male PSC.

Predictive factors for subsequent intrahepatic cholangiocarcinoma associated with hepatolithiasis: Japanese National Cohort Study for 18 years.

BACKGROUND: Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the predictive factors for developing intrahepatic cholangiocarcinoma in hepatolithiasis. METHODS: This cohort is comprised of 401 patients registered in a nationwide survey of hepatolithiasis for 18 years of follow-up. Cox regression analysis was used to elucidate predictive factors for developing intrahepatic cholangiocarcinoma. RESULTS: The median follow-up period of patients was 134 months. Twenty-two patients developed intrahepatic cholangiocarcinoma and all died. Identified independent significant factors were as follows: age 63 years or older (hazard ratio [HR] 3.344), residual stones at the end of treatment (HR 2.445), and biliary stricture during follow-up (HR 4.350). The incidence of intrahepatic cholangiocarcinoma in patients with three factors was significantly higher than that in patients with one or two factors. The incidence in the groups with one or two predictive factors was not different. In 88.9% of patients with both biliary stricture and intrahepatic cholangiocarcinoma, the duration between the diagnoses of biliary stricture and intrahepatic cholangiocarcinoma was ≥ 5 years. However, once intrahepatic cholangiocarcinoma developed, 77.8% of patients died within 1 year. Of 24 patients with no symptoms, no previous choledocoenterostomy, no signs of malignancy, no biliary stricture, and no treatment for hepatolithiasis during follow-up, only one developed intrahepatic cholangiocarcinoma. CONCLUSIONS: Regarding carcinogenesis, complete stone clearance and releasing biliary stricture can prevent the development of intrahepatic cholangiocarcinoma and improve the prognosis of hepatolithiasis.

Endoscopic approach in the diagnosis of high-grade pancreatic intraepithelial neoplasia.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is essential for improving prognosis; however, diagnosing PDAC at an early stage is challenging. In patients with localized high-grade pancreatic intraepithelial neoplasia (HG-PanIN), whose tumorous lesion is undetectable on cross-sectional images such as computed tomography or magnetic resonance image, long-term survival is expected. Pancreatic cystic lesions or main pancreatic duct (MPD) dilatation are important indirect findings for the initial diagnosis of HG-PanIN. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) should play important roles in detecting abnormal image findings, such as local irregular MPD stenosis, caliber MPD changes, small cystic lesions, or branch duct dilatation. Additionally, EUS could detect hypoechoic areas around the MPD stenosis in some patients with HG-PanIN. Subsequently, endoscopic retrograde cholangiopancreatography (ERCP) and its associated pancreatic juice cytology, including serial pancreatic juice aspiration cytologic examination (SPACE) after placement of an endoscopic nasopancreatic drainage (ENPD) tube, may have high diagnostic accuracy for confirming the malignancy in HG-PanIN. Although ERCP and its associated pancreatic cytology, including SPACE, may be associated with post-ERCP pancreatitis (PEP), a recent randomized trial suggested that a 4-Fr ENPD tube may reduce the incidence of PEP. In the future, further prospective multicenter studies are required to establish a standard method of SPACE. Additionally, further studies for novel biomarkers could help to establish evolutionary methods with duodenal fluid and pancreatic juice for the early and accurate diagnosis of early-stage PDAC.

Focal Neurological Symptoms at Initial Presentation Could Be a Potential Risk Factor for Poor Prognosis Among Patients With Multiple Brain Abscesses by Streptococcus anginosus Group: A Case Report With Literature Review.

