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BACKGROUND & AIMS: Approaches to risk stratification for patients with primary biliary cirrhosis (PBC) are limited, single-center based, and often dichotomous. We aimed to develop and validate a better model for determining prognoses of patients with PBC. METHODS: We performed an international, multicenter meta-analysis of 4119 patients with PBC treated with ursodeoxycholic acid at liver centers in 8 European and North American countries. Patients were randomly assigned to derivation (n = 2488 [60%]) and validation cohorts (n = 1631 [40%]). A risk score (GLOBE score) to predict transplantation-free survival was developed and validated with univariate and multivariable Cox regression analyses using clinical and biochemical variables obtained after 1 year of ursodeoxycholic acid therapy. Risk score outcomes were compared with the survival of age-, sex-, and calendar time-matched members of the general population. The prognostic ability of the GLOBE score was evaluated alongside those of the Barcelona, Paris-1, Rotterdam, Toronto, and Paris-2 criteria. RESULTS: Age (hazard ratio = 1.05; 95% confidence interval [CI]: 1.04-1.06; P < .0001); levels of bilirubin (hazard ratio = 2.56; 95% CI: 2.22-2.95; P < .0001), albumin (hazard ratio = 0.10; 95% CI: 0.05-0.24; P < .0001), and alkaline phosphatase (hazard ratio = 1.40; 95% CI: 1.18-1.67; P = .0002); and platelet count (hazard ratio/10 units decrease = 0.97; 95% CI: 0.96-0.99; P < .0001) were all independently associated with death or liver transplantation (C-statistic derivation, 0.81; 95% CI: 0.79-0.83, and validation cohort, 0.82; 95% CI: 0.79-0.84). Patients with risk scores >0.30 had significantly shorter times of transplant-free survival than matched healthy individuals (P < .0001). The GLOBE score identified patients who would survive for 5 years and 10 years (responders) with positive predictive values of 98% and 88%, respectively. Up to 22% and 21% of events and nonevents, respectively, 10 years after initiation of treatment were correctly reclassified in comparison with earlier proposed criteria. In subgroups of patients aged <45, 45-52, 52-58, 58-66, and ≥66 years, age-specific GLOBE-score thresholds beyond which survival significantly deviated from matched healthy individuals were -0.52, 0.01, 0.60, 1.01 and 1.69, respectively. Transplant-free survival could still be accurately calculated by the GLOBE score with laboratory values collected at 2-5 years after treatment. CONCLUSIONS: We developed and validated scoring system (the GLOBE score) to predict transplant-free survival of ursodeoxycholic acid-treated patients with PBC. This score might be used to select strategies for treatment and care.

File： Gastroenterology 2015 GLOBE score.pdf

DOI： 10.1053/j.gastro.2015.07.061

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BACKGROUND: Although impaired glucose tolerance is common in cirrhosis, this condition's pathogenesis remains undefined. This study aimed to clarify pathogenesis related to the pancreas in cirrhotic patients, and to evaluate associations between insulin secretion and pancreatic congestion due to portal hypertension. METHODS: Pancreatic perfusion parameters were analyzed by dynamic contrast-enhanced ultrasound (CE-US) in 41 patients (20 cirrhotic, 21 non-cirrhotic; age, 67.9 ± 13.3; female, 19), and prospectively compared to delta C-peptide immunoreactivity (ΔCPR). In a separate study, a retrospective chart review with human autopsy specimens was conducted, and vessels and islets of the pancreas were analyzed in 43 patients (20 cirrhotic, 23 controls; age, 71.5 ± 11.6; female, 15). RESULTS: In the CE-US study, the clinical characteristics indicative of portal hypertension (e.g., ascites and varices) had significantly higher incidences in the cirrhotic group than in the control group. Pancreatic drainage times were greater in the cirrhotic group (p < 0.0001), and had a significant negative correlation with ΔCPR (R = 0.42, p = 0.0069). In the histopathological study, the islets were enlarged in the cirrhotic group (p < 0.0001). However, the percentage of insulin-positive area per islet was decreased in the cirrhotic group (p < 0.0001), and had a significant negative correlation with the wall thickness of the pancreatic vein (R = 0.63, p < 0.0001). CONCLUSIONS: Pancreatic congestion was present in cirrhotic patients. Moreover, pancreatic congestion and insulin secretion were significantly correlated. This pathogenesis could be a key factor underlying the development of hepatogenous diabetes in cirrhotic patients.

File： J Gastroenterol 2015 Portal hypertesion and pancreatic congestion.pdf

DOI： 10.1007/s00535-014-1001-8

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BACKGROUND: Epidemiologic studies show an association between short sleep duration and the presence of nonalcoholic fatty liver disease (NAFLD). This study examined the association between short sleep duration and the onset of NAFLD. METHODS: This community-based, retrospective, longitudinal cohort study included 6,370 Japanese subjects who had undergone annual health check-ups more than twice at a single center between April 2003 and March 2010. After excluding 3,941 subjects, the records of 2,429 Japanese subjects were reviewed. RESULTS: Two groups comprised the study cohort: those with short (≤ 6 h) sleep durations (n = 1,543) and those with moderate (7-8 h) sleep durations (n = 886). During the observation period, 296 subjects developed NAFLD. Multivariate analysis identified an association between short sleep duration and the reduced onset of NAFLD in men (odds ratio: 0.551, 95% confidence interval 0.365-0.832, p = 0.005). There was no association between short sleep duration and NAFLD onset in women. The prevalence of NAFLD onset in men increased significantly as sleep duration increased, as follows: 12.5, 18.4, and 27.4% among subjects who had sleep durations of ≤ 4, 5-6, and 7-8 h, respectively (p = 0.02). CONCLUSIONS: This study demonstrates an association between sleep duration and NAFLD onset. Short sleep duration reduced the risk of NAFLD onset in men. Correct recognition is important to prevent disease progression and further complications.

File： J Gastroenterol 2014 Short sleep duration & NAFLD.pdf

DOI： 10.1007/s00535-014-0989-0

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

File： Gastroenterology 2015 Pignose appearance IPMN.pdf

DOI： 10.1053/j.gastro.2014.10.057

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BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for diabetes and cardiovascular disease that could progress to nonalcoholic steatohepatitis, cirrhosis, and liver failure. We aimed to assess the relationship between NAFLD and lifestyle habits. METHODS: Using a community-based, cross-sectional design, the records of 11,094 Japanese subjects who had undergone at least 1 annual health checkup were reviewed. RESULTS: Of the 6,370 subjects who qualified for enrolment, 1,346 met the diagnostic criteria for NAFLD. The prevalence rate (PR) of NAFLD increased significantly to 36.6, 41.5, and 41.1 % with no snacking, snacking less than once/day, and snacking ≥2 times/day, respectively, in men (P = 0.0495) and to 10.8, 11.7, and 15.3 %, respectively, in women (P = 0.002). In men, the NAFLD PR decreased significantly to 48.8, 36.9, and 29.9 % with no exercise, exercise consciousness, and periodical exercise, respectively (P < 0.001). In women, the NAFLD PR decreased significantly to 19.3, 13.5, 11, and 8 % with sleep durations of ≤4, 5-6, 7-8, and ≥9 h, respectively (P = 0.003). Periodical exercise was identified as an independent factor associated with NAFLD in men (odds ratio 0.707, 95 % confidence interval 0.546-0.914; P = 0.008). CONCLUSIONS: Performing regular exercise was associated with a reduced risk for NAFLD in men. Men with a high risk for NAFLD can be identified using questionnaires on exercise in an outpatient setting. Disease progression and further complications may be prevented by educating high-risk NAFLD patients about the importance of exercise.

File： J Gastroenterol 2015 Significance of exercise in NAFLD.pdf

DOI： 10.1007/s00535-014-0959-6

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BACKGROUND & AIMS: Noninvasive surrogate end points of long-term outcomes of patients with primary biliary cirrhosis (PBC) are needed to monitor disease progression and evaluate potential treatments. We performed a meta-analysis of individual patient data from cohort studies to evaluate whether patients' levels of alkaline phosphatase and bilirubin correlate with their outcomes and can be used as surrogate end points. METHODS: We performed a meta-analysis of data from 4845 patients included in 15 North American and European long-term follow-up cohort studies. Levels of alkaline phosphatase and bilirubin were analyzed in different settings and subpopulations at different time points relative to the clinical end point (liver transplantation or death). RESULTS: Of the 4845 patients, 1118 reached a clinical end point. The median follow-up period was 7.3 years; 77% survived for 10 years after study enrollment. Levels of alkaline phosphatase and bilirubin measured at study enrollment (baseline) and each year for 5 years were strongly associated with clinical outcomes (lower levels were associated with longer transplant-free survival). At 1 year after study enrollment, levels of alkaline phosphatase that were 2.0 times the upper limit of normal (ULN) best predicted patient outcome (C statistic, 0.71) but not significantly better than other thresholds. Of patients with alkaline phosphatase levels ≤ 2.0 times the ULN, 84% survived for 10 years compared with 62% of those with levels >2.0 times the ULN (P < .0001). Absolute levels of alkaline phosphatase 1 year after study enrollment predicted patient outcomes better than percentage change in level. One year after study enrollment, a bilirubin level 1.0 times the ULN best predicted patient transplant-free survival (C statistic, 0.79). Of patients with bilirubin levels ≤ 1.0 times the ULN, 86% survived for 10 years after study enrollment compared with 41% of those with levels >1.0 times the ULN (P < .0001). Combining levels of alkaline phosphatase and bilirubin increased the ability to predict patient survival times. We confirmed the predictive value of alkaline phosphatase and bilirubin levels in multiple subgroups, such as patients who had not received treatment with ursodeoxycholic acid, and at different time points after study enrollment. CONCLUSIONS: Levels of alkaline phosphatase and bilirubin can predict outcomes (liver transplantation or death) of patients with PBC and might be used as surrogate end points in therapy trials.

File： Gastroenterology 2014 Surrogate markers of prognosis in PBC.pdf

DOI： 10.1053/j.gastro.2014.08.029

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

BACKGROUND & AIMS: Up to 25% of patients diagnosed with primary biliary cirrhosis (PBC) are of childbearing age. However, little is known about disease course during pregnancy. METHODS: We performed a retrospective analysis of women with PBC during pregnancy using a representative large cohort of patients attending the Liver Center at Toronto Western hospital from January 1979 through June 2009 (n = 306). Statistical analysis was performed by using R statistical software. RESULTS: We identified 32 women (50 pregnancies) who either became pregnant after a diagnosis of PBC or in whom pregnancy led to diagnosis. Liver biochemistry remained stable in most patients (70%) throughout pregnancy. However, 23 of 32 patients (72%) had a flare in biochemical disease activity post partum, which was unrelated to biochemical disease activity before conception (P = .53), or during the gestational period (P = .14). No adverse maternal events were observed during pregnancy or post partum, and only 2 of 32 of women (6%) developed progressive disease after delivery. De novo pruritus developed during pregnancy in 17 of 32 women (53%), whereas itch that existed before conception worsened for 4 patients. Fifteen of 21 women (71%) with pregnancy-related pruritus required symptom-specific therapy. Twenty-nine of 32 women (91%) had at least 1 successful live birth; adverse fetal outcome was not influenced by biochemical disease activity before conception (P = .24) or during pregnancy (P = 1.00). CONCLUSION: Pregnancy in women with PBC is frequently symptomatic but mostly uneventful. The majority of women maintain stable liver biochemistry during pregnancy, although postpartum biochemical exacerbations are common.

File： Clin Gastroenterol Hepatol 2014 Pregnancy in PBC.pdf

DOI： 10.1016/j.cgh.2013.11.030

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BACKGROUND & AIMS: Outcomes in primary biliary cirrhosis (PBC) can be predicted by biochemical response to ursodeoxycholic acid (UDCA). Such stratification inadequately captures cirrhosis/portal hypertension, recognised factors associated with adverse events. METHODS: We evaluated a cohort of PBC patients (n=386) attending the Liver Unit in Birmingham (derivation cohort), seeking to identify risk-variables associated with transplant-free survival independent of UDCA-response. A validation cohort was provided through well-characterised patients attending the Toronto Center for Liver Diseases (n=479) and Jena University Hospital (n=150). RESULTS: On multivariate analysis, factors at diagnosis associated with liver transplant (LT)/death were patient age (HR:1.06; p<0.001), elevated bilirubin (HR:1.27; p<0.001), early-onset cirrhosis (HR:2.40; p<0.001) and baseline AST/platelet ratio index (APRI) (HR:1.95; p<0.001). At 1-year, UDCA biochemical non-response predicted poorer transplant-free survival, and additional factors (multivariate) associated with adverse outcome were age (HR:1.02; p<0.05) and 1-year APRI (HR:1.15; p<0.001). Obtaining a cut-point from our derivation cohort, APRI >0.54 at baseline was predictive of LT/death (adjusted HR: 2.40; p<0.001), and retained statistical significance when applied at 1-year (APRI-r1, adjusted HR:2.75; p<0.001) despite controlling for UDCA-response. Across both cohorts, transplant-free survival was poorer for biochemical-responders with an APRI-r1 >0.54 vs. biochemical-responders with a lower APRI-r1 (p<0.01 and p<0.001, respectively); non-responders with high APRI-r1 had the poorest outcomes (p<0.001 and p<0.001). CONCLUSION: In PBC, elevated APRI is associated with future risk of adverse events, independently and additively of UDCA-response. This cross-centre, robustly validated observation will contribute to ongoing efforts to refine existing risk-stratification tools, as well as direct focus for new therapies in patients with PBC.

File： J Hepatol 2014 APRI & PBC.pdf

DOI： 10.1016/j.jhep.2014.01.029

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BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can progress to advanced liver disease and non-liver-related diseases. To prevent NAFLD onset, clinicians must be able to easily identify high-risk NAFLD patients so that intervention can begin at an earlier stage. We sought to identify the predictive factors for NAFLD onset. METHODS: In a community-based, longitudinal design, the records of 6,403 Japanese subjects were reviewed to identify those meeting the criteria for NAFLD onset. Univariate and multivariate logistic regression analyses were used to identify predictive factors for NAFLD onset. The accuracy of different models was evaluated according to their areas under the receiver operating characteristic curves. Comparative risk analysis was performed using the Kaplan-Meier method. RESULTS: Multivariate analysis of 400 subjects who met the criteria for the onset of NAFLD during the observation period confirmed that body mass index (BMI) at baseline was the most useful predictive factor for NAFLD onset in both sexes. Cutoff levels of BMI for NAFLD onset were estimated at 23 kg/m2 for men and 22.2 kg/m2 for women. The cumulative onset rate of NAFLD was significantly higher in the high BMI group than in the low BMI group in both sexes (P < 0.001). CONCLUSION: BMI was confirmed as the most useful predictive factor for NAFLD onset in both sexes; its cutoff levels were similar to those recommended by the World Health Organization for helping to prevent metabolic disease. An accurate BMI cutoff level will enable clinicians to identify subjects at risk for NAFLD onset.

File： J Gastroenterol 2013 BMI as best predictor for NAFLD onset.pdf

DOI： 10.1007/s00535-012-0650-8

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BACKGROUND & AIMS: Little is known about the pathogenic mechanisms of autoimmune pancreatitis (AIP), an increasingly recognized, immune-mediated form of chronic pancreatitis. Current treatment options are limited and disease relapse is frequent. We investigated factors that contribute to the development of AIP and new therapeutic strategies. METHODS: We used quantitative polymerase chain reaction, immunohistochemical, and enzyme-linked immunosorbent analyses to measure the expression of cytokines and chemokines in tissue and serum samples from patients with and without AIP. We created a mouse model of human AIP by overexpressing lymphotoxin (LT)α and β specifically in acinar cells (Ela1-LTab mice). RESULTS: Messenger RNA levels of LTα and β were increased in pancreatic tissues from patients with AIP, compared with controls, and expression of chemokines (CXCL13, CCL19, CCL21, CCL1, and B-cell-activating factor) was increased in pancreatic and serum samples from patients. Up-regulation of these factors was not affected by corticosteroid treatment. Acinar-specific overexpression of LTαβ (Ela1-LTαβ) in mice led to an autoimmune disorder with various features of AIP. Chronic inflammation developed only in the pancreas but was sufficient to cause systemic autoimmunity. Acinar-specific overexpression of LTαβ did not cause autoimmunity in mice without lymphocytes (Ela1-LTab/Rag1(-/-)); moreover, lack of proinflammatory monocytes (Ela1-LTab/Ccr2(-/-)) failed to prevent AIP but prevented early pancreatic tissue damage. Administration of corticosteroids reduced pancreatitis but did not affect production of autoantibodies, such as antipancreatic secretory trypsin inhibitor in Ela1-LTab mice. In contrast, inhibition of LTβR signaling reduced chemokine expression, renal immune-complex deposition, and features of AIP in Ela1-LTab mice. CONCLUSIONS: Overexpression of LTαβ specifically in acinar cells of mice causes features of AIP. Reagents that neutralize LTβR ligands might be used to treat patients with AIP.

File： Gastroenterology 2012 Lymphotoxin β Receptor and AIP .pdf

DOI： 10.1053/j.gastro.2012.07.112

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

File： Am J Hum Gen 2012 Japanese PBC-GWAS.pdf

DOI： 10.1016/j.ajhg.2012.08.010

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BACKGROUND: Untreated nonalcoholic fatty liver disease (NAFLD) may progress to liver cirrhosis or failure and is associated with the development of hepatocellular carcinoma, diabetes, and cardiovascular disease. It is therefore essential to diagnose and treat NAFLD at an early stage. To assist in this effort, this retrospective study explored the risk factors for NAFLD, and derived new surrogates, a revised alanine aminotransferase (ALT) cutoff level and a novel NAFLD index, to identify previously undiagnosed cases of NAFLD. METHODS: Using a community-based, cross-sectional design, the records of 6,370 Japanese subjects who had undergone at least 1 annual health check-up were reviewed for the identification of subjects meeting the diagnostic criteria for NAFLD and the variables associated with NAFLD for the estimation of ideal ALT cutoff levels. RESULTS: The results of multivariate analysis of the 1,346 subjects who met the diagnostic criteria for NAFLD confirmed that metabolic disease markers and a novel NAFLD index, using the variables derived from multivariate analysis, were also markers of NAFLD. The ALT cutoff levels for NAFLD diagnosis were estimated at 25 U/L for males and 17 U/L for females. CONCLUSIONS: ALT level and the novel NAFLD index were confirmed to be surrogate markers for NAFLD in addition to metabolic disease markers. The ALT cutoff level used in NAFLD diagnosis should be revised downward to identify subjects at risk of NAFLD to prevent NAFLD progression and the development of associated diseases.

File： J Gastroenterol 2012 NAFLD-ALT.pdf

DOI： 10.1007/s00535-012-0534-y

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

BACKGROUND: Biliary atresia is a progressive biliary injury which occurs only in infants. AIMS: To review the experience of patients surviving into adulthood without the need for liver transplantation in childhood. METHODS: A multicentre review of patients with biliary atresia treated surgically who survived into adulthood without the need for transplantation. RESULTS: Twenty-two patients were identified across four centres. Median age at the last follow-up was 25 years (range: 18-46), and 21 patients had clinical features of portal hypertension. At last follow-up values of liver enzymes varied from normal to 15 × the upper limit of normal (ULN) for ALT (median 2.11 × ULN) and 9 × the ULN for ALP (median 2.02 × ULN). Six patients had a serum bilirubin > 50 μmol/l. Pruritus and jaundice were noted in 8 of 20 patients (40%) and 11 of 22 patients (50%) respectively. Thirteen patients (59.1%) were shown to have imaging features of sclerosing cholangitis, with strictures of intrahepatic bile duct(s) (IHBD), dilatation of IHBD (n = 8), or stone(s) within the IHBD (n = 5). A history of presumed bacterial cholangitis was present in 11 patients (50%). Successful pregnancies were recorded in three of fourteen female patients. Four patients underwent transplant between the ages of 20-27 years. Twenty-one patients (95.5%) were alive, including 18 (81.8%) with their native liver at the time of last follow-up. CONCLUSIONS: Some patients treated for biliary atresia will survive into adulthood with their native liver, but commonly with secondary biliary disease including cholangitis and portal hypertension.

File： Liver Int 2012 Adult Kasai.pdf

DOI： 10.1111/j.1478-3231.2011.02668.x

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

OBJECTIVES: Laboratory and pathological predictors of future histological progression in primary biliary cirrhosis (PBC) are needed for routine practice and clinical trials. We sought to develop clinically meaningful markers for those with predominantly early disease at risk of progressive liver damage. METHODS: Patients with PBC (n=69) with a follow-up liver biopsy performed approximately 10 years after initial histological diagnosis were identified and reviewed. RESULTS: Histological progression in the stage of fibrosis observed in paired liver biopsies from the same patient was associated with the absence of biochemical response to ursodeoxycholic acid (UDCA) at 2 years: alkaline phosphatase (ALP) >1.67 × ULN (upper limit of normal) (P=0.001, odds ratio (OR) 12.14, 95% confidence interval (CI) 2.69-54.74) when defined as an increase in one stage and ALP > 1.76 × ULN (P=0.03, OR 5.07, 95% CI 1.17-21.95) when defined as an increase in two stages. Ductopenia (>50% loss), as formally evaluated through blinded biopsy review of liver tissue obtained at initial diagnosis in a subset of 34 patients, predicted histological progression (P=0.012), along with biochemical response to UDCA (P=0.002). The presence of interface hepatitis in the same biopsies did not. CONCLUSIONS: Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.

File： Am J Gastroenterol 2010 PBC biopsy study in press.pdf

DOI： 10.1038/ajg.2010.216

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UNLABELLED: Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC-40 multidomain disease-specific quality of life responses and clinical findings. Three hundred twenty-seven patients from a single clinic with PBC (94% female, 92% AMA-positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC-40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. CONCLUSION: Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes.

File： Hepatology 2010 Fatigue in PBC.pdf

DOI： 10.1002/hep.23683

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DOI： 10.1136/bmj.b5039

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BACKGROUND: The course of primary biliary cirrhosis (PBC) is determined by clinical symptoms and histological findings. The present study examined the prognostic importance of imaging parameters in PBC. METHODS: The volumes of the liver and spleen of patients with PBC were assessed by computed tomography (CT). The volume ratio of liver to spleen (LV/SV ratio) was evaluated and used for further analyses. RESULTS: The prognosis was significantly poorer in PBC patients with a low, rather than high, LV/SV ratio. The Cox proportional hazard regression model showed that the serum bilirubin level and the LV/SV ratio could predict the prognosis of PBC patients. In addition, the LV/SV ratio was significantly lower in patients who developed symptoms (s-PBC) than in those who remained asymptomatic (a-PBC) during the observation period. CONCLUSIONS: The LV/SV ratio is of prognostic importance in patients with PBC.

File： J Gastroenterol 2008 Liver-spleen volume ratio in PBC.pdf

DOI： 10.1007/s00535-008-2202-9

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BACKGROUND: Ultrasound-guided procedures are sometimes of limited use because the tumor is located under the diaphragm or near the surface of the liver. We investigated the safety and efficacy of radiofrequency ablation (RFA) with artificial pleural effusion and/or artificial ascites. METHODS: Between January 2002 and May 2006, 43 lesions in 36 patients with hepatocellular carcinoma (HCC) were treated by RFA with artificial pleural effusion and/or artificial ascites. RESULTS: Artificial pleural effusion allowed visualization of the whole tumor for 36 (83.7%) of the 43 lesions that were otherwise not detectable or poorly visible. Artificial ascites was also helpful in visualizing whole tumors that could not be visualized with only artificial pleural effusion. In all lesions, artificial pleural effusion and/or artificial ascites were helpful in performing percutaneous RFA. Artificial ascites was useful for creating a space between the liver's surface and the skin or diaphragm to avoid burns. Adverse effects after the induction of artificial pleural effusion included pneumonia in one patient and temporary atelectasis in another patient. Severe side effects were not observed. Complete necrosis after RFA was obtained in 43 (100%) of the 43 lesions. During a mean follow-up period of 31.8 +/- 5.8 months, local recurrence at the ablation site was found in none of the 43 lesions. CONCLUSIONS: Percutaneous RFA with artificial pleural effusion and/or artificial ascites was a safe and useful treatment that resulted in good local control of HCC.

File： J Gastroenterol 2007 RFA with artificial PE & ascites.pdf

DOI： 10.1007/s00535-006-1949-0

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BACKGROUND: We carried out this study to evaluate recent clinical features of Wilson's disease (WD) with hepatic presentation, especially in terms of age, degree of liver injury, and association with hepatocellular carcinoma (HCC). METHODS: Sixteen patients with hepatic manifestations were diagnosed with WD in the period 1976-2003. We divided this period into two periods, "past" and "recent". The diagnosis was based on the presence of Kayser-Fleisher rings, low serum copper levels, low serum ceruloplasmin levels, increased urinary copper concentrations before or after D-penicillamine challenge, and increased hepatic copper concentrations. This retrospective study was done at Ehime University Hospital. RESULTS: Four patients, including a pair of siblings, had a family history of WD. Four patients had parental consanguinity. There were 6 patients aged over 40 years in the recent period, whereas no patients in the past period were over 40. Four patients had neurological manifestations. Ten patients had liver cirrhosis and 5 had chronic hepatitis. Two had fatty liver without obesity. All patients in the past period had liver cirrhosis. Three patients with liver cirrhosis were found to have HCC during the follow up. All patients were treated with either D-penicillamine or trientine chloride, or both. However, four patients had to discontinue these agents due to the side effects. CONCLUSIONS: Recently, the number of patients diagnosed with WD has been increasing, not only in terms of those with classical-type WD but also in terms of elderly patients or patients with non-cirrhotic liver injury such as fatty liver and chronic hepatitis. The various clinical features of WD should be recognized and particular attention should focus on HCC as a complication.

File： J Gastroenterol 2004 Wilson's disease hepatic.pdf

DOI： 10.1007/s00535-004-1466-y

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BACKGROUND: Primary biliary cirrhosis (PBC) is usually classified as either asymptomatic PBC (a-PBC) or symptomatic PBC (s-PBC). Although the proportion of a-PBC versus s-PBC patients has been consistently increasing, it is not clear whether the present criteria for the staging of PBC are optimal or not. We investigated the clinical stage of PBC patients from the standpoint of esophagogastric varices (EGV). METHODS: One hundred and nine PBC patients were enrolled in this retrospective study. We investigated the clinical features of PBC based on laboratory data, histological stage, symptoms, and existence of EGV. In addition, the clinical course and prognosis in patients who were periodically followed up were also studied. RESULTS: (1) EGV was detected in a-PBC patients, and there was no difference in the grade of EGV between a-PBC and s-PBC patients. (2) a-PBC patients with EGV had more liver damage than those without EGV, and a-PBC patients with EGV had a poorer prognosis than those without EGV. (3) Three of 11 patients who progressed from a-PBC to s-PBC within 3 years had EGV. (4) One of 3 a-PBC patients with EGV had progressed to s-PBC at 3-year follow-up. CONCLUSIONS: These results indicate that EGV is one of the most important factors for evaluating PBC. Therefore, we would like to propose that a-PBC patients with EGV should either be included in the presently defined s-PBC class, or that new prognostic classes of PBC be created that include EGV as a prognostic factor.

File： J Gastroenterol 2003 PBC&Varix.pdf

DOI： 10.1007/s00535-003-1196-6

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DOI： 10.1055/a-2432-3302

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BACKGROUND: Interleukin (IL)-23 is involved in the pathogenesis of ulcerative colitis (UC). A genome-wide significant association between IL23R p.G149R (rs76418789) and UC was previously identified in Japan and Korea. This case-control study aims to examine this association within the Japanese population. METHODS: The study included 384 cases diagnosed with UC within the past 4 years and 661 control subjects. Adjustment was made for sex, age, and smoking. RESULTS: The frequency of the AA genotype of rs76418789 was 0.0 % in cases and 0.5 % in control subjects. In comparison to study subjects with the GG genotype of rs76418789, those with the GA or AA genotype had a significantly reduced risk of UC, with an adjusted odds ratio of 0.67 (95 % confidence interval: 0.44-0.999). A significant multiplicative interaction was observed between rs76418789 and having ever smoked influencing UC (p for interaction = 0.03). A significant positive association was found between having ever smoked and UC in individuals with at least one A allele, while no such positive relationship was observed in those with the GG genotype. CONCLUSION: IL23R SNP rs76418789 showed a significant association with UC. This study provides new evidence regarding the interaction between rs76418789 and smoking in relation to UC.

DOI： 10.1016/j.cyto.2024.156743

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CONTEXT: Estimated remnant cholesterol (Rem-C) level, a risk factor for cardiovascular disease (CVD), is associated with metabolic dysfunction-associated steatotic liver disease (MASLD) diagnosed via ultrasonography. However, the relationship between accurate serum Rem-C level measurements and histological findings of MASLD remains unclear. OBJECTIVE: We aimed to elucidate the relationship between accurately measured serum Rem-C levels and histological findings of MASLD. DESIGN: Cross-sectional single-center observational study. METHODS: We assessed 222 patients (94 men and 128 women; age 20-80) who were diagnosed with MASLD via liver biopsy with available medical history, physical examination, and biochemical measurement data. Serum ester-type cholesterol and free cholesterol contents in the remnant lipoproteins were measured using an enzymatic method. RESULTS: Serum Rem-C levels were significantly higher in patients with NAFLD activity score (NAS) 5-8, ＞66% steatosis grade, lobular inflammation with ≥5 foci, and many cells/prominent ballooning cells (a contiguous patch of hepatocytes showing prominent ballooning injury) than in patients with NAS 1-4, <33% steatosis grade, lobular inflammation with <2 foci, and few ballooning cells (several scattered balloon cells), respectively. While univariate analysis revealed no significant association between Rem-C levels and advanced fibrosis, a significant association between Rem-C levels and NAS was evident. This relationship remained significant in multivariate analysis adjusted for confounders. Furthermore, in the analysis by sex, these relationships were significant for men but not for women. CONCLUSION: High serum Rem-C levels were associated with high NAS, but not with fibrosis stage, particularly in men. Controlling serum Rem-C level may improve MASLD activity.

DOI： 10.1210/clinem/dgae597

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BACKGROUND/AIMS: Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (EUS-HGS) performed at the intrahepatic bile duct segment 3 (B3) is widely used for biliary drainage. Although performing post-puncture procedures is easier in the intrahepatic bile duct segment 2 (B2) when using a conventional oblique-viewing (OV) EUS scope, this method may cause transesophageal puncture and severe adverse events. We evaluated the safety and efficacy of B2 puncture using a novel OV-EUS scope. METHODS: In this single-center retrospective study, we prospectively enrolled and collected data from 45 patients who consecutively underwent EUS-HGS procedures with a novel OV-EUS scope between September 2021 and December 2022 at our cancer center. RESULTS: The technical success rates of B2-EUS-HGS and EUS-HGS were 93.3% (42/45) and 97.8% (44/45), respectively. The early adverse event rate was 8.9% (4/45) with no cases of scope changes or transesophageal punctures. The median procedure time was 13 minutes (range, 5-30). CONCLUSIONS: B2-EUS-HGS can be performed safely with the novel EG-740UT (Fujifilm) OV-scope without transesophageal puncture and with a high success rate. B2-EUS-HGS using this novel OV scope may be the preferred strategy for EUS-HGS.

DOI： 10.5946/ce.2023.129

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Background and objective Examining the factors influencing the career aspirations of medical students is imperative for understanding their orientation toward rural medicine. Such an investigation can serve as a basis for shaping medical education curricula dedicated to nurturing rural focus. Although previous studies have categorized students based on the presence or absence of orientation toward rural medicine and explored their sociodemographic characteristics, these students may not constitute a homogeneous group; their interests can range from aspiring to establish residence and professional practice in a specific region to being merely willing to endure brief regional placements. There is a scarcity of comprehensive examination of the extent and potential variations of rural orientation in the literature. Our survey addresses this gap by exploring the variations in rural orientation among medical students and the differences in their sociodemographic characteristics and preferred specialties based on their degree of rural orientation. Methods We classified medical students into four groups according to their levels of rural orientation: demonstrating proactive engagement towards it, considering it for a defined duration, indicating a preference for avoiding it, and considering it unfeasible. The distribution within each group was investigated. A subsequent analysis of rural orientation and its associated sociodemographic characteristics was performed: a conventional dichotomous study was conducted based on the presence or absence of rural orientation, and a focused study compared students actively interested in rural healthcare with other students. This approach enabled us to explore differences in the degree of rural orientation and associated factors. Results The study included 531 students, with 89 participants demonstrating proactive engagement towards rural medicine, 283 considering it for a defined period, 95 indicating an inclination to avoid it, and 63 students stating that it is unfeasible for them. Associated sociodemographic characteristics were explored based on the presence or absence of rural orientation and included recommendations for admission by a designated high school, the presence of a physician role model, and aspirations for obstetrics and gynecology departments. Conversely, when exclusively focusing on students with a desire for proactive engagement in rural medicine, positive correlations were observed with characteristics such as being from the same non-urban prefecture as that of the university where the study was conducted, having a history of residing in a rural area, having a physician role model, and expressing aspirations for general practice or family medicine. Aspiring to be an organ-specific specialist showed a negative correlation with high levels of rural orientation. Conclusions Based on our findings, rural orientation is not uniform among medical students; distinct levels of this aspect were observed, each associated with different sociodemographic factors.

DOI： 10.7759/cureus.55743

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A 70-year-old woman presented with stage III pancreatic head cancer. After endoscopic sphincterotomy, a fully covered self-expandable metallic stent (FCSEMS) was placed in the common bile duct to manage jaundice. The patient developed a fever and abdominal pain 40 days after stent placement, with a suspected diagnosis of infected pancreatic pseudocyst. Purulent discharge from the papilla was observed during FCSEMS removal, and pancreatography revealed a pseudocyst connected to the main pancreatic duct. The pancreatic pseudocyst resolved after transpapillary drainage. Pancreatic pseudocysts should be suspected after biliary FCSEMS placement, and prompt removal and endoscopic drainage of the FCSEMS should be considered.

DOI： 10.2169/internalmedicine.3178-23

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BACKGROUND: Poor lifestyle habits may worsen nonalcoholic fatty liver disease (NAFLD), with progression to nonalcoholic steatohepatitis (NASH) and cirrhosis. This study investigated the association between glycemic control status and hepatic histological findings to elucidate the effect of glycemic control on NAFLD. METHODS: This observational study included 331 patients diagnosed with NAFLD by liver biopsy. Effects of the glycemic control status on histological findings of NAFLD were evaluated by comparing the following four glycemic status groups defined by the glycosylated hemoglobin (HbA1c) level at the time of NAFLD diagnosis: ≤5.4%, 5.5%-6.4%, 6.5%-7.4%, and ≥7.5%. RESULTS: Compared with the lowest HbA1c group (≤5.4%), the higher HbA1c groups (5.5%-6.4%, 6.5%-7.4%, and ≥7.5%) were associated with advanced liver fibrosis and high NAFLD activity score (NAS). On multivariate analysis, an HbA1c level of 6.5%- 7.4% group was significantly associated with advanced fibrosis compared with the lowest HbA1c group after adjusting for age, sex, hemoglobin, alanine aminotransferase, and creatinine levels. When further controlling for body mass index and uric acid, total cholesterol, and triglyceride levels, the higher HbA1c groups were significantly associated with advanced fibrosis compared with the lowest HbA1c group. On the other hand, compared with the lowest HbA1c group, the higher HbA1c groups were also associated with a high NAS in both multivariate analyses. CONCLUSION: Glycemic control is associated with NAFLD exacerbation, with even a mild deterioration in glycemic control, especially a HbA1c level of 6.5%-7.4%, contributing to NAFLD progression.

DOI： 10.4093/dmj.2023.0200

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BACKGROUND: High-sensitivity C-reactive protein (hsCRP) is a sensitive marker of inflammation. This study aimed to determine whether increased hsCRP levels are associated with all-cause mortality rate. METHODS: We examined data for participants from the 2002 Nomura Cohort Study who attended follow-ups for 20 years (follow-up rate: 93.3%). Of these, 793 were male (aged 61 ± 14 years) and 1040 were female (aged 63 ± 11 years). The Japanese Basic Resident Registry provided data on adjusted relative hazards for all-cause mortality. The data were subjected to a Cox regression analysis using a time variable of age and confounding risk factors. RESULTS: The median (interquartile range) follow-up period was 6548 days (6094-7452 days). The follow-up confirmed that there were 632 (34.8%) deaths, of which 319 were male (40.2% of all males) and 313 were female (30.6% of all females). Multivariable-adjusted hazard ratio (1.27; 95% confidence interval, 1.01-1.59) in the highest hsCRP category was also significantly higher compared with reference. A higher hsCRP was associated with a greater risk of all-cause mortality in male participants aged ≥65 years, a BMI < 25 kg/m2 , and no history of CVD or diabetes, and this association was particularly significant among participants with both of the latter two risk factors (p = 0.004 and 0.022 for interaction, respectively). CONCLUSIONS: Our results indicate a significant association between hsCRP levels and all-cause mortality in a rural Japanese population. Specifically, hsCRP appears to be a crucial biomarker for predicting long-term survival, particularly among older persons.

DOI： 10.1002/jcla.25015

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Introduction An elevated ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) not only independently affects aging-related health but also plays a critical role in mortality. However, there is limited predictive data on all-cause mortality, particularly in the context of community-dwelling individuals in Japan. This study examined the association between the AST/ALT ratio and survival prognosis in a cohort study using two follow-up studies based on 19-year and 7-year intervals. Methods The study included 1,573 male (63 ± 14 years; range, 20-90 years) and 1,980 female participants (65 ± 12 years; range, 19-89 years). The participants were those involved in a Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort) that continued to participate throughout the follow-up periods (follow-up rates were 90.3% and 97.4% for each cohort). A Cox proportional hazards model was adopted to calculate the multivariate-adjusted hazard ratios (HRs) of death from the baseline health check-up to the follow-up periods while controlling for potential confounding factors. Results The follow-up survey revealed that there were 473 male deaths (30.1% of total male participants) and 432 female deaths (21.8% of total female participants). The univariate Cox regression analysis showed that HRs for all-cause mortality were greater for participants in higher AST/ALT ratio quartiles (p < 0.001). The multivariate Cox regression analysis with adjusted variables showed a significant association between those in the fourth AST/ALT ratio quartile (HR: 1.83, 95% confidence interval, 1.46-2.29) and the risk of all-cause mortality. This association holds irrespective of gender, age, and elevated gamma-glutamyl transpeptidase, particularly in the case of participants with a body mass index < 25 kg/m2 without a history of cardiovascular disease or diabetes. Conclusions Our results reveal that an elevated AST/ALT ratio is an independent factor that can predict the risk of all-cause mortality among community-dwelling individuals.

DOI： 10.7759/cureus.52224

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Background: Smoking status is known to be an independent and significant predictor of health outcomes related to aging and plays a crucial role in overall mortality rates. This cohort study investigated the relationship between smoking status and survival outcomes over follow-up periods of 9 and 21 years. Methods: The sample consisted of 3526 participants with a mean age of 64 ± 12 years, 44.1% of whom were male. The median follow-up duration was 6315 days, with an interquartile range of 3441 to 7727 days. Smoking status [i.e., Brinkmann index (BI)] was calculated by multiplying the number of years smoked by the number of cigarettes smoked daily. Based on this, participants were categorized into non-smokers, former smokers, and current smokers. The data were analyzed using Cox regression, employing age as the time variable and accounting for various risk factors. Results: A total of 1111 participants (49.2%) were confirmed to have died. Among these, 564 were male (36.2% of all male participants), and 547 were female (27.8% of all female participants). The multivariate-adjusted odds ratio (95% confidence interval) for all-cause mortality compared with never-smokers was 1.51 (1.17-1.96) for former smokers with BI > 800, 1.61 (1.20-2.17) for current smokers with BI of 400-799 and 1.62 (95% CI, 1.24-2.10) with BI of ≥800 (P for trend <0.001). Participants who died within three years of follow-up were excluded to avoid the possibility of reverse causation, but the results were essentially unchanged. Conclusion: We found that the BI is a valid predictor of future mortality risk and that BI 800 for former smokers and BI 400 for current smokers were useful cutoff values. Efforts to control smoking should focus not only on current smokers but also on former smokers to reduce the risk of premature death associated with smoking.

DOI： 10.1177/1179173X241275881

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BACKGROUND AND AIM: Although diet is one of the potential environmental factors affecting ulcerative colitis (UC), evidence is not sufficient to draw definitive conclusions. This Japanese case-control study examined the association between the consumption of coffee, other caffeine-containing beverages and food, and total caffeine and the risk of UC. METHODS: The study involved 384 UC cases and 665 control subjects. Intake of coffee, decaffeinated coffee, black tea, green tea, oolong tea, carbonated soft drinks, and chocolate snacks was measured with a semiquantitative food-frequency questionnaire. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, body mass index, and intake of vitamin C, retinol, and total energy. RESULTS: Higher consumption of coffee and carbonated soft drinks was associated with a reduced risk of UC with a significant dose-response relationship (P for trend for coffee and carbonated soft drinks were <0.0001 and 0.01, respectively), whereas higher consumption of chocolate snacks was significantly associated with an increased risk of UC. No association was observed between consumption of decaffeinated coffee, black tea, green tea, or oolong tea and the risk of UC. Total caffeine intake was inversely associated with the risk of UC; the adjusted odds ratio between extreme quartiles was 0.44 (95% confidence interval: 0.29-0.67; P for trend <0.0001). CONCLUSIONS: We confirmed that intake of coffee and caffeine is also associated with a reduced risk of UC in Japan where people consume relatively low quantities of coffee compared with Western countries.

DOI： 10.1111/jgh.16439

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Rural career preference is known to be affected by rural self-efficacy. This study aims to explore whether the presence of a physician role model and having a medical department of interest influence rural self-efficacy among medical students. The study sample comprised 813 students (464 male and 349 female). We assessed rural self-efficacy using a validated scale that comprised 15 questions. The effect of the presence of a physician role model and the choice of medical department on rural self-efficacy score was examined. Multivariable-adjusted regression analysis showed that the presence of a physician role model was significantly associated with the rural self-efficacy score (β = 0.236, p < 0.001), as were gender (β = -0.096, p = 0.004), admission while living in hometown (β = 0.077, p = 0.041), receiving a scholarship for regional duty (β = 0.079, p = 0.025), admission based on school recommendation (β = 0.077, p = 0.031), and subjective difficulty with living in a rural area (β = -0.201, p < 0.001). Moreover, a higher rural self-efficacy score was significantly associated with students who listed general medicine/family medicine (β = 0.204, p < 0.001), pediatrics (β = 0.098, p = 0.004), or obstetrics and gynecology (β = 0.108, p = 0.002) as their department of choice, while anesthesiology (β = -0.075, p = 0.023) was significantly associated with a lower rural self-efficacy score. These relationships were consistent for both males and females. The presence of a physician role model and the choice of medical department are important factors for higher rural self-efficacy scores.