Streptococcus anginosus group (SAG) is one of the most common microbes of brain abscesses. Brain abscesses caused by SAG have often delayed diagnosis since both blood and cerebrospinal fluid cultures are negative in half of the cases. A 68-year-old man developed persistent fever, headache, and myalgias for two weeks and visited our department. He was treated with oral antibiotics without laboratory work. Although examination showed no focal neurological symptoms, a careful interview revealed a history of unusual behavior for a few minutes on the previous day. Whole body contrast-enhanced computed tomography (CT) and head magnetic resonance imaging (MRI) showed two ring enhancements close to the bilateral ventricles, which were consistent with a diagnosis of the brain abscesses. An emergent surgical puncture for the larger abscess with intravenous antimicrobial therapy quickly improved his condition, and he was discharged on day 36 with no sequelae. We retrospectively reviewed works of literature on cases with multiple brain abscesses by SAG to assess potential prognostic factors for neurological sequelae. Statistical analyses of 12 cases, including 11 cases from the literature review and the current case, were performed between groups with or without poor prognosis. Among potential risk factors of age, sex, focal neurological symptoms, duration from onset to treatment, abscess formation of other organs, presence of surgical drainage, and positive for blood culture, only focal neurological symptoms at the initial presentation were significantly associated with poor prognosis (no poor prognosis, 1/4 cases vs poor prognosis group, 8/8 cases; p=0.01). Careful interviews and detailed examinations should be conducted to assess the possibility of brain abscesses among patients with fever of unknown etiology. Otherwise, a delayed diagnosis might result in poor prognoses such as death or neurological sequelae due to this disease's nature, which has few specific symptoms in the early stages.

Donor age (≥45 years) and reduced immunosuppression are associated with the recurrent primary sclerosing cholangitis after liver transplantation - a multicenter retrospective study.

The present study investigated the possible risk factors, including relationship/HLA matching between donor and recipient, and immunosuppressive therapies on the recurrence of primary sclerosing cholangitis (PSC) after liver transplantation (LT). Subjects were 197 recipients of LT for PSC, among whom 180 surviving more than 1 year after LT were further analyzed for risk factors of recurrence. The 5- and 10-year patient- and graft survival rates were 83% and 68%, and 71% and 62%, respectively. The overall PSC recurrence rate was 25% with a 5- and 10-year graft survival rate of 34% and 18%, which was significantly lower than the survival rate of those without recurrence (P < 0.001). Univariate analysis identified the following as risk factors for recurrence: donor age (P < 0.001), cyclosporine use (P = 0.012), mono or no immunosuppressive agent (P < 0.001), postoperative biliary complication (P < 0.001), and active intestinal bowel disease after LT (P < 0.001). Among these factors, donor age ≥45 years [hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.21-2.69; P = 0.003] and mono or no immunosuppressive agent 1-year after LT (HR, 2.38; 95% CI, 1.23-3.45; P = 0.011) were identified as independent risk factors in the final multivariate Cox regression model. The results were similar in sub-analysis for ABO-identical/compatible adult living donor LT cases.

Clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2020: (Revision of the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012).

Several years have passed since the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012 were published. New findings and knowledge have accumulated since then. The Research Committees for IgG4-related Diseases and for Intractable Diseases of the Liver and Biliary Tract, in association with the Ministry of Health, Labor, and Welfare of Japan and the Japan Biliary Association, have established a working group consisting of researchers specializing in IgG4-SC and have drawn up new clinical diagnostic criteria for IgG4-SC 2020. The diagnosis of IgG4-SC is based on a combination of the following six criteria: (a) narrowing of the intra- or extrahepatic bile duct; (b) thickening of the bile duct wall; (c) serological findings; (d) pathological findings; (e) other organ involvement; and (f) effectiveness of steroid therapy. These new diagnostic criteria for IgG4-SC are useful in practice for general physicians and other non-specialists.

Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma.

PURPOSE: Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells. METHODS: LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors. RESULTS: DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFß. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC. CONCLUSION: Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFß.

Periostin antisense oligonucleotide prevents hepatic steatosis and fibrosis in a mouse model of non-alcoholic steatohepatitis.