DOI： 10.7759/cureus.46174

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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AIM: Hepatitis C complicated by diabetes mellitus (DM) is considered a risk factor for the progression of fibrosis and development of hepatocellular carcinoma (HCC) and cardiovascular diseases. However, several studies may have lacked appropriate diagnosis of glucose intolerance. We aimed to examine the risk associated with abnormal glucose intolerance in the development of liver-related diseases, including HCC and complications of liver cirrhosis, such as ascites, esophageal and gastric varices, and hepatic encephalopathy, and cardiovascular diseases in patients with hepatitis C accurately diagnosed with impaired glucose tolerance. METHODS: This longitudinal retrospective study included 365 patients with chronic hepatitis C admitted to Ehime University Hospital for anti-hepatitis C therapy between September 1991 and January 2015. Patients were classified into normal glucose tolerance (NGT), prediabetes, and DM groups based on 75-g oral glucose tolerance test results. RESULTS: Both univariate and multivariate (adjusted for potential confounders) analyses revealed a significantly higher risk of developing HCC and cardiovascular events in the DM group than in the NGT group. However, in multivariate analysis, liver-related events, particularly liver cirrhosis complications, revealed no significant association. In addition, the prediabetes group had no significant risk of any outcome. CONCLUSIONS: Patients with hepatitis C complicated by DM, compared with patients with hepatitis C with NGT or complicated with prediabetes, have a higher risk of HCC and cardiovascular disease events, but not liver-related events, particularly in not developing liver cirrhosis complications. Therefore, appropriate follow-up is required for patients with hepatitis C based on their glucose tolerance status.

DOI： 10.1111/hepr.13925

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BACKGROUND: Many of the existing research studies have shown that serum uric acid (SUA) is a predictor of renal disease progression. More recently, studies have suggested an association between renal function-normalized SUA and all-cause mortality in adults. This study aims to examine the association between the ratio of SUA to creatinine (SUA/Cr) and all-cause mortality with a focus on hypertensive patients. METHODS: This study is based on 2,017 participants, of whom 916 were male (mean age, 67 ± 11 years) and 1,101 were female (mean age, 69 ± 9 years). All participants were part of the Nomura Cohort Study in 2002 (cohort 1) and 2014 (cohort 2), as well as the follow-up period (2002 follow-up rate, 94.8%; 2014 follow-up rate, 98.0%). We obtained adjusted relative risk estimates for all-cause mortality from a basic resident register. In addition, we employed a Cox proportional hazards model and adjusted it for possible confounders to determine the hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Of the total participants, 639 (31.7%) were deceased; of these, 327 (35.7%) were male and 312 (28.3%) were female. We found an independent association between a higher ratio of SUA/Cr and a higher risk of all-cause mortality in female participants only (HR, 1.10; 95% CI, 1.02-1.18). The multivariable-adjusted HRs (95% CI) for all-cause mortality across quintiles of baseline SUA/Cr were 1.28 (0.91-1.80), 1.00, 1.38 (0.95-1.98), 1.37 (0.94-2.00), and 1.57 (1.03-2.40) for male participants, and 0.92 (0.64-1.33), 1.00, 1.04 (0.72-1.50), 1.56 (1.06-2.30), and 1.59 (1.06-2.38) for female participants. When the data were further stratified on the basis of age (< 65 or ≥ 65 years), body mass index (< 22.0 or ≥ 22.0 kg/m2), estimated glomerular filtration rate (< 60 or ≥ 60 mL/min/1.73 m2), and presence of SUA-lowering medication, trends similar to those of the full population were found in all groups. CONCLUSION: Baseline SUA/Cr is independently and significantly associated with future all-cause mortality among hypertensive patients.

DOI： 10.1186/s40885-023-00235-8

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BACKGROUND: Uric acid is both a pro-oxidant and an antioxidant. This study examined whether serum uric acid (SUA) is associated with all-cause mortality and cardiovascular biomarkers in members of the general population who had varying levels of handgrip strength (HGS). METHODS: The analysis is based on 1736 participants, of whom 785 were male (69 ± 11 years old) and 951 were female (69 ± 9 years old). We obtained adjusted relative risk estimates for all-cause mortality from the Japanese Basic Resident Registry and used a Cox proportional hazards model (adjusted for possible confounders) to determine the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: The results indicated a significant interaction between the effects of SUA levels and HGS on all-cause mortality risk. Among participants with low HGS (<30.0 kg in males, <20.0 kg in females), low SUA levels (<3.5 mg/dL in males, <3.0 mg/dL in females; HR: 2.40; 95% CI: 1.07-5.40) and high SUA levels (≥8.0 mg/dL in males, ≥7.0 mg/dL in females; HR: 3.05; 95% CI: 1.41-6.59) were associated with a significantly higher HR for all-cause mortality than medium SUA levels (3.5-7.9 mg/dL in males, 3.0-6.9 mg/dL in females). Among participants with high HGS (≥30.0 kg in males; ≥20.0 kg in females), there was no difference between the HR for all-cause mortality between the three SUA-category groups. CONCLUSIONS: The association between SUA and the risk of all-cause mortality was U-shaped for this population of community-dwelling adults. This was primarily true for those with low HGS.

DOI： 10.1016/j.metop.2022.100227

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Language：Japanese   Publisher：(一社)日本内科学会  

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Patients with viral hepatitis-related chronic liver disease (CLD) under surveillance for hepatocellular carcinoma (HCC) are often diagnosed with pancreatic cancer (PC) at an early stage. However, the long-term outcomes of these patients are unclear. We aimed to clarify the long-term outcomes of patients with PC with viral hepatitis-related CLD using a chart review. Data collection included the Union for International Cancer Control (UICC) stage at PC diagnosis, hepatitis B virus and hepatitis C virus status, and long-term outcomes. The distribution of the entire cohort (N = 552) was as follows: early stage (UICC 0-IB; n = 52, 9.5%) and non-early stages (UICC IIA-IV; n = 500, 90.5%). At diagnosis, the HCC surveillance group (n = 18) had more patients in the early stages than the non-surveillance group (n = 534) (50% vs. 8.0%), leading to a higher indication rate for surgical resection (72.2% vs. 29.8%) and a longer median survival time (19.0 months vs. 9.9 months). We confirmed that patients with viral hepatitis-related CLD under HCC surveillance were diagnosed with PC at an early stage. Because of the higher indication rate for surgical resection in these patients, they had favorable long-term outcomes for PC.

DOI： 10.3390/cancers15030561

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There is limited research on the association between longitudinal variability in serum uric acid (SUA) and all-cause mortality in the general population, although recent studies have suggested that changes in SUA are associated with all-cause mortality in adults. This study aims to examine the association between percentage change in SUA (%dSUA = 100 × (cohort 2 SUA - cohort 1 SUA)/(time × cohort 1 SUA) and all-cause mortality. This study is based on 1,301 participants, of whom 543 were male (63 ± 11 years) and 758 were female (63 ± 9 years). We obtained adjusted relative risk estimates for all-cause mortality and used a Cox proportional hazards model, adjusted for possible confounders, to determine the hazard ratio (HR) and 95% confidence interval (CI) of %dSUA. Of all the participants, 79 (6.1%) were deceased, and of these, 45 were male (8.3%) and 34 were female (4.5%). The multivariable-adjusted HRs (95% CI) for all-cause mortality for the first, second to fourth (reference), and fifth %dSUA quintiles were 3.79 (1.67-8.48), 1.00, and 0.87 (0.29-2.61) for male participants and 4.00 (1.43-11.2), 1.00, and 1.19 (0.46-3.05) for female participants, respectively. Participants with a body mass index of <22 kg/m2 had a significantly higher HR, forming a U-shaped curve for the first (HR, 7.59; 95% CI, 2.13-27.0) and fifth quintiles (HR, 2.93; 95% CI, 1.05-8.18) relative to the reference. Percentage change in SUA is independently and significantly associated with future all-cause mortality among community-dwelling persons.

DOI： 10.1155/2023/7382320

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Anthropometric evaluation is a simple yet essential indicator of muscle and fat mass when studying life prognosis in aging. This study aimed to investigate the contributions of anthropometric measurements, independent of body mass index, to measures of all-cause mortality. We examined data for 1,704 participants from the 2014 Nomura Cohort Study who attended follow-ups for the subsequent eight years (follow-up rate: 93.0%). Of these, 765 were male (aged 69 ± 11 years) and 939 were female (aged 69 ± 9 years). The Japanese Basic Resident Registry provided data on adjusted relative hazards for all-cause mortality. The data were subjected to a Cox regression analysis, wherein the time variable was age and the risk factors were gender, age, anthropometric index, smoking habits, drinking habits, exercise habits, cardiovascular history, hypertension, lipid levels, diabetes, renal function, and serum uric acid. Of the total number of participants, 158 (9.3%) were confirmed to have died, and of these, 92 were male (12.0% of all male participants) and 66 were female (7.0% of all female participants). The multivariable Cox regression analysis revealed that a smaller thigh-hip ratio predicted eight-year all-cause mortality in male participants, but only baseline body mass index was associated with all-cause mortality in female participants. Thigh-hip ratio is a useful predictor of death in Japanese community-dwelling men.

DOI： 10.1371/journal.pone.0292287

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The relationship between advanced nonalcoholic steatohepatitis (NASH) and plasma fatty acid composition remains unknown. We aimed to examine the plasma fatty acid composition in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD) and evaluate the relationship between histological findings and fatty acid composition. Overall, 235 patients (134 women) with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. Multivariate analyses adjusted for age, sex, body mass index, alanine aminotransferase, hemoglobin A1c, creatinine, total cholesterol, triglyceride, and NAFLD Activity Score values showed that lower levels of arachidic, behenic, α-linolenic, eicosatetraenoic, docosapentaenoic, and docosahexaenoic acids and higher levels of mead acid were associated with fibrosis stage 3-4. Furthermore, higher lauric acid, myristic acid, and palmitic acid levels and monounsaturated fatty acids such as palmitoleic acid and oleic acid were significantly associated with high NAS in analyses adjusted for the same factors and fibrosis stage. The plasma fatty acid composition was associated with the histological evidence of NASH. Increased synthesis of fatty acids is associated with NASH; insufficient intake of n-3 essential fatty acids and reduced elongation of fatty acids are associated with fibrosis in NASH. These features may help clinicians to understand and treat advanced NASH cases.

DOI： 10.3390/biomedicines10102540

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BACKGROUND: The interleukin (IL)-23/Th17 pathway plays a critical role in ulcerative colitis (UC). The IL-12p40 subunit, which is shared by IL-23 and IL-12, is encoded by the IL12B gene. The current case-control study investigated the association between IL12B SNP rs6887695 and the UC risk. METHODS: There were 384 cases within 4 years of UC diagnosis and 661 controls who were enrolled. Adjustments were made for sex, age, pack-years of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Subjects with the GG IL12B SNP rs6887695 genotype had a significantly increased risk of UC compared with those with the CC genotype (adjusted odds ratio [AOR], 1.60; 95% confidence interval [CI], 1.08-2.36). This positive association was also significant using the additive and recessive models (AOR, 1.25; 95% CI, 1.03-1.52; AOR, 1.50; 95% CI, 1.08-2.09, respectively). An independent inverse relationship was observed between ever alcohol consumption and the UC risk in those with the CC genotype while no significant association was found in those with at least one G allele (P for interaction = 0.0008). CONCLUSIONS: IL12B SNP rs6887695 was significantly associated with UC. The influence of alcohol consumption might rely on rs6887695.

DOI： 10.1016/j.cyto.2022.155901

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BACKGROUND: In Japan, community medicine clerkships facilitate positive attitudes toward rural medical practice and encourage rural recruitment. Rural self-efficacy has been shown to influence rural career intent following a rural clinical placement. However, the impact of subjective difficulties of living in a rural area on future rural career intent is also important. This study aims to explore whether rural self-efficacy influences the relationship between difficulty with living in a rural area and rural career intent.  METHODS: The subjects included 308 male and 255 female participants aged 20-41 [median (interquartile range): 22 (21-22)] years. Rural self-efficacy was based on a validated scale consisting of 15 questions. Difficulty with living in a rural area was measured asking students. A cohort survey was conducted to evaluate the effect of the rural self-efficacy score on the rural career intent of Japanese medical students after they completed their rural clinical training. RESULTS: The following variables were significantly associated with a higher rural self-efficacy score: female sex (p = 0.003), age < 21 years (p = 0.013), having a doctor as a role model (p < 0.001), gaining admission through a school recommendation (p = 0.016), living in a rural or remote area until the age of 18 years (p = 0.018), and orientation towards general medicine (p < 0.001). In addition, baseline difficulty with living in a rural area was significantly associated with a lower self-efficacy score (p < 0.001). Participants with a stronger intent to practice in a rural area before rural clinical training had higher rural self-efficacy and showed a stronger positive rural career intent after rural clinical training (p < 0.001). A multivariable logistic regression analysis demonstrated that difficulty with living in a rural area [odds ratio (OR): 0.61; 95% confidence interval (CI), 0.39-0.84] was still associated with lower rural career intent after rural clinical training, independent of all confounders such as gender, age, scholarship for regional duty, rural background, and orientation towards general medicine. However, when rural self-efficacy (OR, 1.12; 95% CI, 1.07-1.16) was added as a factor for rural career intent, difficulty with living in a rural area (OR, 0.68; 95% CI, 0.43-1.06) was no longer observed as an associated factor. CONCLUSION: Subjective difficulty with living in a rural area was shown to reduce future rural career intent, but high rural self-efficacy ameliorated this decline.

File： s12909-022-03511-7.pdf

DOI： 10.1186/s12909-022-03511-7

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Background: Serum uric acid (SUA) is a key determinant of cardiovascular diseases (CVDs). Studies have also shown that SUA independently impacts age-related health outcomes, although their findings differ between males and females. Furthermore, predictive data on all-cause mortality remain limited, particularly for the Japanese population. Thus, this study examined the association between SUA and survival prognosis among males and females based on a follow-up period of 7 or 19 years. Methods: The study was based on 1,573 male (63 ± 14 years) and 1,980 female (65 ± 12 years) participants who participated in a Nomura Cohort Study in 2002 (Cohort 1) and 2014 (Cohort 2), and continued throughout the follow-up period. A basic resident register was referenced to derive the adjusted relative risk estimates for all-cause mortality. Finally, a Cox proportional hazards model analysis was conducted and was adjusted for possible confounders to estimate hazard ratios (HRs). 95% confidence intervals (CIs) were computed separately for male and female participants. Results: Of the total 3,553 participants, 905 (25.5%) were deceased. Of these, 473 were male (30.1% of all males) and 432 were female (21.8% of all females). Hyperuricemia was defined in males with SUA levels of 8.5 mg/dL or higher, and in females with SUA levels of 7.5 mg/dL or higher, and was associated with a significantly increased HR for all-cause mortality (males: 1.67; 95% CI: 1.06-2.63; females: 2.17; 95% CI: 1.20-3.94). The data were further stratified based on age (< 65 years or ≥ 65 years), body mass index (BMI) (< 25.0 kg/m2 or ≥ 25.0 kg/m2), History of cardiovascular disease, estimated glomerular filtration rate (< 60 mL/min/1.73 m2 or ≥ 60 mL/min/1.73 m2), and presence of SUA-lowering medication. All stratified groups demonstrated a similar trend. The hyperuricemia group in particular reported a significant increase in HR. On the other hand, a U-shaped increase in HR was observed in those with BMI greater than 25 kg/m2 and SUA-lowering medication, but interaction effect was not significant. Conclusions: Hyperuricemia is a key risk indicator for all-cause mortality in male and female community-dwelling individuals in Japan.

File： Metabolism Open 2022 Hyperuricemia is associated with all-cause mortality.pdf

DOI： 10.1016/j.metop.2022.100186

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AIMS/INTRODUCTION: To investigate whether the Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease. MATERIALS AND METHODS: Based on fatty liver disease and Fibrosis-4 index (cut-off value 1.3), we retrospectively divided 9,449 individuals, who underwent at least two annual health checkups, into four groups stratified by sex: normal; high Fibrosis-4 index without fatty liver disease; low Fibrosis-4 index with fatty liver disease; and high Fibrosis-4 index with fatty liver disease. RESULTS: Onset rates for diabetes mellitus in the normal, high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were 1.6%, 4.3%, 6.8% and 10.2%, respectively, in men, and 0.6%, 0.9%, 5.3% and 7.0%, respectively, in women. Compared with the normal group, the high Fibrosis-4 index without fatty liver disease, low Fibrosis-4 index with fatty liver disease and high Fibrosis-4 index with fatty liver disease groups were at a significant risk for diabetes mellitus onset in both male and female participants. Furthermore, in both sexes, high Fibrosis-4 index with fatty liver disease remained a significant risk factor on multivariate analysis (high fibrosis-4 index with fatty liver disease group: adjusted hazard ratio 4.03, 95% confidence interval 2.19-7.42 [men] and adjusted hazard ratio 6.40, 95% confidence interval 1.77-23.14 [women]). CONCLUSIONS: Individuals with fatty liver disease and high Fibrosis-4 index had a higher risk of diabetes mellitus onset. Therefore, Fibrosis-4 index can help stratify the risk of diabetes mellitus in patients with fatty liver disease and identify patients requiring intervention.

File： J Diabetes Investig 2022 Fibrosis-4 index & fatty liver for stratifying the risk for DM.pdf

DOI： 10.1111/jdi.13812

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BACKGROUND: This study examined the relationship between survival prognosis and alanine aminotransferase (ALT), a critical factor contributing to aging-related health and mortality. The research is based on a follow-up study with 6- and 10-year intervals. METHODS: The participants included 1,610 males (63 ± 14 years old) and 2,074 females (65 ± 12 years old) who were part of the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort). The multivariable-adjusted hazard ratios (HRs) of death between the baseline health checkup and the end of the follow-up periods were estimated using a Cox proportional hazards model, controlling for potential confounding factors. RESULTS: The follow-up survey revealed 180 male deaths (11.2% of male participants) and 146 female deaths (7.0% of female participants). The univariate Cox regression analysis showed a significant increase in the HRs of all-cause mortality with decreasing ALT levels (p < 0.001). Furthermore, compared with individuals with ALT levels of 20-29 IU/L, the multivariable-adjusted HRs (95% confidence interval) for all-cause mortality were 2.73 (1.59-4.70) for those with ALT levels <10 IU/L, 1.45 (1.05-2.00) for those with ALT levels of 10-19 IU/L, and 1.63 (1.05-2.53) for those with ALT levels ≥30 IU/L. CONCLUSIONS: Our findings show that abnormally low ALT levels and high within the normal range were related to all-cause mortality in Japan's community-dwelling individuals. Especially, ALT activity may be an important biomarker for predicting the long-term survival of older adults.

File： J Clin Lab Anal 2022 ALT & all-cause mortality rate.pdf

DOI： 10.1002/jcla.24445

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INTRODUCTION: Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM. METHODS: This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.

File： Diabetes Ther 2022 Luseogliflozin & Semaglutide for NASH with Type 2 DM.pdf

DOI： 10.1007/s13300-022-01239-7

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INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is diagnosed after excluding other liver diseases. The pathogenesis of NAFLD when complicated by other liver diseases has not been established completely. Metabolic dysfunction-associated fatty liver disease (MAFLD) involves more metabolic factors than NAFLD, regardless of complications with other diseases. This study aimed to clarify the effects of fatty liver occurring with metabolic disorders, such as MAFLD without diabetes mellitus (DM), on the development of DM. MATERIALS AND METHODS: We retrospectively assessed 9,459 participants who underwent two or more annual health check-ups. The participants were divided into the MAFLD group (fatty liver disease with overweight/obesity or non-overweight/obesity complicated by metabolic disorders), simple fatty liver group (fatty liver disease other than MAFLD group), metabolic disorder group (metabolic disorder without fatty liver disease), and normal group (all other participants). RESULTS: The DM onset rates in the normal, simple fatty liver, metabolic disorder, and MAFLD groups were 0.51, 1.85, 2.52, and 7.36%, respectively. In the multivariate analysis, the MAFLD group showed a significantly higher risk of DM onset compared with other three groups (P < 0.01). Additionally, the risk of DM onset was significantly increased in fatty liver disease with overweight/obesity or pre-diabetes (P < 0.01). CONCLUSIONS: Fatty liver with metabolic disorders, such as MAFLD, can be used to identify patients with fatty liver disease who are at high risk of developing DM. Additionally, patients with fatty liver disease complicated with overweight/obesity or prediabetes are at an increased risk of DM onset and should receive more attention.

File： J Diabetes Investig 2022 MAFLD & onset of DM.pdf

DOI： 10.1111/jdi.13772

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Objective S-1 and modified FOLFIRINOX (mFFX) were often used as the second-line chemotherapies after failure of gemcitabine plus nab-paclitaxel (GnP) in unresectable pancreatic cancer (UPC) until nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy was approved as an alternative in Japan in 2020. However, the clinical outcomes of S-1 and mFFX after GnP have scarcely been reported. Therefore, we retrospectively studied them. Methods We extracted the clinical data of 86 patients with UPC who received second-line chemotherapy after GnP between 2015 and 2020. Among the patients who had a good organ functions and no massive ascites, 41 patients treated with S-1 and 21 treated with mFFX were enrolled. Results Compared to S-1, mFFX tended to be used for younger patients with a good general condition (median age, 63 vs. 71 years, p<0.01; and performance status 0, 67% vs. 37%, p<0.05). The median progression-free and overall survival were similar between the S-1 (3.7 and 7.2 months, respectively) and mFFX (3.3 and 7.4 months, respectively) groups. The response rate in patients with measurable lesions was 4% (n=1/23) in the S-1 group and 17% (n=2/12) in the mFFX group. The incidence of grade 3 or 4 adverse events was 20% in the S-1 group and 57% (neutrophil count decreased in 43%) in the mFFX group (p<0.01). Conclusion S-1 and mFFX were both acceptable second-line chemotherapies after GnP therapy for UPC, although attention should be paid to myelosuppression during mFFX treatment. Further studies involving nanoliposomal irinotecan plus 5-fluorouracil/leucovorin therapy are necessary to facilitate the selection of the optimal regimen for each patient.

File： Intern Med 2022 Second-line chemotherapy for PC.pdf

DOI： 10.2169/internalmedicine.8736-21

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

We herein report two cases of potentially life-threatening arrhythmia due to hyperkalemia triggered by the excessive consumption of "Hoshi-Imo" (dried sweet potato). Both patients with chronic renal disease on renin-angiotensin-aldosterone system inhibitors presented at the emergency room with non-specific symptoms. Electrocardiograms revealed potentially life-threatening arrhythmia due to hyperkalemia in both cases: sinus arrest with a ventricular escape rhythm, tall and peaked T waves; and a widened QRS complex in a nearly sine-wave configuration without discernible P wave. Both patients fully recovered after intensive care for hyperkalemia. Physicians should recognize the excessive consumption of "Hoshi-Imo" may lead to the development of life-threatening arrhythmia, especially in patients with risk factors for hyperkalemia.

File： Intern Med 2021 %22Hoshi-Imo%22.pdf

DOI： 10.2169/internalmedicine.8479-21

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BACKGROUND AND AIM: Although an inverse relationship between current smoking and the development of ulcerative colitis (UC) has been shown in North America and Europe, evidence is limited in Asian countries, where the incidence of UC is rapidly increasing. This Japanese case-control study examined the association between active and passive smoking and risk of UC. METHODS: A self-administered questionnaire was used to obtain information on smoking and potential confounding factors in 384 cases with a diagnosis of UC within the past 4 years and 665 controls. RESULTS: Compared with having never smoked, having ever smoked was associated with an increased risk of UC (adjusted odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.23-2.37). No association was observed between current smoking and risk of UC, but former smokers had a significant elevation in risk (adjusted OR = 2.40, 95% CI: 1.67-3.45). There was a positive dose-response relationship with pack-years smoked (P for trend = 0.006). Among never smokers, passive smoking exposure at home was significantly associated with an increased risk of UC (adjusted OR = 1.90, 95% CI: 1.30-2.79). A significant dose-response gradient was also observed between pack-years of passive smoking at home and risk of UC (P for trend = 0.0003). CONCLUSIONS: We confirmed that former smoking elevated the risk of UC, whereas an inverse association between current smoking and the risk of UC did not reach a statistically significant level. Passive smoking may be associated with an increased risk of UC.

File： J Gastroenterol Hepatol 2021 Smoking & UC.pdf

DOI： 10.1111/jgh.15745

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>The small intestinal mucosa-associated microbiota (MAM) can potentially impact the etiology of primary biliary cholangitis (PBC). Herein, we investigate the MAM profile to determine its association with liver pathology in patients with PBC. Thirty-four patients with PBC and 21 healthy controls who underwent colonoscopy at our hospital were enrolled in our study. We performed 16S ribosomal RNA gene sequencing of MAM samples obtained from the mucosa of the terminal ileum and examined the relationship between the abundance of ileal MAM and chronic nonsuppurative destructive cholangitis using liver specimens from patients with PBC. There was a significant reduction in microbial diversity within individuals with PBC (<italic>P</italic> = 0.039). Dysbiosis of ileal MAM was observed in patients with PBC, with a characteristic overgrowth of <italic>Sphingomonadaceae</italic> and <italic>Pseudomonas</italic>. Multivariate analysis showed that the overgrowth of <italic>Sphingomonadaceae</italic> and <italic>Pseudomonas</italic> is an independent association factor for PBC (<italic>P</italic> = 0.0429, <italic>P</italic> = 0.026). Moreover, the abundance of <italic>Sphingomonadaceae</italic> was associated with chronic nonsuppurative destructive cholangitis in PBC (<italic>P</italic> = 0.00981). The overgrowth of <italic>Sphingomonadaceae</italic> and <italic>Pseudomonas</italic> in ileal MAM was found in patients with PBC. <italic>Sphingomonadaceae</italic> may be associated with the pathological development of PBC.

File： Scientific Reports 2021 PBC Kitahata Project.pdf

DOI： 10.1038/s41598-021-99314-9

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Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is a key adaptor protein of inflammasomes and a proapoptotic molecule; however, its roles in signal transduction in pancreatic ductal adenocarcinoma (PDAC) cells remain unknown. Here, we clarified the role and mechanisms of action of ASC in PDAC using clinical evidence and in vitro data. ASC expression in PDAC tissues was analyzed using public tumor datasets and immunohistochemistry results of patients who underwent surgery, and PDAC prognosis was investigated using the Kaplan-Meier Plotter. ASC expression in PDAC cells was downregulated using small-interfering RNA, and gene expression was assessed by RNA sequencing. Review of the Oncomine database and immunostaining of surgically removed tissues revealed elevated ASC expression in PDAC tumors relative to non-tumor tissue, indicating poor prognosis. We observed high ASC expression in multiple PDAC cells, with ASC silencing subsequently inhibiting PDAC cell growth and altering the expression of cell cycle-related genes. Specifically, ASC silencing reduced cyclin D1 levels and stopped the cell cycle at the G1 phase but did not modulate the expression of any apoptosis-related molecules. These results show that ASC inhibited tumor progression via cell cycle modulation in PDAC cells and could be a potential therapeutic target.

File： Sci Rep 2021 ASC & Pancreatic Cancer.pdf

DOI： 10.1038/s41598-021-01465-2

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Authorship：Corresponding author   Language：English  

We report the eldest female case of myasthenia gravis (MG) that initially presented with aspiration pneumonia. A 91-year-old female with a high-grade fever and general malaise who had suffered from expectoration for several years was diagnosed with aspiration pneumonia. Thorough medical history taking and physical examination suggested the possibility of MG as a cause of aspiration pneumonia. Positive acetylcholine receptor antibody and waning phenomenon on a nerve conduction study confirmed the diagnosis. Treatment with intravenous immunoglobulin, prednisolone, and pyridostigmine resulted in a rapid improvement. Physicians should always consider the etiology of aspiration pneumonia to prevent further negative events.

File： Aspiration pneumonia as initial presentation of MG.pdf

DOI： 10.7759/cureus.19268

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ABSTRACT: Most patients with pancreatic cancer are ineligible for curative resection at diagnosis, resulting in poor prognosis. This study aimed to evaluate the prognostic factors in patients with unresectable pancreatic cancer.We retrospectively collected clinical data from 196 patients with unresectable pancreatic cancer who received palliative chemotherapy (N = 153) or palliative care alone (N = 43) from January 2011 to December 2013. Patients' background data and overall survival were analyzed using the Cox proportional hazard regression model.In patients receiving palliative chemotherapy (gemcitabine-based regimen, 88.2%) and palliative care alone, the median (range) ages were 68 (43-91) and 78 (53-90) years, and metastatic diseases were present in 80% (N = 123) and 86% (N = 37), respectively. Multivariate analysis in the palliative chemotherapy patients showed that liver metastasis (hazard ratio [HR] 2.25, 95% confidence interval [CI] 1.58-3.20, P < .001), neutrophil-to-lymphocyte ratio (>4.5 vs ≤4.5; HR 3.45, 95% CI 2.22-5.36, P < .001), and cancer antigen 19-9 (CA19-9) (≥900 vs <900 U/mL; HR 1.45, 95% CI 1.02-2.05, P = .036) were independent prognostic factors. In those receiving palliative care alone, lung (HR 3.27, 95% Cl 1.46-7.35, p = 0.004) and peritoneum (HR 2.50, 95% CI 1.20-5.18, P = .014) metastases and the C-reactive protein-to-albumin ratio (≥1.3 vs <1.3; HR 3.33, 95% Cl 1.51-7.35, P = .003) were independent prognostic factors. Furthermore, patients with multiple factors had worse prognosis in both groups. Median survival time of palliative chemotherapy patients with risk factors 0, 1, 2, and 3 were 13.1 (95% CI 8.0-16.9), 9.4 (95% CI 7.9-10.1), 6.6 (95% CI 4.9-7.8), and 2.5 (95% CI 1.7-4.0) months, respectively. Similarly, median survival time was 5.7 (95% CI 1.3 -8.0), 2.1 (95% CI 1.5-3.9), and 1.3 (95% CI 0.6-1.7) months, respectively, for palliative care alone patients with risk factor 0, 1, and 2 to 3.Prognostic markers for pancreatic cancer were neutrophil-to-lymphocyte ratio, liver metastasis, and CA19-9 in patients undergoing palliative chemotherapy and C-reactive protein-to-albumin ratio and lung/peritoneum metastases in patients undergoing palliative care alone. These simple markers should be considered when explaining the prognosis and therapeutic options to patients.

File： Medicine 2021 Simple prognostic markers in unrectable PC.pdf

DOI： 10.1097/MD.0000000000027591

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BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) independently impacts aging-related health outcomes and plays a critical role in cardiovascular diseases (CVDs). However, there are limited predictive data on all-cause mortality, especially for the Japanese community population. In this study, it was examined whether LDL-C is related to survival prognosis based on 7 or 10 years of follow-up. METHODS: Participants included 1610 men (63 ± 14 years old) and 2074 women (65 ± 12 years old) who participated in the Nomura cohort study conducted in 2002 (first cohort) and 2014 (second cohort) and who continued throughout the follow-up periods (follow-up rates: 94.8 and 98.0%). Adjusted relative risk estimates were obtained for all-cause mortality using a basic resident register. The data were analyzed by a Cox regression with the time variable defined as the length between the age at the time of recruitment and that at the end of the study (the age of death or censoring), and risk factors including gender, age, body mass index (BMI), presence of diabetes, lipid levels, renal function, serum uric acid levels, blood pressure, and history of smoking, drinking, and CVD. RESULTS: Of the 3684 participants, 326 (8.8%) were confirmed to be deceased. Of these, 180 were men (11.2% of all men) and 146 were women (7.0% of all women). Lower LDL-C levels, gender (male), older age, BMI under 18.5 kg/m2, and the presence of diabetes were significant predictors for all-cause mortality. Compared with individuals with LDL-C levels of 144 mg/dL or higher, the multivariable-adjusted Hazard ratio (and 95% confidence interval) for all-cause mortality was 2.54 (1.58-4.07) for those with LDL-C levels below 70 mg/dL, 1.71 (1.15-2.54) for those with LDL-C levels between 70 mg/dL and 92 mg/dL, and 1.21 (0.87-1.68) for those with LDL-C levels between 93 mg/dL and 143 mg/dL. This association was particularly significant among participants who were male (P for interaction = 0.039) and had CKD (P for interaction = 0.015). CONCLUSIONS: There is an inverse relationship between LDL-C levels and the risk of all-cause mortality, and this association is statistically significant.

File： Lipids Health Dis 2021 LDL-c and all-cause mortality rate.pdf

DOI： 10.1186/s12944-021-01533-6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAIWAN SOC GERIATRIC EMERGENCY & CRITICAL CARE MEDICINE-TSGECM  

Background: The incidence of hypertension is increasing worldwide, and handgrip strength (HGS) is an easily obtainable measure of physical health and muscle function. However, there is limited data available on the relationship between HGS and hypertension among community-dwelling persons in Japan. Therefore, we performed a population-based cohort study to examine whether relative HGS, defined by HGS/body mass index (BMI) ratio, was associated with hypertension.Methods: A follow-up cohort study included 257 men aged 66 +/- 9 years and 369 women aged 67 +/- 8 years from a rural village (Nomura Cho, Seiyo City, in Ehime prefecture, Japan). Logistic regression models were used to evaluate the relative HGS as a significant predictor of hypertension.Results: The median HGS was 36.4 (interquartile range: 31.3-40.7) kg in men and 21.9 (19.8-24.7) kg in women, while the mean HGS/BMI ratio was 1.62 +/- 0.33 m(2) in men and 1.04 +/- 0.21 m(2) in women. Of the participants, 120 men (46.7%) and 137 women (37.1%) had hypertension. The prevalence of hypertension was significantly decreased in relation to an increasing baseline relative HGS only among men. After adjustment for confounding factors, the respective odds ratios (95% confidence interval) of the three tertiles of the gender-specific relative HGS for hypertension were 1.00, 0.65 (0.35-1.22), and 0.27 (0.14-0.54) in men, and 1.00, 0.71 (0.42-1.19), and 0.56 (0.33-0.95) in women.Conclusion: These results suggest that the relative HGS is significantly and negatively associated with an increased risk of hypertension in Japanese-community dwelling persons. Copyright (C) 2021, Taiwan Society of Geriatric Emergency & Critical Care Medicine.

DOI： 10.6890/IJGE.202107_15(3).0014

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Aim Portal hypertension induces pancreatic congestion and impaired insulin secretion in patients with liver cirrhosis (LC). However, its mechanism is unclear, with no established noninvasive imaging method for the evaluation of its pathogeneses. The present study focused on pancreas stiffness, as assessed by shear wave elastography (SWE), and examined its association with portal hypertension and insulin secretion.Methods Shear wave elastography and contrast-enhanced ultrasonography were utilized to evaluate pancreas stiffness and congestion, respectively. A glucagon challenge test was used for insulin secretion assessment. Furthermore, rat models of carbon tetrachloride (CCl4)-induced LC and portal hypertension were used to identify the direct effects of pancreatic congestion. Immunohistochemistry staining of the pancreas was carried out on human autopsy samples.Results Pancreas stiffness measured by SWE was higher in patients with LC than in controls and showed significant correlation with pancreatic congestion. The glucagon challenge test indicated a lower value for the change in C-peptide immunoreactivity in the LC group, which was inversely correlated with pancreas stiffness and congestion. Additionally, portal hypertension and insulin secretion dysfunction were confirmed in CCl4 rat models. Autopsy of human samples revealed congestive and fibrotic changes in the pancreas and the relationship between insulin secretion and their factors in patients with LC.Conclusions In patients with LC, pancreas stiffness measured by SWE could be a potential noninvasive test for evaluating pancreatic congestion and fibrosis due to portal hypertension. Moreover, it was associated with impaired insulin secretion, and could aid in guiding the treatment for hepatogenous diabetes.

File： Hepatol Res 2021 Pancreas stiffness in LC and hepatogeneous diabetes.pdf

DOI： 10.1111/hepr.13672

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1111/hepr.13672

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OBJECTIVES: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk. METHODS: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index. RESULTS: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively). CONCLUSIONS: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk.

File： Nutrition2021 UC Study.pdf

DOI： 10.1016/j.nut.2021.111378

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BACKGROUND: Serum uric acid (SUA) is a key risk factor contributing to renal failure, a serious public health problem. However, few studies have examined whether the interactive relationship between alcohol consumption and SUA is independently associated with the estimated glomerular filtration rate (eGFR). METHODS: Our sample comprised 742 men aged 69 ± 11 years (mean ± standard deviation) and 977 women aged 69 ± 10 years from a rural area. We cross-sectionally examined the relationships between the confounding factors of alcohol consumption and SUA with renal function denoted by eGFR estimated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations modified by a Japanese coefficient. RESULTS: In both genders, eGFR increased with a rise in alcohol consumption. This tendency was more pronounced in participants with hyperuricemia, where SUA was greater than 7.0 mg/dL in men and greater than 6.0 mg/dl in women (men: F = 41.98, p < 0.001; women: F = 41.98, p < 0.001). A multiple linear regression analysis showed that alcohol consumption (men: β = 0.112, p < 0.001; women: β = 0.060, p = 0.011) and SUA (men: β = -0.282, p < 0.001; women: β = 0.317, p < 0.001) were significantly and independently related to eGFR. Further, the interactive relationship between alcohol consumption and SUA (men: F = 6.388, p < 0.001; women: F = 5.368, p < 0.001) was a significant and independent indicator of eGFR. CONCLUSIONS: These results suggested that alcohol consumption and SUA were synergistically associated with renal dysfunction among community-dwelling persons.

File： J Clin Lab Anal. 2021 Alcohol and UA associated with renal dysfunction .pdf

DOI： 10.1002/jcla.23812

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PURPOSE: In addition to playing a critical role in cardiovascular health, muscle mass and strength independently impact aging-related health outcomes in adults. There are limited predictive data for all-cause mortality, particularly for community-dwelling persons in Japan. This study examined whether handgrip strength (HGS) and thigh circumference are related to survival prognosis based on a 6-year follow-up period. METHODS: Participants were 787 men (aged 69 ± 11 years) and 963 women (aged 69 ± 9 years) who took part in a Nomura cohort study conducted in 2014 and who continued with follow-ups for the subsequent 6 years (follow-up rate: 95.5%). We obtained adjusted relative hazards of all-cause mortality from the basic resident register. The data were subjected to a Cox regression with age as the time variable and gender, age, anthropometric index, smoking habits, drinking habits, exercise habits, cardiovascular history, blood pressure, lipid levels, diabetes, renal function, and serum uric acid as risk factors. RESULTS: Of the 1750 participants, a total of 97 (5.5%) were confirmed to have died, of which 56 were men (7.1% of all male participants), and 41 were women (4.3% of all female participants). The multivariable Cox regression analysis revealed that smaller thigh circumference and lower HGS in men were found to predict 6-year all-cause mortality, but in women only baseline HGS was associated with all-cause mortality. CONCLUSION: Thigh circumference and HGS are useful predictors of death in Japanese community-dwelling men.

DOI： 10.1007/s41999-021-00515-2

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Language：Japanese   Publisher：(一社)日本プライマリ・ケア連合学会  

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BACKGROUND: Causes of non-alcoholic fatty liver disease and its progression include visceral fat accumulation and loss of muscle mass; however, which of the two phenomena is more critical is unclear. Therefore, we intended to examine the relationship between body composition and non-alcoholic fatty liver disease progression as indicated by fibrosis and the non-alcoholic fatty liver disease activity score. METHODS: This cross-sectional study comprised 149 patients (55 men; age, 20-76 years) treated for non-alcoholic fatty liver disease between December 2010 and January 2020. Body composition measurements, histological examinations of liver samples, and comprehensive blood chemistry tests were performed. The relationship between body composition and non-alcoholic fatty liver disease histology findings was analyzed using the logistic regression model. RESULTS: Fibrosis was significantly and inversely correlated with muscle mass and appendicular skeletal muscle mass and significantly and positively correlated with fat mass, fat mass/height squared, visceral fat area, and waist-hip ratio (P < 0.05). After adjustment for sex, blood chemistry measurements, and body composition indices, fibrosis remained associated with appendicular skeletal muscle mass, fat mass, fat mass/height squared, and visceral fat area (P < 0.05). Non-alcoholic fatty liver disease activity score ≥ 5 significantly correlated with fat mass and fat mass/height squared in a univariate but not multivariate analysis. CONCLUSIONS: Fibrosis in non-alcoholic fatty liver disease, an indicator of unfavorable long-term outcomes, is associated with more indices of fat mass than of those of muscle mass. Hence, fat mass should be controlled to prevent non-alcoholic fatty liver disease progression.

File： BMC Gastroenterol 2021 Body composition and histology of NAFLD.pdf

DOI： 10.1186/s12876-021-01748-y

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INTRODUCTION: Fatty liver disease (FLD) is a surrogate condition for glucose intolerance development. FLD may involve normal or abnormal liver enzyme levels. Whether FLD is a risk factor for glucose intolerance, regardless of liver enzyme levels, remains unknown. We assessed relationships between the development of impaired fasting glucose (IFG) and FLD, liver enzyme abnormalities, and alcohol consumption. MATERIALS AND METHODS: We retrospectively evaluated 8,664 participants with more than two annual health check-ups. Participants were classified according to sex, alcohol consumption, alanine aminotransferase (ALT) levels, and fatty liver status. RESULTS: In univariate analyses, IFG onset among men was related to normal or high ALT levels with FLD in the nonalcoholic and alcoholic groups (P-trend < 0.01). In multivariate analyses, IFG onset among nonalcoholic men was associated with normal or high ALT levels with FLD, independent of potential confounding factors (P-trend < 0.01). However, IFG onset was non-independently associated with any condition among alcoholic men. In univariate analyses, IFG onset among women was related to normal or high ALT levels with FLD in the nonalcoholic group (P-trend < 0.01) and high ALT levels with FLD in the alcoholic group (P-trend < 0.05). In multivariate analyses, IFG onset was independently associated with only normal ALT levels in nonalcoholic FLD women. CONCLUSIONS: Among nonalcoholic men and women, FLD was a risk factor for IFG onset, including normal ALT concentrations. Care is needed for individuals with nonalcoholic FLD, regardless of liver injury, possibly helping reduce glucose intolerance risk.