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis, inflammation, and hepatocellular injury with varying degrees of fibrosis. There are currently no established treatment approaches for NASH other than lifestyle interventions. Periostin, a matricellular protein required for tissue remodeling and fibrosis, plays an important role in hepatic steatosis and fibrosis and could be a potential target for NASH treatment. Advances in molecular biology and biochemical engineering have led to the development of antisense oligonucleotides (ASOs) that can inhibit target genes with no significant toxic effects. Herein, we investigated the therapeutic effects of periostin-targeting ASO (PNASO) in NASH. METHODS: C57BL/6J mice were fed a choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD) to induce NASH with or without intraperitoneal injection of mouse PNASO. To explore the role of periostin in hepatocellular steatosis, Hc3716 cells, an immortalized human hepatocyte line, were treated with recombinant periostin in vitro. RESULTS: The induced periostin expression in the liver of CDAHFD-fed mice was significantly suppressed by PNASO. The deletion of hepatic periostin by PNASO significantly ameliorated hepatic steatosis while restoring the expression levels of peroxisome proliferator-activated receptor-alpha (PPAR-α) and its target genes. PNASO also inhibited hepatic fibrosis, reflected by the reduction of alpha-smooth muscle actin, collagen type I, and other fibrotic markers. In vitro experiments demonstrated that treatment with recombinant periostin increased cellular lipid accumulation in Hc3716 cells accompanied with the downregulation of PPAR-α. CONCLUSIONS: Periostin-targeting ASO is a potential therapeutic approach for the efficient treatment of hepatic steatosis and fibrosis in NASH.

Key diagnostic characteristics of fever of unknown origin in Japanese patients: a prospective multicentre study.

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.

Geographical distribution of family physicians in Japan: a nationwide cross-sectional study.

BACKGROUND: Geographical maldistribution of physicians, and their subsequent shortage in rural areas, has been a serious problem in Japan and in other countries. Family Medicine, a new board-certified specialty started 10 years ago in Japan by Japan Primary Care Association (JPCA), may be a solution to this problem. METHODS: We obtained the workplace information of 527 (78.4%) of the 672 JPCA-certified family physicians from an online database. From the national census data, we also obtained the workplace information of board-certified general internists, surgeons, obstetricians/gynaecologists and paediatricians and of all physicians as the same-generation comparison group (ages 30 to 49). Chi-squared test and residual analysis were conducted to compare the distribution between family physicians and other specialists. RESULTS: Five hundred nineteen JPCA-certified family physicians and 137,587 same-generation physicians were analysed. The distribution of family physicians was skewed to municipalities with a lower population density, which shows a sharp contrast to the urban-biased distribution of other specialists. The proportion of family physicians in non-metropolitan municipalities was significantly higher than that expected based on the distribution of all same-generation physicians (p < 0.001). CONCLUSIONS: Family physicians distributed in favour of rural areas much more than any other specialists in Japan. The better balance of family physician distribution reported from countries with a strong primary care orientation seems to hold even in a country where primary care orientation is weak, physician distribution is not regulated, and patients have free access to healthcare. Family physicians comprise only 0.2% of all Japanese physicians. However, if their population grows, they can potentially rectify the imbalance of physician distribution. Government support is mandatory to promote family medicine in Japan.

Protective effect of phosphatidylcholine on lysophosphatidylcholine-induced cellular senescence in cholangiocyte.

BACKGROUND: Pancreaticobiliary maljunction and intrahepatic gallstones are at a high risk for biliary malignancy. Lysophosphatidylcholine (LPC) is increased in the bile of these patients, and we have previously reported that LPC-induced cytotoxicity causes senescence-associated secretory phenotype (SASP) in cholangiocytes. We aimed to determine the protective effect of phosphatidylcholine (PC) on LPC-induced cholangiocyte cytotoxicity. METHODS: MMNK-1, a human immortalized cholangiocyte cell line was treated with LPC with or without PC. To assess the biological effects of SASP components on cholangiocarcinoma, HuH28 and HuCCT1 (human cholangiocarcinoma cell lines) were cultured in the conditioned media where MMNK-1 cells treated with LPC. RESULTS: The presence of PC reduced reactive oxygen species generation and oxidative DNA damage in MMNK-1 treated with LPC. Moreover, SA-ß-gal activity was markedly downregulated by PC. The secretion of SASP components, including interleukin (IL)-8, IL-6, and C-C motif chemokine ligand 2 was also substantially reduced in the presence of PC. Cellular proliferation and migration were enhanced in HuCCT1 and HuH28 cells when cultured in the conditioned media, and these observations were suppressed by simultaneous addition of PC. CONCLUSION: PC protects cholangiocytes against LPC-induced cytotoxicity and cellular senescence, suggesting its potential as a target for inhibiting LPC-related carcinogenesis and its promotion.