File： J Diabetes Investig 2021 NAFLD is a risk factor for glucose intolerance onset in men.pdf

DOI： 10.1111/jdi.13548

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Digital clubbing has been regarded as an important sign in medicine. A 33-year-old woman with no history of hepatic, pulmonary, or malignant disease was referred to our hospital. She had been taking lubiprostone every day for three years for constipation. Clubbing in her upper and lower limb digits began gradually about two years ago. The results of laboratory investigations were almost normal. We suspected the clubbed digits were a side effect of lubiprostone and confirmed that the levels of urinary prostaglandin E2 (PGE2), which can cause clubbed digits, were elevated. Thus, we instructed the woman to stop taking lubiprostone and monitored this lab value. However, the value continued to rise over 2 months to 41.9 μg/g Cr. During that time, she had been taking sennoside A B calcium instead of lubiprostone for constipation. Since sennoside A B calcium also has the effect of increasing PGE2, we ordered the discontinuation. Her urinary PGE2 to creatinine level normalized, and the clubbing improved after the discontinuation of these two medications.

File： Intern Med 2021 Clubbed Digits by Lubiprostone.pdf

DOI： 10.2169/internalmedicine.6104-20

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A 62-year-old woman presented with a dry cough lasting 18 months. She had previously been examined by multiple doctors, but no abnormalities were observed. Several medications such as rabeprazole and inhaled corticosteroids were administered as test treatments without any improvement. Therefore, the possibility of biological disease, including acid reflux, had been mistakenly ruled out. We examined the sputum gram stain. The result showed phagocyted normal bacterial flora, suggesting aspiration. Laryngoscopy revealed edema of the arytenoid cartilage. The patient was finally diagnosed with laryngopharyngeal reflux and silent aspiration. This case suggested that the ineffectiveness of proton-pump inhibitors cannot always exclude the presence of reflux disease and the usefulness of gram stain examination to detect silent aspiration.

File： J Gen Fam Med 2020 Laryngopharyngeal reflux-associated chronic cough.pdf

DOI： 10.1002/jgf2.348

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PURPOSE: Body mass index (BMI) is a simple index of weight-to-height that is commonly used to classify people as underweight, overweight or obesity, and high BMI has been clearly linked to increased risk of illness in adults. However, few studies have examined the significance of upper normal weight as a risk factor for the development of chronic kidney disease (CKD) in the general Japanese population. METHODS: We conducted a prospective cohort study designed as part of the Nomura study. We recruited a random sample of 421 men aged 67 ± 10 (mean ± standard deviation; range 24-95) years and 565 women aged 68 ± 9 (22-84) years during their annual health examination in a single community. We examined the relationship between quartiles of baseline BMI and renal dysfunction after a 3-year evaluation based on estimated glomerular filtration rate (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations modified by the Japanese coefficient. CKD was defined as having dipstick-positive proteinuria (≥ 1 +) or a low eGFR (< 60 mL/min/1.73 m2). RESULTS: Of the 986 participants, a total of 134 (13.6%) participants, including 72 (17.1%) men and 62 (11.0%) women, received a new diagnosis of CKD during the study period, and 25 (9.7%), 19 (8.0%), 47 (19.0%), and 43 (17.8%) diagnoses were received in the BMI-1 (BMI, < 20.7 kg/m2), BMI-2 (BMI, 20.7 to 22.5 kg/m2), BMI-3 (BMI, 22.6 to 24.4 kg/m2), and BMI-4 (BMI ≥ 24.5 kg/m2) groups, respectively. Using BMI-2 as the reference group, the non-adjusted odds ratio (OR) (95% confidence interval) for CKD was 2.70 (1.53-4.75) for BMI-3 and 2.49 (1.40-4.42) for BMI-4, and the multivariable-adjusted OR was 2.52 (1.40-4.56) for BMI-3 and 2.30 (1.26-4.22) for BMI-4. CONCLUSIONS: Increased BMI from upper normal weight is strongly associated with the development of CKD in community-dwelling persons.

DOI： 10.1007/s11255-020-02501-2

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Language：English   Publisher：INT JOURNAL MEDICAL EDUCATION-IJML  

File： Int J Med Educ 2020 Effect of short-term exposure to rural interprofessional work on medical students.pdf

DOI： 10.5116/ijme.5eb6.81cb

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BACKGROUND: Chronic kidney disease (CKD) is a major public health concern. Baseline serum uric acid (SUA) levels were independently associated with incident renal dysfunction, but whether baseline and changes in SUA produce an interactive effect on renal dysfunction remains unclear. METHODS: The subjects comprised 460 men aged 68 ± 10 (mean ± standard deviation) years and 635 women aged 68 ± 9 years from a rural village. We have found participants who underwent a similar examination 3 years later, and analyzed the relationship between baseline SUA, changes in SUA, and a 3-year follow-up renal function evaluated by estimated glomerular filtration rate (eGFR). RESULTS: A total of 93 (20.2%) men and 76 (12.0%) women had hyperuricemia (men: SUA ≥ 7.0 mg/dL and women: SUA ≥ 6.0 mg/dL) at baseline. Multiple regression analysis using changes in eGFR as objective variable, adjusted for risk factors as explanatory variables, showed that the baseline SUA and changes in SUA were linearly associated with changes in eGFR (β = －0.115, P < .001 and β = －0.431, P < .001, respectively). In both normal SUA group and hyperuricemia group, changes in SUA significantly associated with changes in eGFR (β = －0.473, P < .001 and β = －0.197, P = .009, respectively). Participants with increased SUA from normal to hyperuricemia group had greater eGFR decline over the follow-up period, and their multivariate-adjusted 3-year follow-up eGFR was significantly lower than in other groups (P < .001). CONCLUSION: Our data demonstrated that baseline and longitudinal changes in SUA were independently and interactively associated with the renal function decline among community-dwelling persons.

File： J Clin Lab Anal 2019 Interactive association of baseline and changes in UA on renal dysfunction.pdf

DOI： 10.1002/jcla.23166

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BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been widely evaluated as a biomarker in various medical and surgical prognoses, but its usefulness in diabetic kidney disease is not yet known. METHODS: This prospective observational study included outpatients, comprised of 184 men aged 73 ± 11 (mean ± standard deviation) years and 174 women aged 76 ± 10 years at baseline, from a rural hospital. We examined the relationship between baseline NLR calculated by analyzing the differential leukocyte counts in the complete blood count and the 2-year estimated glomerular filtration rate (eGFR) decline rate (i.e. 2-year eGFR-baseline eGFR) ∗100/baseline eGFR. Rapid eGFR decline rate was defined as a value < -25%. RESULTS: Multiple linear regression analysis using rapid eGFR decline rates as objective variables, adjusted for confounding factors as explanatory variables, showed that NLR (β = 0.138, p = 0.007) as well as presence of antidyslipidemic medication, hemoglobinA1c, and urinary albumin excretion stage were significantly and independently associated with a rapid eGFR decline rate. The multivariate-adjusted odds ratios (95% confidence interval) of the 2nd and 3rd tertiles of baseline NLR for rapid eGFR decline rate were 3.62 (0.70-18.7) and 8.03 (1.54-41.9), respectively. Multivariate-adjusted mean eGFR (95% confidence interval) values after 2 years categorized by tertile of baseline NLR were: 1st, 63.9 (61.8-66.1); 2nd, 60.8 (58.7-62.9); and 3rd, 58.9 (56.8-61.0). CONCLUSIONS: These results suggest that baseline NLR might be a useful biomarker for renal function decline in outpatients with diabetes.

DOI： 10.1016/j.dsx.2020.04.029

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BACKGROUND: Endoscopic balloon dilation and/or plastic stent placement has been a standard method for treating biliary strictures complicated post living donor liver transplantation (LDLT). The strictures may be refractory to endoscopic treatment and require long-term stent placement. However, consensus on the optimal period of the stent indwelling and usefulness of the inside stent does not exist. METHODS: We evaluated the long-term efficacy of stent treatment in patients with biliary stricture post LDLT. In addition, we compared the stent patency between inside stent and conventional outside stent. RESULTS: A total of 98 ERC sessions (median 6: range 1-14) performed on 16 patients receiving endoscopic treatment for biliary strictures post LDLT with duct-to-duct biliary reconstruction were analyzed. Biliary strictures successfully treated in 14 patients (88%) included 7 patients (44%) showing improvement of biliary strictures with repeated endoscopic stent placement. Stent replacement was carried out every 6 to 12 months for the remainder 7 patients (44%). Biliary stents were placed in 87 sessions (77 inside sessions and 10 outside sessions). Stent migration occurred 13 times (16%) and none of the inside stent sessions and the outside stent sessions, respectively. Median patency of inside stent and outside stent were 222 days (range; 8-1736) and 99 days (range; 7-356), respectively. The stent occlusion was significantly less in inside stent than in outside stent (p < 0.001). Stone formation was observed in 14 (18%) of the inside stent and 3 (30%) of the outside stent. Biliary stones were small and successfully removed endoscopically. CONCLUSIONS: The endoscopic treatment using inside stent was useful in the management of biliary strictures after LDLT.

File： BMC Gastroenterology 2020 Koizumi_et_al.pdf

DOI： 10.1186/s12876-020-01226-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is an important independent cardiovascular risk factor. However, Lp(a) levels are lower in patients with chronic liver disease than in healthy subjects. Furthermore, Lp(a) levels decrease as residual liver function declines. Although non-alcoholic fatty liver disease (NAFLD), especially advanced non-alcoholic steatohepatitis (NASH), increases the risk of cardiovascular diseases, the relationship between serum Lp(a) level and NASH is unknown. Thus, we examined the relationship between serum Lp(a) levels and biopsy-proved NAFLD and clarified the significance of Lp(a) measurements for cardiovascular disease screening in patients with NAFLD. METHODS: A total of 176 patients with NAFLD were enrolled. Comprehensive blood chemistry tests and histological examinations of liver samples were conducted. The relationship between serum Lp(a) levels and NAFLD was analyzed. RESULTS: Serum Lp(a) levels in advanced fibrosis (stage 3-4) were lower than those in non-advanced fibrosis (stage 0-2) (p < 0.05). After adjustment for age, sex, body mass index, alanine aminotransferase (ALT), creatinine (Cre), HbA1c level, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the use of lipid-lowering agents, the significant inverse association between advanced fibrosis and serum Lp(a) levels remained (p < 0.01). Although the Lp(a) level was inversely associated with an NAFLD Activity Score (NAS) of 5-8, there was no significant association between Lp(a) levels and NAS adjusted for age, sex, body mass index, ALT, Cre, HbA1c level, HDL-C, LDL-C, TG, and the use of lipid-lowering agents. CONCLUSIONS: Advanced NASH is associated with low serum Lp(a) levels; therefore, Lp(a) levels may not be useful in evaluating cardiovascular risk.

DOI： 10.1016/j.atherosclerosis.2020.02.026

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective The long-term effect of the ABO blood type on the clinical course of patients with pancreatic cancer (PC) is inconclusive. This study aimed to determine whether or not the ABO blood type influences the long-term outcomes of PC in Japanese patients. Methods The medical records of Japanese patients with PC were reviewed. Data, including the age, sex, and outcomes, from the Ehime Pancreato-Cholangiology Study Group were analyzed. Results The mean age of the 406 patients was 71.0±10.5 years, and 220 (54.2%) were men. A total of 44.6%, 20.7%, 22.4%, and 12.3% had blood type A, B, O, and AB, respectively. The median survival time (MST) of patients with A alleles was shorter than that of patients with non-A alleles (p=0.048), especially among those who underwent resection (p=0.031). In contrast, no marked difference in the MST was noted among those who underwent chemotherapy and palliative care. Finally, a multivariate analysis confirmed A alleles as an independent factor associated with the long-term outcome of PC (p<0.05 in 2 different models). Conclusion The ABO blood type influenced the long-term outcomes of Japanese patients with PC, presumably due to its impact on disease onset and tumor behavior.

File： Intern Med 2020 Pancreatic cancer & ABO blood type.pdf

DOI： 10.2169/internalmedicine.3748-19

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Background: The incidence of hypertension is increasing worldwide and obesity is one of the most significant risk factors. Obesity can be defined by various anthropometric indices such as body mass index (BMI), waist-to-hip ratio (WHpR), and waist-to-height ratio (WHtR). This study examined a range of anthropometric indices and their relationships with hypertension. Methods: This study included 768 men aged 70 ± 10 years and 959 women aged 70 ± 8 years from a rural village. The relationship between anthropometric indices (BMI, WHpR, and WHtR) and hypertension was examined using cross-sectional (baseline, N = 1727) and cohort data (follow-up, N = 419). Receiver operating characteristic (ROC) analysis was used to determine the predictive ability of obesity indices for hypertension in both genders. Logistic regression models were used to evaluate WHtR as a significant predictor of hypertension. Results: In the cross-sectional study, WHtR, BMI, and WHpR showed significant predictive abilities for hypertension in both genders, with WHtR showing the strongest predictive ability. Also, in the cohort study, WHtR showed a significant predictive ability for incident hypertension in both genders, and, for women, BMI as well as WHtR had also predictive ability. In the cross-sectional study, the optimal WHtR cutoff values were 0.53 (sensitivity, 44.3%; specificity, 80.2%) for men and 0.54 (sensitivity, 60.9%; specificity, 68.6%) for women. In the cohort study, the optimal WHtR values were 0.47 (sensitivity, 85.4%; specificity, 39.8%) for men and 0.51 (sensitivity, 66.7%; specificity, 58.2%) for women. Conclusions: The results suggest that WHtR is a useful screening tool for hypertension among Japanese middle-aged and elderly community-dwelling individuals.

File： Clin Hypertens 2020 Waist-to-height ratio in screening incident hypertension.pdf

DOI： 10.1186/s40885-020-00142-2

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Background: The risk associated with serum uric acid (SUA) levels when within the normal range is unknown. This study aims to examine whether SUA within the normal range is a predictor of hypertension. Methods: The subjects comprised 704 men aged 71 ± 9 (mean ± standard deviation) years and 946 women aged 70 ± 8 years recruited for a survey at the community based annual medical check-up. The main outcome was the presence of hypertension (antihypertensive medication and/or having SBP ≥140 mmHg and/or DBP ≥90 mmHg). Results: At baseline, 467 (66.3%) men and 608 (64.3%) women had hypertension. Comparing to lowest quartile in women (SUA-1, uric acid < 4.1 mg/dL), the unadjusted odds ratios (ORs) [95% confidence interval (CI)] for hypertension of SUA-2 (4.1 to 4.7 mg/dL), SUA-3 (4.8 to 5.4 mg/dL), and SUA-4 (≥5.5 mg/dL) were 1.11 (0.78-1.59), 1.75 (1.20-2.55), and 1.89 (1.30-2.77), respectively. These associations were apparent even after adjustments for age, but ORs were attenuated after adjusting for all confounding factors. During a follow-up of 3.0 years, there were 35 (24.0%) hypertension cases in men and 51 (20.8%) in women. In women only, a significant association between increased SUA categories and incidence of hypertension was observed, and the multivariate-ORs (95% (CI) for incident hypertension of SUA-3 (4.5-5.2 mg/dL) and SUA-4 (≥5.3 mg/dL) were 2.23 (0.81-6.11) and 3.84 (1.36-10.8), respectively. Conclusions: These results suggest that baseline SUA within the normal range could be an important predictor for incidence of hypertension in Japanese community-dwelling elderly women.

File： Clin Hypertens 2020 High UA within the normal range is a predictor of hypertension.pdf

DOI： 10.1186/s40885-020-00155-x

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PURPOSE: Metabolic syndrome (MetS) is increasing worldwide with the continuous increase in obesity prevalence. Chronic kidney disease (CKD) is also a major public health problem, but there is controversy over whether baseline MetS is a predictor of decreased renal function among Japanese community-dwelling middle-aged and elderly Japanese. METHODS: We conducted a prospective cohort study designed as part of the Nomura study. We recruited a random sample of 410 men aged 68 ± 8 (mean ± standard deviation; range, 50-95) years and 549 women aged 69 ± 7 (50-84) years during their annual health examination in a single community. We examined the relationship between baseline MetS and renal dysfunction after a 3-year evaluation based on estimated glomerular filtration rate (eGFRCKDEPI) using the CKD-EPI equations modified by the Japan coefficient. CKD was defined as dipstick-positive proteinuria (> or = 1 +) or a low eGFRCKDEPI (< 60 mL/min/1.73 m2). RESULTS: Of the 959 participants, 413 (43.1%) had MetS at baseline. Annual eGFR decline rate was significantly greater in those with MetS than in those without MetS, and the annual eGFR decline rate of < - 1.2 mL/min/1.73 m2/year increased significantly in relation to presence of baseline MetS, especially low HDL cholesterol (HDL-C). Moreover, the incidence rate of CKD after 3 years was 13.5% and increased significantly in relation to presence of baseline MetS, especially its components such as elevated HbA1c. The multivariate-adjusted odd ratio (OR) for CKD in participants with MetS versus those without MetS was 1.55 (0.99-2.43). The multivariate-adjusted ORs for rapid annual eGFR decline rate were significantly high in patients aged ≥ 65 years and presence of medication, regardless of gender and eGFR value. CONCLUSIONS: Low HDL-C and elevated HbA1c levels correlated significantly with eGFR decline in a short period of 3 years. MetS also showed a significant association with eGFR decline. This study suggests the importance of low HDL-C and elevated HbA1c in the effect of MetS on eGFR decline rather than obesity among Japanese community-dwelling middle-aged and elderly Japanese without CKD.

DOI： 10.1007/s11255-019-02320-0

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File： Euroasian J Hepatogastroenterol. 2019 Familial Pancreatic Cancer.pdf

DOI： 10.5005/jp-journals-10018-1296

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Background: Serum uric acid (SUA) has been shown to be a predictor of renal disease progression in most but not all studies. This study aims to test whether renal function-normalized SUA {i.e, SUA/creatinine (Cr) ratio} is a predictor of decreased renal function among diabetic patients.Methods: The subjects comprised 185 men aged 72 +/- 11 (mean +/- standard deviation) years and 175 women aged 77 +/- 10 years from a rural hospital. We examined the relationship between SUA/creatinine (Cr) ratio and renal function evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation.Results: Annual eGFR decline rate was significantly increased with increased tertile of baseline SUA/Cr ratio (p = 0.011), and prevalence of the rapid progression types (>= 3.0 ml/min/1.73 m(2)/year) was significantly higher in the second and third tertile (>= 7,21) of baseline SUA/Cr ratio than the first tertile (<5.86) (p = 0.032). Pearson's correlation coefficient showed that baseline SUA/Cr ratio (r = 0.136, p = 0.012) as well as systolic blood pressure (SBP) and SUA were significantly correlated with annual eGFR decline rate. Multiple regression analysis using annual eGFR decline rate as an objective variable, adjusted for confounding factors as explanatory variables, showed that baseline SUA/Cr ratio (beta = 0.334, p < 0.001) as well as gender and SBP were significantly and independently associated with annual eGFR decline rate. The multivariate-adjusted odds ratios (ORs) (95% confidence interval) of the baseline tertile of the SUA/Cr ratio for rapid progression of annual eGFR decline rate were 1.0, 3.15 (1.66-5.95) and 3.19 (1.57-6.51), respectively.Conclusion: Our data demonstrated that baseline SUA/Cr ratio was independently and significantly associated with future renal function decline among diabetic patients. (C) 2019 Published by Elsevier Ltd on behalf of Diabetes India.

DOI： 10.1016/j.dsx.2019.04.023

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Background: Metabolic syndrome (MetS) is related to the increased risk of major cardiovascular diseases (CVD). The link between high serum total bilirubin (TBL) is cross-sectionally related to MetS and its components. However, whether serum TBL predicts incidence of MetS and its components remains inconclusive.Methods: The present study included 893 women aged 70 +/- 9 years from a rural village. We examined the relationship between serum TBL and MetS based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report in a cross-sectional (N 1/4 893) and cohort (N 1/4 288) data.Results: In the cross-sectional study, serum TBL (beta = 0.536, p < 0.001) as well as age, alcohol consumption, exercise habits, history of CVD, SUA, GGT, and ALT was significantly and dependently associated with number of MetS components, but in the cohort study serum TBL was not associated with number of MetS components. Compared with the 1st tertile of serum TBL (0.20-0.55 mg/dL), multivariate-adjusted odds ratio (95% confidence interval) for the 2nd - 3rd tertiles of serum TBL (0.54-2.00mg/dL) was 0.70 (0.51-0.95) in the cross-sectional study and 0.41 (0.21-0.81) in the cohort study.Conclusions: Our data demonstrated an independently negative association between serum TBL and MetS in Japanese community-dwelling women. (c) 2019 Diabetes India. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dsx.2019.02.009

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

BACKGROUND: Metabolic syndrome (MetS) is related to the increased risk of major cardiovascular disease. The link between high serum uric acid (SUA) and creatinine (Cr) levels is causally related to MetS and its components. However, whether renal function-normalized SUA [i.e., SUA to Cr ratio (SUA/Cr)] predicts incident MetS and its components remains inconclusive. MATERIALS AND METHODS: We conducted a prospective cohort study designed as part of the Nomura study. The subjects comprised 447 men ages 68 ± 10 years and 625 women ages 68 ± 9 years from a rural village, and 155 (34.7%) men and 310 women (49.6%) had MetS at baseline. We found participants who underwent a similar examination 3 years later and analyzed the relationship between baseline SUA/Cr and incident MetS defined according to the modified criteria of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III). RESULTS: One hundred forty-nine (33.3%) men and 286 (45.8%) women had MetS after a 3-year follow-up. Multiple linear regression analysis was performed to evaluate the contribution of possible confounding factors for MetS. In women only, baseline SUA/Cr, as well as baseline number of MetS and age, was significantly and independently associated with the number of MetS components at follow-up. The multivariable-adjusted odds ratios (95% confidence interval) for incident MetS across three quartiles of baseline SUA/Cr (1st-2nd, 3rd, and 4th) were 1.00, 1.62 (0.97-2.69), and 2.07 (1.20-3.56), respectively. Furthermore, when subjects were stratified by age, estimated glomerular filtration rate (eGFR), and presence of baseline MetS, baseline SUA/Cr was also a significant and independent determinant for incident MetS in women with age ≥60 years, eGFR ≥70 mL/min/1.73 m2, and presence of baseline MetS. CONCLUSIONS: Baseline SUA/Cr was significantly associated with incident MetS among community-dwelling women.

DOI： 10.1089/met.2018.0055

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PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) was widely studied as a prognostic marker in various medical and surgical specialties, but its significance in diabetic kidney disease is not yet established. METHODS: The subjects comprised 199 men aged 73 ± 11 (mean ± standard deviation) years and 187 women aged 77 ± 10 years from a rural hospital. We examined the relationship between NLR calculated by analyzing differential leukocyte count in complete blood picture and renal function evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation and urinary albumin excretion (UAE). RESULTS: NLR was negatively related to eGFR and positively related to UAE. Multiple linear regression analysis using eGFR and UAE as an objective variables, adjusted for confounding factors as explanatory variables showed that NLR (β = - 0.101, p = 0.009) as well as age, body mass index, serum uric acid, and presence of uric acid lowing medication were significantly and independently associated with eGFR, and NLR (β = 0.113, p = 0.031) as well as prevalence of cardiovascular disease, systolic blood pressure, presence of antihypertensive medication, presence of antilipidemic medication, and eGFR were significantly and independently associated with UAE. The multivariate-adjusted odds ratios (95% confidence interval) of NLR for stage 3a (eGFR < 60 mL/min/1.73 m2), stage 3b (eGFR < 45 mL/min/1.73 m2), and microalbuminuria (UAE ≥ 30 mg/g Cr) were 1.90 (1.02-3.56) and 2.99 (1.28-6.98), and 1.77 (1.04-3.01), respectively. Next, to examine the consistency of the observed association between NLR and eGFR, we performed subgroup analyses. There was a significant interaction (p = 0.006) only between the two groups regarding antihypertensive medication (absence: β = - 0.272, p < 0.001 and presence: β = - 0.029, p = 0.564). CONCLUSIONS: Our data suggested that NLR might be important as a potential factor for evaluating patients with a higher degree of albuminuria among diabetic outpatients.

DOI： 10.1007/s11255-018-02065-2

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Skeletal muscle is the main target organ for glycemic control, and the serum creatinine level is a convenient indicator of the skeletal muscle mass. This study aimed to assess the potential relationship between the serum creatinine level and the onset of impaired fasting glucose (IFG). Methods In this large, community-based, retrospective longitudinal cohort study, we examined the records of 7,905 Japanese participants (3,863 men, 4,042 women) of 18-80 years of age who underwent annual health checkups at a single center between April 2003 and August 2013. After applying the exclusion criteria, 6,490 participants were reviewed to identify those with the onset of IFG, defined as a fasting plasma glucose ≥6.11 mM. Among the participants, 278 met the criterion for the onset of IFG during the observation period. Results Creatinine levels were higher in male subjects who exercised periodically and were exercise conscious in comparison to those who did not exercise, and were higher in female subjects who exercised periodically in comparison to female subjects who did not exercise and who were not exercise conscious. Additionally, the serum creatinine level was negatively associated with the onset of IFG in both men [adjusted hazard ratio, 0.98; 95% confidence interval (CI), 0.96-0.99; p=0.008] and women (adjusted hazard ratio, 0.94; 95% CI, 0.91-0.97; p<0.001) after adjustment for variables previously reported to be risk factors for the onset of glucose intolerance and factors associated with chronic kidney disease. Conclusion A low creatinine level might be associated with the onset of IFG. Moreover, the fact that serum creatinine levels increase with exercise might demonstrate the importance of exercise therapy.

File： Intern Med 2019 Creatinine level and onset of impaired fasting glucose.pdf

DOI： 10.2169/internalmedicine.0760-18

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

We experienced a rare case of acute pancreatitis caused by Candida infection. A 52-year-old man was admitted to our hospital with a chief complaint of abdominal pain. Blood tests revealed high amylase and hepatobiliary enzyme abnormalities, and the patient was hospitalized for acute pancreatitis. Abdominal computed tomography showed a 15-mm space-occupying lesion at the parenchyma of the pancreatic head. Endoscopic retrograde cholangiopancreatography was performed after conservative treatment, which revealed a cystic lesion with a suspected solid component inside involving both lower bile duct and pancreatic duct. Cytology of collected bile and pancreatic juice revealed innumerous hyphae and spores morphologically consistent with Candida spp., as did endoscopic ultrasound-guided fine needle aspiration biopsy of the tumor site. Empiric therapy with oral fluconazole resulted in reduction of the space-occupying lesion 3 months after discharge. However, acute pancreatitis recurred about 1 year and 6 months after discharge. After conservative treatment was carried out again, the same lesion was fenestrated by endoscopic sphincteroplasty, and its internal solid components were resected using a basket catheter. Pathological analysis confirmed the presence of fungus balls and degenerated substances. Candida Albicans was identified by fungal culture examination. After the excretion of the fungus balls, pancreatitis did not recur thereafter during outpatient follow-up.

File： Clin J Gastroenterol 2018 Acute pancreatitis caused by Candida.pdf

DOI： 10.1007/s12328-018-0896-7

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Intraductal papillary mucinous neoplasms (IPMNs) are cystic neoplasms with the potential for progression to pancreatic cancer. Accurate prediction of the malignant potential is challenging and a proper treatment strategy has not been well established. Preoperative neutrophil-to-lymphocyte ratio (NLR) is a biomarker of the malignant potential in patients with several types of malignancy. We explored malignant potential in patients with IPMN. The present study included 56 patients aged of 73 ± 9 years (mean ± standard deviation) who underwent curative resection for IPMN from 1996 to 2017. We analyzed the relationship between the characteristics including NLR and malignant component for predicting pathological results. The nonmalignant IPMN group (N = 21) included patients with low-grade dysplasia (LGD) and intermediate-grade dysplasia (IGD), and the malignant IPMN group (N = 35) included patients with high-grade dysplasia (HGD) and invasive carcinoma. In a univariate analysis, NLR ⩾ 2.2 (P = .001), prognostic nutritional index (PNI) < 45 (P = .016), CA 19-9 > 37 U/mL (P = .039), and cystic diameter ⩾ 30 mm (P = .010), and mural nodule (P = .010) were significantly different between the malignant IPMN and the nonmalignant IPMN groups. Multivariate analysis showed that high NLR (⩾2.2) (odds ratio 9.79; 95% confidence interval: 2.06-45.6), cystic diameter ⩾ 30 mm (4.65; 1.14-18.9), and mural nodule (4.91; 1.20-20.1) were independently predictive of malignant IPMN. These results suggest that preoperative NLR is a useful predictive biomarker for evaluating malignant potential in patients with IPMN.1.

File： Biomarker Insights 2019 NLR is a predictive factor of malignant potential for IPMN.pdf

DOI： 10.1177/1177271919851505

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This study examined a range of anthropometric indices and their relationships with metabolic syndrome (MetS). Despite recommendations that central obesity assessment should be employed as a marker of metabolic health, there is no consensus regarding the protocol for measurement. The present study included 720 men aged 71 ± 8 years and 919 women aged 71 ± 7 years from a rural village. We examined the relationship between anthropometric indices {e.g., body mass index (BMI), waist-to-height ratio (WHtR), waist-to-hip ratio (WHpR)}, and MetS based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report in a cross-sectional (N = 1,639) and cohort (N = 377) data. A receiver operating curve (ROC) analysis was performed to determine the optimal cut-off value and best discriminatory value of each of these anthropometric indices to predict MetS. In the cross-sectional study, WHtR as well as BMI and WHpR showed significantly predictive abilities for MetS in both genders; and WHtR showed the strongest predictive ability for the presence of MetS. Also in the cohort study, WHtR as well as BMI and WHpR showed significantly predictive abilities for incident MetS in both genders, and in men WHtR showed the strongest predictive ability for incident MetS, but in women BMI showed the strongest predictive ability. In the cross-sectional study, the optimal WHtR cutoff values were 0.52 (sensitivity, 71.0%; specificity, 77.9%) for men and 0.53 (sensitivity, 79.8%; specificity, 75.7%) for women. In the cohort study, the optimal WHtR values were 0.50 (sensitivity, 60.7%; specificity, 73.2%) for men and 0.50 (sensitivity, 75.0%; specificity, 56.1%) for women. Increased WHtR was significantly and independently associated with prevalence of MetS in both genders. These results suggest that WHtR is a useful screening tool for determining metabolic risk in Japanese elderly community dwelling individuals.

File： PLoS One 2019 Waist-to-height ratio in screening incident metabolic syndrome.pdf

DOI： 10.1371/journal.pone.0216069

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Objective Low urine pH is associated with several metabolic diseases, such as dyslipidemia, diabetes, and metabolic syndrome. However, the association between low urine pH and non-alcoholic fatty liver disease (NAFLD) remains unknown. Therefore, we conducted a community-based cross-sectional study to investigate this association. Methods Between April 2013 and March 2014, the records of 4,945 Japanese subjects who had undergone annual health checkups were reviewed to identify subjects who met the diagnostic criteria for NAFLD. Patients Based on urine pH, the participants were classified into four groups; a low urine pH was defined as ≤5.5. Of the 3,411 subjects who qualified for enrollment, 1,028 met the diagnostic criteria for NAFLD. Results The prevalence of NAFLD was significantly increased with decreasing urine pH in both men and women (p<0.01 and p=0.02, respectively). A multivariate analysis, including adjustments for age, metabolic markers, and the renal function, showed a significant association between low urine pH and NAFLD in men and women (odds ratio, 1.37; 95% confidence interval, 1.01-1.85, p=0.04 and odds ratio, 1.73; 95% confidence interval, 1.15-2.62, p<0.01, respectively). Conclusion Our study indicates that NAFLD is associated with a low urine pH in both sexes, findings that might help clinicians identify patients at high risk for NAFLD.

File： Intern Med 2018 Urine pH and NAFLD.pdf

DOI： 10.2169/internalmedicine.0167-17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AIMS/INTRODUCTION: The association between urine pH and abnormal glucose tolerance in men and women is unclear; therefore, we carried out a community-based, cross-sectional study to investigate sex-specific associations between these values, possible indicators of prediabetes and type 2 diabetes. MATERIALS AND METHODS: We enrolled 4,945 Japanese individuals (2,490 men and 2,455 women), who had undergone annual health checkups. To investigate the relationship between low urine pH and abnormal glucose tolerance, participants were divided into three groups based on their fasting plasma glucose levels (<6.11 mmol/L, 6.11-6.99 mmol/L and ≥6.99 mmol/L), and three groups based on their glycated hemoglobin levels (≤44.3 mmol/mol, 44.3-47.5 mmol/mol and ≥47.5 mmol/mol). To examine the effects of urine pH on abnormal glucose tolerance, participants were categorized into five groups based on their urine pH (5.0, 5.5, 6.0, 6.5 and ≥7.0). RESULTS: Multivariate analysis adjusted for age, body mass index, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, uric acid, creatinine and antidiabetic agent use showed significant associations between low urine pH and both high fasting plasma glucose and high glycated hemoglobin levels (P for trend = 0.0260, 0.0075) in men. Furthermore, after the same adjustments, prevalence rates of abnormal glucose tolerance (≥6.11 mmol/L and ≥6.99 mmol/L), increased significantly as urine pH levels decreased (P for trend = 0.0483, 0.0181) in men. In women, a similar trend was observed without a significant difference. CONCLUSIONS: Low urine pH is significantly associated with abnormal glucose tolerance; therefore, measuring urine pH might prove useful for identifying patients at high risk for diabetes.

File： J Diabetes Investig. 2018 Urine pH and abnormal glucose tolerance.pdf

DOI： 10.1111/jdi.12777

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Introduction: Higher glycated hemoglobin (Hb) (HbA1c) is significantly associated with an increased risk of cardiovascular disease (CVD). Serum uric acid (SUA) levels are associated with glucose intolerance and type 2 diabetes. Whether gender-specific differences regarding the relationship between SUA levels and HbA1c exist is unknown. Aim: We recruited 1636 (men, 696 aged of 70 ± 10 years
women, 940 aged of 70 ± 9 years) participants and enrolled in the study during their annual health examination from a single community. We investigated the association between SUA levels and HbA1c within each gender. Results: Multiple linear regression analysis showed that in men, SUA (β = −0.091, p = 0.014) with prevalence of antidiabetic medication (β = 0.428, p &lt
 0.001) and eGFR (β = 0.112, p = 0.016) were significantly and negatively associated with HbA1c, and in women, SUA (β = 0.101, p = 0.002) with prevalence of antidiabetic medication (β = 0.458, p &lt
 0.001) were significantly and positively associated with HbA1c. Moreover, the interaction between gender and SUA (β = 0.445, p &lt
 0.001) as well as gender (β = −0.465, p &lt
 0.001), prevalence of antidiabetic medication (β = 0.444, p &lt
 0.001), eGFRCKDEPI (β = 0.074, p = 0.014), and SUA (β = −0.356, p &lt
 0.001) was a significant and independent determinant of HbA1c. A significant interactive effect of gender and SUA on determinants of HbA1c was noted in patients not on antidiabetic medications, regardless of age, HbA1c, and renal function. Conclusions: The interaction between gender and SUA was associated with HbA1c independent of other metabolic factors in community-dwelling persons.

DOI： 10.1007/s40618-017-0760-5

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer International Publishing  

Introduction: Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. In women, increased serum uric acid (SUA) levels are associated with MetS and its components. However, whether baseline and changes in SUA predict incidence of MetS and its components remains unclear. Methods: The subjects comprised 407 women aged 71 ± 8 years from a rural village. We have identified participants who underwent a similar examination 11 years ago, and examined the relationship between baseline and changes in SUA, and MetS based on the modified criteria of the National Cholesterol Education Program’s Adult Treatment Panel (NCEP-ATP) III report. Results: Of these subjects, 83 (20.4%) women at baseline and 190 (46.7%) women at follow-up had MetS. Multiple linear regression analysis was performed to evaluate the contribution of each confounding factor for MetS
both baseline and changes in SUA as well as history of cardiovascular disease, low-density lipoprotein cholesterol, and estimated glomerular filtration ratio (eGFR) were independently and significantly associated with the number of MetS components during an 11-year follow-up. The adjusted odds ratios (ORs) (95% confidence interval) for incident MetS across tertiles of baseline SUA and changes in SUA were 1.00, 1.47 (0.82–2.65), and 3.11 (1.66–5.83), and 1.00, 1.88 (1.03–3.40), and 2.49 (1.38–4.47), respectively. In addition, the combined effect between increased baseline and changes in SUA was also a significant and independent determinant for the accumulation of MetS components (F = 20.29, p &lt
0.001). The ORs for incident MetS were significant only in subjects with age ≥ 55 years, decline in eGFR, and no baseline MetS. Conclusions: These results suggested that combined assessment of baseline and changes in SUA levels provides increased information for incident MetS, independent of other confounding factors in community-dwelling women.

DOI： 10.1007/s40618-017-0822-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is often associated with type 1 autoimmune pancreatitis, and the frequency of isolated IgG4-SC seems to be quite low, making the diagnosis of isolated IgG4-SC challenging. A 63-year-old male was admitted to our hospital for frequent fever. Abdominal magnetic resonance cholangiopancreatography showed diffuse narrowing of the common bile duct and post-stenotic dilatation of the right posterior bile duct. Laboratory tests showed abnormalities in the levels of hepatobiliary enzymes and serum IgG4 levels. Endoscopic retrograde cholangiopancreatography showed diffuse narrowing of intrahepatic bile ducts and post-stenotic dilatation of the right posterior bile duct but no abnormalities in the pancreas. Intraductal ultrasonography showed symmetric circumferentially thickened walls of both narrowed and non-narrowed common bile ducts. Histologic examination of the common bile duct mucosa showed infiltration of IgG4-positive plasma cells. Laparoscopic observations showed discoloration with red lobular markings and multiple small depressed lesions. Liver histology showed mild cholangitis with infiltration of IgG4-positive plasma cells around the bile ducts. From these findings, the patient was diagnosed with isolated IgG4-SC. After treatment with a steroid, bile duct dilatations improved. Laparoscopy and intraductal ultrasonography were useful to diagnose isolated IgG4-SC.

File： Clin J Gastroenterol 2017 IgG4-SC.pdf

DOI： 10.1007/s12328-017-0787-3

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

We herein report a 55-year-old woman who presented with erythema and bilateral hilar lymphadenopathy 4 months prior to the detection of pancreatic lesions on an ultrasound. A skin biopsy showed evidence of sarcoidosis. The largest lesion in the tail of the pancreas was hypoechoic on endoscopic ultrasonography (EUS). The lesion was initially iso-enhanced on contrast enhanced-EUS (CE-EUS) but subsequently became hypoenhanced. The lesion revealed heterogeneous components of both soft and hard tissue on EUS elastography. She was ultimately diagnosed with pancreatic sarcoidosis based on the presence of noncaseating granulomas seen on pancreatic tissue retrieved through an EUS-guided fine needle aspiration biopsy.

File： Intern Med 2018 Pancreatic Sarcoidosis.pdf

DOI： 10.2169/internalmedicine.9084-17

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AUSTRALIAN RURAL HEALTH EDUC NETWORK  

Introduction: In Japan, the community medicine clerkship was introduced in order to foster positive attitudes towards rural practice and encourage rural recruitment The purpose of the present research was to elucidate self-efficacy for rural practice.Method: Medical students comprised 166 women aged 22 +/- 2 (mean +/- standard deviation) (range 19-34) years and 243 men aged 23 +/- 3 (range 18-41) years. The participants were from academic years 1-3 (60.9%) and 4-6 (39.1%). The authors conducted a cross-sectional survey to identify questionnaire items that measure self efficacy of intent for rural practice based on the portfolio of students who experienced community medicine clerkships.Results: Using factor analysis, a rural self-efficacy scale of four factors consisting of 15 items was identified. The factors extracted were work preferences, evaluation of rural practice, evaluation of rural living and personal character. The Cronbach's alpha coefficient for the questionnaire was 0.849, acceptable for newly developed scales. The scree plot indicated for factors explained 45.8% of the total variance. The average score was 43 +/- 6 for women and 44 +/- 6 for men, and was significantly increased with stronger intent for rural practice in each gender. The factors of work preferences, evaluation of rural practice and evaluation of rural living showed a significant and independently positive correlation with the intent for rural practice. Moreover, multiple linear regression analysis using rural self-efficacy score as an objective variable, adjusted for confounding factors as explanatory variables, showed that the following were also significantly and independently associated with rural self-efficacy score: encounter with a doctor as a role model and general medicine orientation, for both men and women; and lower grade academic year, graduation from public high school and not failed entrance exam, for men.Conclusions: The present study suggests that medical schools might recruit medical students with higher rural self-efficacy score and have to foster their rural-oriented attitudes in order to provide physicians to rural areas.

File： Rural Remote Health 2018 Rural self-efficacy measuring intent for rural practice among Japanese medical students.pdf

DOI： 10.22605/RRH4791

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SCIENDO  

Background: There are few effective medications for non-alcoholic steatohepatitis (NASH). We investigated the efficacy of ipragliflozin (selective sodium-glucose cotransporter-2 inhibitor [SGLT2I]) for the treatment of patients with type 2 diabetes mellitus (T2DM) complicated by non-alcoholic fatty liver disease (NAFLD). Methods: We prospectively enrolled patients with T2DM complicated by NAFLD treated at our institutions from January 2015 to December 2016. Patients received oral ipragliflozin (50 mg/day) once daily for 24 weeks. Body composition was evaluated using an InBody720 analyzer. We used transient elastography to measure liver stiffness and the controlled attenuation parameter for the quantification of liver steatosis in patients with NASH. Results: Forty-three patients with T2DM and NAFLD were enrolled (12 with biopsy-proven NASH and 31 with NAFLD diagnosed by ultrasonography). After 24 weeks, body weight, hemoglobin A1c (HbA1c), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase, body fat mass, and steatosis were significantly decreased compared to baseline measurements in patients with NASH. However, muscle mass was not reduced, and liver stiffness showed a statistically insignificant tendency to decrease. NAFLD patients also showed a significant reduction in body weight, HbA1c, AST, and ALT compared to baseline measurements. Conclusion: Ipragliflozin may be effective in patients with T2DM complicated by NAFLD.

File： Open Med 2018 Ipragliflozin and NAFLD.pdf

DOI： 10.1515/med-2018-0059

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

Background: Elevated serum uric acid (SUA) levels are associated with glucose control. However, whether baseline and changes in SUA predict long-term follow-up glucose control [e.g., glycated hemoglobin (HbA1c)] remains unclear. Methods: The subjects comprised 393 women aged 71 ± 8 years and 279 men aged 71 ± 10 years from a rural village. We have identified participants who underwent a similar examination 11 years prior, and subjects were divided into four groups based on the tertiles of baseline and changes in SUA, and examined the relationship between baseline and changes in SUA, and glucose control evaluated by follow-up HbA1c after 11-years. Results: In both genders, follow-up SUA were significantly higher in Group 4 (i.e., women: Group 4, baseline SUA ≥ 4.0 mg/dL and changes in SUA ≥ 0.8 mg/dL; men: Group 4, ≥ 5.3 mg/dL and ≥ 0.4 mg/dL) than in the other Groups, but eGFR was significantly lower. Only in women, there were significant differences among the four groups regarding follow-up HbA1c, and follow-up HbA1c was highest in Group 4. In addition, the interaction between baseline and changes in SUA (F = 5.391, p = 0.021) as well as baseline low-density lipoprotein cholesterol (LDL-C) (F = 13.793, p < 0.001), estimated glomerular filtration ratio (F = 10.715, p = 0.001), HbA1c (F = 118.285, p < 0.001), SUA (F = 9.457, p = 0.002), and changes in SUA (F = 7.757, p = 0.006) was a significant and independent determinant of follow-up HbA1c. Multivariate-adjusted follow-up HbA1c (p = 0.002) were significantly higher in Group 4 than the other groups. Conclusions: These results suggested that combined assessment of baseline and changes in SUA provides increased information for long-term predictive glucose control, independent of other confounding factors in community-dwelling women.

File： Diabetol Metab Syndr 2018 Uric Acid in predicting glucose control.pdf

DOI： 10.1186/s13098-018-0356-z

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BACKGROUND: The effect of cigarette smoking on the onset of nonalcoholic fatty liver disease (NAFLD) is unclear, especially that associated with drinking small amounts of alcohol. We conducted a longitudinal study to investigate the relationship between cigarette smoking and NAFLD onset, which was stratified according to the amount of alcohol consumed. METHODS: We enrolled 7,905 Japanese subjects who had received annual health checkups more than twice between April 2003 and August 2013, 4,045 of whom met at least one of the following exclusion criteria and were excluded: (a) fatty liver at baseline; (b) hepatitis B or hepatitis C; (c) alcohol consumption (men: ≥210 g/wk; women: ≥140 g/wk); (d) change in alcohol drinking status between baseline and the study's endpoint; (e) change in cigarette smoking habits between baseline and the study's endpoint; or (f) current treatment with antidiabetic agents, antihypertensive agents, and/or lipid-lowering agents. The remaining 3,860 subjects (1,512 men, 2,348 women) were divided into two groups based on average alcohol consumption. RESULTS: After adjusting for the variables associated with metabolic disease, smoking was associated with fatty liver disease onset compared with nonsmokers in nondrinkers (adjusted hazard ratio = 1.988, 95% confidence interval 1.057-3.595; p = 0.034). No association was found between smoking and fatty liver disease onset in the low alcohol consumption group (men: <210 g alcohol/week; women: <140 g alcohol/week). The fatty liver disease incidence increased significantly among the nondrinkers as the number of cigarettes smoked increased (p = 0.001). CONCLUSIONS: Cigarette smoking may be a significant risk factor associated with NAFLD onset in nondrinkers. These results may help clinicians to identify patients who are at a high risk of developing NAFLD and to prevent the progression of NAFLD by promoting earlier interventions that help people discontinue unhealthy lifestyle habits.

File： PLoS One 2018 Smoking and fatty liver in nondrinkers.pdf

DOI： 10.1371/journal.pone.0195147

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Background: Few data is available on the association between body mass index (BMI), serum uric acid (SUA) levels and blood pressure (BP) categories in the disease continuum, when efforts for its prevention may be applicable. Methods: We performed a cross-sectional study to examine the association between BMI, SUA and BP in a community-dwelling sample of Japanese men. Individuals not on antihypertensive and uric acid lowering medications, and aged 50 to 90 years [817men aged 66 ± 9 (mean ± standard deviation) years] were recruited for the survey during a community based annual medical check-up. The main outcome was the presence of prehypertension [systolic BP (SBP) 120-139 mmHg and/or diastolic BP (DBP) 80-89 mmHg] and hypertension [SBP ≥ 140 and /or DBP ≥ 90]. Results: In participants with a BMI of < 21.0 kg/m2, increased SUA levels were positively associated with SBP and DBP, but in those with a BMI of ≥ 21.0 kg/m2, increased SUA levels were negatively associated with SBP and DBP. The interaction between BMI and SUA as well as BMI and SUA was a significant and independent determinant for both SBP (β = - 1.125, p = 0.001) and DBP (β = - 0.995, p = 0.005). Among participants, the respective prevalence of normotension, prehypertension, and hypertension was 19.5% and 53.7%, and 19.8%. The prevalence of normotension and prehypertension decreased with increasing BMI and the prevalence of hypertension increased with increasing BMI. In participants with a BMI ≥ 21.0 kg/m2, the adjusted-odds ratio of SUA for hypertension was 0.75 (95% CI, 0.59-0.95) compared with normotension and 0.82 (0.70-0.96) compared with prehypertension. In those with a BMI of < 21.0 kg/m2, these associations were not shown. Conclusion: BMI may modify the association between SUA and blood pressure status among community-dwelling men.

File： Clin Hypertens 2018 BMI and uric acid in relation to blood pressure.pdf

DOI： 10.1186/s40885-018-0087-3

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier (Singapore) Pte Ltd  

Background: Alcohol consumption is an important lifestyle factor for a variety of health problems, we investigated whether alcohol consumption is associated with handgrip strength (HGS), which is a useful indicator of sarcopenia, among Japanese community-dwelling persons. Methods: The present study included 764 men aged 70 (69–70) years and 955 women aged 70 (69–70) years from a rural village. Daily alcohol consumption was measured using the Japanese liquor unit in which a unit corresponds to 22.9 g of ethanol, and the participants were classified into never drinkers, occasional drinkers, daily light drinkers (1–2 units/day), and daily moderate drinkers (2–3 units/day). Results: HGS were significantly correlated with age in both men and women. HGS increased significantly with increased daily alcohol consumption in both genders, and in men HGS in daily moderate drinkers were significantly greater than those in never, occasional, and daily light drinkers. In women, HGS in daily light and moderate drinkers were significantly greater than those in never drinkers. In men, Multivariate-adjusted HGS were significantly greater in daily light {mean: 33.4 (95% confidence interval: 32.3–34.5) kg} and moderate drinkers {33.6 (32.8–34.0) kg} than in never drinkers {31.7 (30.8–32.7) kg}, and in women multivariate-adjusted HGS in occasional drinkers {21.5 (21.0–22.1) kg} was significantly greater in never drinkers {20.7 (20.5–21.0) kg}. Conclusion: These results suggest that alcohol consumption may have a protective role in aging-associated decline in muscle strength in community-dwelling persons.

File： Int J Gerontol 2018 Alcohol Consumption and Handgrip Strength.pdf

DOI： 10.1016/j.ijge.2018.03.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AIM: Assessing disease progression in patients with primary biliary cholangitis (PBC) is necessary in order to evaluate therapeutic effectiveness. Therefore, the aims of this study were to evaluate both the diagnostic accuracy of both real-time tissue elastography (RTE) and vibration-controlled transient elastography (VCTE), and the usefulness of hepatic and splenic elasticity as predictive markers for the progression of symptomatic PBC. METHODS: The study participants were 44 patients with PBC. We assessed hepatic and splenic elasticity using RTE and VCTE and measured serum markers related to fibrosis and hepatic and splenic blood flow using Doppler ultrasonography. We then compared RTE and VCTE for diagnostic accuracy. Patients with asymptomatic PBC were followed every 1-3 months. RESULTS: Both RTE and VCTE performed well and had superior diagnostic accuracy compared with biochemical markers. The areas under the receiver operating characteristic curve for RTE and VCTE were 0.92 and 0.92, 0.95 and 0.91, and 0.97 and 0.91 for F ≥ 2, F ≥ 3, and F = 4, respectively. During follow-up, nine patients (25.0%) developed liver-related symptoms. Multivariate analysis revealed that splenic elasticity assessed using RTE was a significant independent factor for the development of liver-related symptoms (odds ratio, 2.19; P = 0.024). CONCLUSIONS: Real-time tissue elastography offered better diagnostic accuracy for severe fibrosis and cholangitis than VCTE. Splenic elasticity determined using RTE is a useful parameter for evaluating liver-related symptoms and an effective predictive marker of disease progression in patients with asymptomatic PBC.

File： Hepatol Res 2017 Elastography in PBC.pdf

DOI： 10.1111/hepr.12861

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MARY ANN LIEBERT, INC  

BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of major cardiovascular events. Alanine aminotransferase (ALT) at high levels and total bilirubin (T-BiL) at low levels were oxidative potentials, but it was uncertain whether ALT and T-BiL had an additive interaction for the risk of MetS. METHODS: From a single community, we recruited 864 women (70 ± 8 years) during their annual health examination. We cross-sectionally investigated whether ALT and T-BiL are associated with MetS and its components based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report. RESULTS: Of these subjects, 415 women (48.0%) had MetS. Participants with MetS had a higher ALT and lower T-BiL level than those without MetS. The adjusted-odds ratios (OR) (95% confidence interval [CI]) for MetS across tertiles of ALT and T-BiL were 1.00, 1.19 (0.78-1.81), and 1.86 (1.24-2.80) and 1.00, 0.96 (0.65-1.43), and 0.54 (0.36-0.81), respectively. When ALT and T-BiL were categorized into three binary characteristics by tertiles of ALT and T-BiL, high T-BiL was associated with decreased risk for MetS in a multivariable model (OR: 0.55, 95% CI: 0.37-0.82), especially among those with 1st tertile ALT. Similarly, high ALT was also associated with increased risk for MetS in a multivariate model (OR: 1.81, 95% CI: 1.20-2.71), especially among those with 2nd & 3rd tertiles of T-BiL. In the formal testing of addictive interaction between ALT and T-BiL for MetS, presence of T-BiL <0.72 mg/dL (1st and 2nd tertile) alone was not associated with increased risk of MetS in a multivariate analysis, and presence of ALT ≥16 IU/L (2nd and 3rd tertile) alone was not associated with increased risk of MetS. CONCLUSIONS: These results suggested that higher ALT and lower T-BiL levels were synergistically associated with MetS, independent of other confounding factors among Japanese women.

DOI： 10.1089/met.2017.0064

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Content Ed Net Taiwan Limited  

Background/Purpose: Flexibility is one of the components of physical fitness as well as muscle strength that decrease with age. Flexibility has been identified as one of the primary etiologic factors in preventive treatment of musculotendinous strains, and may be triggered by oxidative stress. We investigated whether changes in the oxidative stress marker, malondialdehyde-modified low density lipoprotein (MDA-LDL), is associated with change in trunk flexibility, which is a useful indicator of physical fitness, by a 12-week exercise administered to Japanese community-dwelling persons. Methods: The present study included 62 women aged 67 ± 7 years from a rural village. Nordic walking exercise of 120 min per week was performed for 12 weeks. Twelve-week changes in the various factors were calculated by subtracting the baseline values from the 12-week values. Results: Changes in sit-and-reach increased progressively with decreased changes in the MDA-LDL after the 12-week walking exercise(r=‒0.312 p=0.014). Multiple linear regression analysis showed that change in the MDA-LDL (β=‒0.284, p=0.021) as well as change in waist circumference (β=‒0.258, p=0.036) was significantly and independently associated with change in sit-and-reach. When the data were further stratified by age, change in the MDA-LDL was significantly associated with change in sit-and-reach in women aged of ≤70 years. Conclusions: These results suggest that decreased change in MDA-LDL is a confounding factor for sit-and-reach after a 12-week NW exercise in community-dwelling women.

DOI： 10.24816/jcgg.2017.v8i3.03

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

BACKGROUND: Palmitic acid is an important risk factor for the pathogenesis of non-alcoholic steatohepatitis (NASH), but changes in palmitic acid intestinal absorption in NASH are unclear. The aim of this study was to clarify changes in palmitic acid intestinal absorption and their association with the pathogenesis of NASH. METHODS: A total of 106 participants were recruited to the study, of whom 33 were control subjects (control group), 32 were patients with NASH Brunt stage 1-2 [early NASH (e-NASH)], and 41 were patients with NASH Brunt stage 3-4 [advanced NASH (a-NASH)]. 13C-labeled palmitate was administered directly into the duodenum of all participants by gastrointestinal endoscopy. Breath 13CO2 levels were measured to quantify palmitic acid absorption, and serum Apolipoprotein B-48 (ApoB-48) concentrations were measured after a test meal to quantify absorbed chylomicrons. Expressions of fatty acid (FA) transporters were also examined. The associations of breath 13CO2 levels with hepatic steatosis, fibrosis and insulin resistance was evaluated using laboratory data, elastography results and liver histology findings. RESULTS: Overall, 13CO2 excretion was significantly higher in e-NASH patients than in the control subjects and a-NASH patients (P < 0.01). e-NASH patients had higher serum ApoB-48 levels, indicating increased palmitic acid transport via chylomicrons in these patients. Jejunal mRNA and protein expressions of microsomal triglyceride transfer protein and cluster of differentiation 36 were also increased in both NASH patient groups. The 13CO2 excretion of e-NASH patients was significantly correlated with the degree of hepatic steatosis, fibrosis and insulin resistance (P = 0.005, P < 0.001, P = 0.019, respectively). CONCLUSIONS: Significantly upregulated palmitic acid absorption by activation of its transporters was evident in patients with NASH, and clinical progression of NASH was related to palmitic acid absorption. These dietary changes are associated with the onset and progression of NASH.

File： J Gastroenterol 2017 Dietary palimitic acids and NASH.pdf

DOI： 10.1007/s00535-016-1298-6

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

PURPOSE: Chronic kidney disease is a major public health concern. Serum uric acid (SUA) at high levels was oxidative stress agents, and total bilirubin (T-BiL) at mildly increased levels was potent antioxidants, but whether SUA and T-BiL produce an additive interaction for the risk of renal dysfunction remains unclear. METHODS: The subjects comprised 567 men aged 71 ± 8 (mean ± standard deviation) years and 853 women aged 70 ± 8 years from a rural village. We examined the relationship between SUA and T-BiL, and renal function was evaluated by estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease Study Group equation. RESULTS: Stepwise multiple regression analysis using eGFR as an objective variable, adjusted for risk factors as explanatory variables, showed that SUA (β = -0.358, p < 0.001) as well as age (β = -0.534, p < 0.001), drinking status (β = 0.119, p < 0.001), and the presence of antihypertensive medication (β = -0.058, p = 0.005) were significantly and independently associated with eGFR, but T-BiL was not associated with eGFR. While in the group with the highest tertile of SUA, T-BiL (β = 0.081, p = 0.032) was significantly and independently associated with eGFR, and in the group with the lowest to middle tertile of SUA, T-BiL was not associated with eGFR. In addition, interaction between SUA and T-BiL (F = 8.512, p = 0.004) as well as age, drinking status, the presence of antihypertensive medication, SUA, and T-BiL was a significant and independent determinant for eGFR. CONCLUSIONS: Our data demonstrated that low T-BiL could be important as a potential risk factor for renal dysfunction in those with high SUA.

DOI： 10.1007/s11255-017-1633-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BACKGROUND: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why. METHODS: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test. RESULTS: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%). CONCLUSIONS: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.

File： BMC Gastroenterology 2017 Chemotherapy for elderly pancreatic cancer.pdf

DOI： 10.1186/s12876-017-0623-8

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications Ltd  

Abnormally high glycated hemoglobin (Hb) (HbA1c) is significantly associated with oxidative stress and an increased risk of cardiovascular disease (CVD). Serum total bilirubin (T-B) may have a beneficial role in preventing oxidative changes and be a negative risk factor of CVD. Limited information is available on whether serum T-B is an independent confounding factor of HbA1c. The study subjects were 633 men aged 70± 9 (mean ±standard deviation (SD)) years and 878 women aged 70 + 8 years who were enrolled consecutively from among patients aged ≥40 years through a community-based annual check-up process. We evaluated the relationship between various confounding factors including serum T-B and HbA1c in each gender. Multiple linear regression analysis pertaining to HbA1c showed that in men, serum T-B (β=0.139) as well as waist circumference (β = 0.099), exercise habit (β = 0.137), systolic blood pressure (SBP) (β = 0.076), triglycerides (β = 0.087), and uric acid (β=0.123) were significantly and independently associated with HbA1c, and in women, serum T-B (β=0.084) as well as body mass index (β = 0.090), smoking status (β = - 0.077), SBP (β = 0.117), diastolic blood pressure (DBP) (β = - 0.155), low-density lipoprotein cholesterol (β = 0.074), prevalence of antidyslipidemic medication (β = 0.174), and uric acid (β = 0.090) were also significantly and independently associated with HbA1c. Multivariateadjusted serum HbA1c levels were significantly high in subjects with the lowest serum T-B levels in both genders. Serum T-B is an independent confounding factor for HbA1c among community-dwelling middle-aged and elderly persons.

File： J Circ Biomark 2017 Total bilirubin negatively associated with HbA1c .pdf

DOI： 10.1177/1849454417726609

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

The acidic (leucine-rich) nuclear phosphoprotein 32 family member B (ANP32B), a highly conserved member of the acidic nuclear phosphoprotein 32 (ANP32) family, is critical for the development of normal tissue. However, its role in the development of hepatocellular carcinoma (HCC) is controversial. In this study, we elucidated the role of ANP32B in HCC cell lines and tissues. ANP32B expression in HCC cell lines was modulated using siRNA and ANP32B expression plasmids and lentiviruses. The levels of apoptosis-related proteins were analyzed by real-time RT-PCR and Western blotting. The expression of ANP32B in tissues from patients with HCC was investigated using real-time RT-PCR and immunohistochemistry. ANP32B knockdown by siRNA altered the expression of apoptosis-related proteins in HCC cell lines and reduced the expression of cleaved forms of caspase 3 and caspase 9, but not that of caspase 8, in HCC cells cultured with the pro-apoptotic agent staurosporine. Phosphorylated Bad was upregulated, whereas Bak was downregulated. Moreover, ABT-737, which binds to and inhibits anti-apoptotic proteins of the Bcl-2 family, rendered HCC cells resistant to apoptosis induced by ANP32B silencing. Conversely, ANP32B overexpression decreased Bad phosphorylation and upregulated Bak, but did not induce apoptosis because Bax expression was downregulated. In tissues from patients with HCC, a low tumor/non-tumor ratio of ANP32B mRNA expression was related to advanced UICC stage (p = 0.032). TUNEL-positive cells were observed in parallel with ANP32B expression in HCC tissues. ANP32B modulates Bad phosphorylation as well as Bak and Bax expression, resulting in regulation of apoptosis in HCC. These findings indicate the potential value of ANP32B as a therapeutic target for HCC.

File： PLoS One 2017 Downregulation of ANP32B and HCC.pdf

DOI： 10.1371/journal.pone.0177343

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Background/Purpose Oxidative stress is thought to be involved in the development of vascular dysfunction. Arterial stiffness is one of the most significant manifestations of aging and vascular disease. We investigated whether increased malondialdehyde-modified low-density lipoprotein (MDA-LDL), which is responsible for oxidative stress, was associated with increased arterial stiffness, independent of confounders of cardiovascular disease. Methods The participants comprised 10 men aged 70 ± 7 years (range, 61–82 years) and 86 women aged 67 ± 7 years (range, 53–81 years). Peripheral arterial stiffness was evaluated by the mean of the right and left brachial to ankle pulse wave velocity (baPWV). Results and conclusion Both right and left baPWV values of Tertile-2 (61–81 U/L) and Tertile-3 (82–218 U/L) categorized by tertiles of the MDA-LDL level were significantly higher than those of Tertile-1 (34–60 U/L
p = 0.022 and p = 0.018, respectively). The multivariate-adjusted baPWV increased significantly from the lowest to the highest MDA-LDL group. Both baPWV values of Tertile-2 (61–81 U/L) and Tertile-3 (82–218 U/L) were significantly higher than those of Tertile-1 (34–60 U/L) (p = 0.044 and p = 0.044, respectively). To further investigate whether MDA-LDL can explain baPWV levels independent of other known confounding factors, multiple linear regression analyses for baPWV were conducted, which showed that MDA-LDL levels (β = 0.164, p = 0.037) were independently and significantly associated with baPWV as well as gender, age, and presence of raised blood pressure. In addition, we found that a slightly high–normal MDA-LDL level within a normal range is significantly associated with a higher baPWV. MDA-LDL levels are associated with an increased risk of arterial stiffness in community-dwelling persons.

File： J Clin Gerontol Geriatr 2016 Oxidative stress and arterial stiffness.pdf

DOI： 10.1016/j.jcgg.2016.05.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: In Japan, the absolute deficiency of doctors and maldistribution of doctors by specialty is a significant problem in the Japanese health care system. The purpose of this study was to investigate the factors contributing to specialty preference in career choice among Japanese medical students. METHODS: A total of 368 medical students completed the survey giving an 88.2 % response rate. The subjects comprised 141 women aged 21 ± 3 (range, 18-34) years and 227 men aged 22 ± 4 (range, 18-44) years. Binary Logistic regression analysis was performed using specialty preferences as the criterion variable and the factors in brackets as six motivational variables (e.g., Factor 1: educational experience; Factor 2: job security; Factor 3: advice from others; Factor 4: work-life balance; Factor 5: technical and research specialty; and Factor 6: personal reasons). RESULTS: Women significantly preferred pediatrics, obstetrics & gynecology, and psychology than the men. Men significantly preferred surgery and orthopedics than the women. For both genders, a high odds ratio (OR) of "technical & research specialty" and a low OR for "personal reasons" were associated with preference for surgery. "Technical & research specialty" was positively associated with preference for special internal medicine and negatively for pediatrics. "Work-life balance" was positively associated with preference for psychology and negatively for emergency medicine. Among the women only, "technical & research specialty" was negatively associated with preference for general medicine/family medicine and obstetrics & gynecology, and "job security" was positively associated for general medicine/family medicine and negatively for psychology. Among men only, "educational experience" and "personal reasons" were positively, and "job security" was negatively associated with preference for pediatrics. For both genders, "work-life balance" was positively associated with preference for controllable lifestyle specialties. CONCLUSION: We must acknowledge that Japanese medical students have dichotomized some motivations for their specialty preference based on gender. Systematic improvements in the working environment are necessary to solve these issues.

File： BMC Med Educ 2016.pdf

DOI： 10.1186/s12909-016-0811-1

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：TOHOKU UNIV MEDICAL PRESS  

Handgrip strength (HGS) is a useful measure of health-related quality of life and general muscle strength. Serum total bilirubin (T-B) may present potential beneficial effects in preventing oxidative changes which are associated with a risk of metabolic syndrome and the development of cardiovascular disease. Limited information is available regarding whether HGS is an independent confounding factor for serum T-B. The study participants were 214 men aged 71 ± 8 (mean ± standard deviation) years and 302 women aged 71 ± 7 years that were enrolled consecutively from among paticipants aged ≥ 50 years through an annual check-up process. We evaluated the relationship between serum T-B and confounding factors within each sex. HGS related significantly with serum T-B in both men (r = 0.156, p = 0.023) and women (r = 0.173, p = 0.003). Multiple linear regression analysis showed that in men, HGS (β = 0.173) as well as smoking status (β = -0.147), exercise habit (β = 0.138), low-density lipoprotein cholesterol (β = 0.146), and hemoglobin A1c (HbA1c) (β = -0.198) were significantly and independently associated with serum T-B. In women, HGS (β = 0.159) as well as smoking status (β = -0.116), high-density lipoprotein cholesterol (β = 0.159), and HbA1c (β = -0.161) were significantly and independently associated with serum T-B. Multivariate-adjusted serum T-B levels were significantly lower in subjects with the lowest HGS level in both sexes. Increased HGS is strongly associated with increased serum T-B, independent of confounding factors in both sexes.

File： Tohoku J Exp Med 2016 Handgrip strength and total bilirubin.pdf

DOI： 10.1620/tjem.240.221

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: Type 1 autoimmune pancreatitis (AIP) is clinically characterized by a response to steroid therapy. Despite having a favorable prognosis, AIP has a high relapse rate and factors predicting relapse in AIP patients treated with steroids have not yet been established. METHODS: A retrospective chart review was conducted of 32 newly diagnosed type 1 AIP patients who had undergone enhanced computed tomography (CT) pre- and post-steroid therapy. RESULTS: Ten patients experienced relapse. Pancreatic volume was reduced significantly in all patients (pre-treatment volume, 88.5 ± 32.9 cm(3) vs. post-treatment volume, 45.4 ± 21.1 cm(3); P < 0.001), although the pre-treatment pancreatic volume did not differ between the relapse and non-relapse groups (92.6 ± 10.5 cm(3) vs. 86.6 ± 7.1 cm(3), P = 0.401). However, the post-treatment pancreatic volume was significantly greater in the relapse group than that in the non-relapse group (56.9 ± 6.3 cm(3) vs. 40.2 ± 4.2 cm(3), P = 0.008). Similarly, the percent reduction in pancreatic volume was significantly smaller in the relapse group than that in the non-relapse group (36.6 ± 4.7 % vs. 52.1 ± 3.2 %, P = 0.002). Multivariate analysis identified post-treatment pancreatic volume (HR, 1.04, 95 % CI: 1.01-1.08, P = 0.010) and percent reduction in pancreatic volume (HR, 0.87, 95 % CI: 0.79-0.94, P < 0.001) as predictive factors for relapse of type 1 AIP. A post-treatment pancreatic volume of 50 cm(3) < (P = 0.009) and a percent reduction in the pancreatic volume of <35 % (P = 0.004) had a significantly high relapse rate. These data suggest that early pancreatic volume changes after steroid therapy may be a useful prognostic value, because type 1 AIP patients with a high post-treatment pancreatic volume or low pancreatic volume reduction showed significant relapse. CONCLUSIONS: Early pancreatic volume reduction on CT after steroid therapy indicates the therapeutic effects of steroids, and a low decrease in the pancreatic volume may be associated with a limited response that predicts future relapse in patients with type 1 AIP. Reduction of steroids in these cases must be observed carefully with consideration of immunomodulator use.

File： OJRD 2016 AIP & Pancreas volume.pdf

DOI： 10.1186/s13023-016-0487-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

INTRODUCTION: Serum uric acid (SUA) and triglyceride (TG) levels are strongly correlated with insulin resistance; however, the association after a walking exercise program in community-dwelling older women has not been investigated. METHODS: The present study included 100 postmenopausal women (mean ± standard deviation, 68 ± 7 years) from a rural village in Japan. The Nordic walking program of 120 min per week was performed for 12 weeks. Before and after the intervention, SUA, TG, various relevant factors and homeostasis model assessment of insulin resistance (HOMA-IR) were measured. RESULTS AND CONCLUSIONS: Multivariate linear regression analysis showed that baseline TG and γ-glutamyltransferase (GGT) were significantly associated with baseline HOMA-IR. After the 12-week training program, changes in TG, SUA and GGT were significantly associated with changes in HOMA-IR. In addition to their direct associations, we observed a synergistic association between changes in TG and SUA and changes in HOMA-IR. Participants were divided into three groups (tertiles) according to changes in TG and SUA. The tertiles of changes in SUA correlated significantly with changes in HOMA-IR in participants in the tertile with the greatest decrease in TG (r = 0.525, p = 0.001), but not in the other two tertiles of change in TG (r = 0.049, p = 0.699). There was a significant interaction between SUA and TG for changes in HOMA-IR (β = 0.281, p = 0.005). These results suggest that changes in TG and SUA are synergistic factors associated with changes in insulin resistance after a 12-week walking exercise program in community-dwelling older women.

DOI： 10.3109/07435800.2015.1094085

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：GEORG THIEME VERLAG KG  

Pancreatobiliary fistulas associated with intraductal papillary mucinous neoplasms (IPMN) often develop obstructive jaundice and cholangitis; thus, early diagnosis is important. However, computed tomography and cholangiography, the current methods for detecting pancreatobiliary fistulas, are not always effective. We previously reported a case of IPMN-associated pancreatobiliary fistula and proposed a potential new diagnostic marker: the "pig-nose" appearance of the duodenal papilla, which results from dilated pancreatic and bile ducts and can be visualized via endoscopy. In this study, we report another three cases of IPMN-associated pancreatobiliary fistulas detected by a different technology, intraductal ultrasonography (IDUS). As with our previously reported case, we confirmed the utility of the "pig-nose" appearance and IDUS in the diagnosis of IPMN-associated pancreatobiliary fistulas. In addition, we found it difficult to manage biliary obstruction that resulted from the flow of mucinous material through pancreatobiliary fistulas. The obstruction was treated with endoscopic nasal biliary drainage (ENBD), but this was not always successful. In two of our cases, additional treatment with a large diameter fully covered metal stent failed to improve jaundice. Therefore, we conclude that standard endoscopic stenting may not be effective, and that alternative endoscopic methods or surgery may be necessary.

File： Endosc Int Open 2016 IPMN fistula.pdf

DOI： 10.1055/s-0042-102956

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ PUBLISHING GROUP  

Objective Hepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC.
Design Risk factor analysis was performed in over 15 centres from North America and Europe spanning &gt;40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates.
Results Of 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p&lt;0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p&lt;0.0001), elevated serum aspartate transaminase (HR 1.24, p&lt;0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p&lt;0.0001), and hepatic decompensation (HR 9.89, p&lt;0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p&lt;0.0001; IR 6.6 vs 1.4, p&lt;0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p&lt;0.001; IR 18.2 vs 5.4, p&lt;0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p&lt;0.0001).
Conclusions This uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.

File： Gut 2016 PBC & HCC.pdf

DOI： 10.1136/gutjnl-2014-308351

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Diabetes is strongly associated with several mechanisms of tissue damage such as oxidative stress. Serum bilirubin may have a beneficial role in preventing oxidative changes in cardiovascular disease (CVD). Limited information is available on whether serum bilirubin is an independent confounding factor for carotid atherosclerosis among elderly persons with type 2 diabetes. The study subjects were 169 men aged 79 ± 8 (mean ± SD) years and 205 women aged 81 ± 8 years that were enrolled consecutively from patients in the medical department. Carotid intima-media thickness (IMT) and plaque were derived via B-mode ultrasonography. Multiple linear regression analysis showed that serum total bilirubin (β = -0.160) was significantly associated with carotid IMT. Compared to subjects with a serum total bilirubin of tertile-1 (0.13-0.58 mg/dL), the multivariate-adjusted odds ratio (95% confidence interval) of carotid IMT ≥1.0 mm including plaque and carotid plaque was 0.46 (0.23-0.93) and 0.32 (0.17-0.60) in the Tertile-3 group (0.87-1.93 mg/dL), respectively. Next, data were further stratified by gender, age, smoking status, medication and prevalence of CVD. There were no significant differences in serum total bilirubin levels between selected subgroups. Our data demonstrated a negative association between serum total bilirubin and carotid atherosclerosis among elderly persons with type 2 diabetes.

DOI： 10.3109/10641963.2015.1060990

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3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

File： Intern Med 2016 Hyperthyroidism and NASH.pdf

DOI： 10.2169/internalmedicine.55.6640

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BACKGROUND: In Japan, there is a shortage of young physicians in various specialties; the present situation of general medicine or family medicine (GM/FM) in particular is risky. The factors influencing the career choice of Japanese medical students are poorly understood. This study aims to identify factors related to choosing GM/FM as a career. METHODS: The study was designed as a cross-sectional survey. Students at one medical school in Japan filled out a questionnaire. Students were asked to state their intended medical specialty, and they rated the importance of specific individual and occupational aspects using a 4-point likert scale. Factor analysis was performed on the variables. Reliability of the factor scores was estimated using Cronbach's alpha coefficients; biserial correlations between the factors and career choices were calculated. Furthermore, multiple linear regression analysis was performed using career choice (GM/FM vs. others) as the criterion variable and the factors plus demographic characteristics as confounding variables. RESULTS: Factor analysis produced six factors that explained future career plans. Medical students in this study had a positive and realistic idea about GM/FM, but only 18.8% of them chose GM/FM first as a career. The significant variables associated with choosing GM/FM first as a career were: 'Admission from hometown' (β=0.189, P=0.001), 'Student preparing for the entrance exam' (β=0.172; P=0.001), 'Intent for rural practice' (β=0.123, P=0.016), and 'Work-life balance' (β=0.126, P=0.013). While significant variables that were negatively associated with choosing GM/FM were 'Presence of medical relatives' (β=-0.107, P=0.037) and 'Scientific orientation' (β=-0.125, P=0.013). CONCLUSIONS: Strategies have been suggested, such as recruiting medical students with significant variables that were associated with choosing GM/FM first as a career. By engaging students early in their choice of career, we may be able to increase enthusiasm for this specialty.

File： Med Educ Online 2016 General medicine as a career among medical students.pdf

DOI： 10.3402/meo.v21.29448

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Serum uric acid (UA) has strong anti-oxidant properties. Muscle strength and mass decrease with age, and recently, this decrease has been defined as sarcopenia. Sarcopenia may be triggered by oxidative stress. We investigated whether serum UA is associated with handgrip strength (HGS), which is a useful indicator of sarcopenia, among Japanese community-dwelling elderly persons. The present study included 602 men aged 72 ± 7 years and 847 women aged 71 ± 6 years from a rural village. We examined the cross-sectional relationship between serum UA and HGS. In both genders, HGS increased significantly with increased serum UA levels. A multiple linear regression analysis using HGS as an objective variable and various confounding factors as explanatory variables showed that in men age, drinking status, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and estimated glomerular filtration ratio (eGFRCKDEPI) were independently and significantly associated with HGS, and in women, serum UA as well as age, body mass index, drinking status, diastolic blood pressure, and eGFRCKDEPI were independently and significantly associated with HGS. In women, age and multivariate-adjusted HGS were significantly higher in the Quartile-3 (4.8-5.4 mg/dL) and Quartile-4 groups (5.5-9.3 mg/dL) of serum UA than in the lower groups (0.7-4.7 mg/dL). These results suggest that serum UA may have a protective role in aging-associated decline in muscle strength in community-dwelling elderly women.

File： PLoS One 2016 Uric Acid and Handgrip Strength.pdf

DOI： 10.1371/journal.pone.0151044

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The association of low muscle strength with cardio-metabolic risks remains controversial. The present study included 742 men aged 70 ± 9 years and 937 women aged 70 ± 8 years from a rural village. We examined the cross-sectional relationship between relative muscle strength defined by handgrip strength (HGS)/body weight (BW) ratio, and metabolic syndrome (MetS) based on the modified criteria of the National Cholesterol Education Program's Adult Treatment Panel (NCEP-ATP) III report and its components. Of these, 203 men (27.4%) and 448 women (47.8%) had MetS. In men, increasing quartile of HGS/BW ratio was significantly and independently associated with high waist circumference {odds ratio, 0.31; 95% confidence interval (CI), 0.24-0.41} and elevated triglyceridemia (0.71, 0.59-0.86). In women, it was also significantly and independently associated with high waist circumference (0.41; 0.36-0.48), high blood pressure (0.78; 0.66-0.92), Low HDL-cholesterolemia (0.84; 0.73-0.98) and elevated triglyceridemia (0.65; 0.53-0.79). In both genders, the prevalence of MetS significantly decreased in relation to increasing HGS/BW ratio. After adjustment for age, smoking status, drinking status, LDL-C, estimated glomerular filtration ratio (eGFR), and medication, the respective odds ratio (95% CI) for the quartile of HGS/BW ratio for MetS was 1.00, 0.54 (0.34-0.85), 0.32 (0.19-0.53), and 0.16 (0.09-0.29) in men, and 1.00, 0.76 (0.50-1.16), 0.33 (0.22-0.51), and 0.16 (0.10-0.25) in women. These results suggest that HGS/BW ratio was significantly and negatively associated with an increased risk of cardio-metabolic disorders in Japanese-community dwelling persons.

DOI： 10.3109/10641963.2015.1081232

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Bile duct injury is a potential complication of radiofrequency ablation (RFA). Bipolar RFA devices have recently become available. Because visibility of the bipolar RFA electrodes is not good on ultrasonography, more careful usage of the electrodes to avoid bile ducts is needed. We present a case with hepatocellular carcinoma (HCC) located near the B5 intrahepatic bile duct. To view the bile duct, we used contrast medium for ultrasonography, administered through a biliary drainage catheter for endoscopic nasobiliary drainage (ENBD). Infusing the contrast medium allowed clear visualization of the HCC adjacent to the major bile duct during RFA. We also used a navigation system for bipolar RFA to confirm positions of the electrodes and HCC. We confirmed complete ablation of the HCC while avoiding bile duct injury and late bile duct stenosis. Administration of contrast medium for ultrasonography through an ENBD tube appears useful to avoid bile duct injury during RFA.

File： Clin J Gastroenterol 2015 RFA for HCC adjacent major bile duct.pdf

DOI： 10.1007/s12328-015-0599-2

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Arterial stiffness represents the cumulative effects of cardiovascular risk factors, including aging, on the arterial wall, and has been found to be a surrogate marker of cardiovascular disease. However, it remains unknown whether baseline arterial stiffness is independently associated with improvement in functional abilities after exercise training. The subjects were 72 adults (9 men and 63 women) aged 67 ± 7 years from a rural village. Before and at the end of a 12-week Nordic walking program, 6-min walk distance (6MWD) as functional abilities, metabolic characteristics, and the mean of the right and left brachial-ankle pulse wave velocity (baPWV) as a marker of arterial stiffness were measured. Higher baseline mean baPWV levels correlated significantly with shorter baseline 6MWD (P < 0.001), and also with the follow-up 6MWD (P < 0.001) and change rate (P = 0.019) in 6MWD after the 12-week training program. Multivariate linear regression analysis was employed to evaluate the contribution of baseline mean baPWV for 6MWD parameters showing that baseline mean baPWV values were significantly and independently associated with follow-up 6MWD (β = -0.523, P < 0.001) and change rate in 6MWD (β = -0.399, P < 0.001) as well as baseline 6MWD (β = -0.522, P < 0.001), but was not associated with change after the 12-week training program. Higher baPWV, a measurement of arterial stiffness, might be a predictor of functional abilities after exercise training, independent of confounding factors, in the general population.

File： Aging Clin Exp Res. 2015 baPWV and walking distance.pdf

DOI： 10.1007/s40520-014-0262-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AUSTRALIAN RURAL HEALTH EDUC NETWORK  

Introduction: In Japan, the maldistribution of physicians between urban and rural areas is increasing. It is important to know the practice location expectations of future physicians.
Methods: The study was designed as a cross-sectional survey. In 2009-2013, students at a medical school in Japan completed a questionnaire containing 50 items with four-point Likert scales. The students rated the importance of specified individual and occupational aspects. Furthermore, students were asked to state their intention to practice in a rural area.
Results: The study sample consisted of 368 students (88.2% response rate). Significant variables that were associated with a positively motivated intent for rural practice were 'presence of a role model' (odds ratio (OR), 5.42; 95% confidence interval (CI), 1.58-18.5), 'admission by school recommendation' (OR, 7.68; 95% CI, 2.14-27.6), 'growing up in a rural area' (OR, 6.16; 95% CI, 1.01-37.6), 'general medicine/family medicine as the first career choice' (OR, 5.88; 95% CI, 2.43-14.2), 'interest in the targeted population' (OR, 16.7; 95% CI, 3.97-69.9), 'memorable experience at a class or clinical rotation' (OR, 3.94; 95% CI, 3.73-416), and 'location of their medical school' (OR, 11.4; 95% CI, 2.79-46.2).
Conclusions: The present study suggests that medical schools might recruit students with characteristics associated with intention for rural practice.

File： Rural Remote Health 2015 Medical students associated with their intention for rural practice.pdf

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PURPOSE: This study aimed at prospectively evaluating bile duct anatomy on ultrasonography and evaluating the safety and utility of radiofrequency ablation (RFA) assisted by virtual ultrasonography from gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). METHODS: The institutional review board approved this study, and patients provided written informed consent prior to entry into the study. Bile duct anatomy was assessed in 201 patients who underwent Gd-EOB-DTPA-enhanced MRI for the evaluation of hepatic tumor. Eighty-one of these patients subsequently underwent RFA assisted by ultrasound imaging. In 23 patients, the tumor was located within 5 mm of the central bile duct, as demonstrated by MRI. RESULTS: Virtual ultrasonography constructed by Gd-EOB-enhanced MRI was able to visualize the common bile duct, left hepatic duct, and right hepatic duct in 96.5, 94.0, and 89.6 % of cases, respectively. The target hepatic tumor nodule and biliary duct could be detected with virtual ultrasonography in all patients, and no severe complications occurred. CONCLUSION: The running pattern of the bile ducts could be recognized on conventional ultrasound by referencing virtual ultrasonography constructed by Gd-EOB-DTPA-enhanced MRI. RFA assisted by this imaging strategy did not result in bile duct injury.

DOI： 10.1007/s10396-014-0598-9

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Nordic walking (NW), characterized by the use of two walking poles, has positive effects on several muscle groups. Muscle strength and mass decrease with age, and recently, this decrease is defined as sarcopenia. Sarcopenia may be triggered by oxidative stress. We investigated whether changes in the oxidative stress marker, malondialdehyde-modified low-density lipoprotein (MDA-LDL)/LDL-cholesterol (LDL-C) ratio are associated with change in handgrip strength (HGS), which is a useful indicator of sarcopenia, by a 12-week NW exercise among Japanese community-dwelling persons. The present study included 65 women aged 67±7 years and 9 men aged 71±8 years from a rural village. NW exercise of 120 min per week was performed for 12 weeks. Before and at the end of the 12-week intervention, various confounding factors and HGS were measured. 12-week changes in various factors were calculated by subtracting the baseline values from the 12-week values. Changes in HGS and follow-up HGS increased progressively with decreased changes in the MDA-LDL/LDL-C ratio after the 12-week walking exercise (r=-0.32, P=0.006 and r=-0.35, P=0.002, respectively). Multiple linear regression analysis showed that changes in HDL-C (β=0.26, P=0.019) and MDA-LDL/LDL-C ratio (β=-0.32, P=0.004) were significantly and independently associated with changes in HGS. When the data were further stratified by gender, change in the MDA-LDL/LDL-C ratio was significantly and similarly associated with change in HGS in women only. These results suggest that change in MDA-LDL/LDL-C ratio may be a predictor for HGS after a 12-week NW exercise in community-dwelling persons.

File： Endocrine. 2015 LDL-c and handgrip strength.pdf

DOI： 10.1007/s12020-014-0360-5

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"Soft pancreas" has often been reported as a predictive factor for postoperative pancreatic fistula (POPF) after pancreatectomy. However, pancreatic stiffness is judged subjectively by surgeons, without objective criteria. In the present study, pancreatic stiffness was quantified using intraoperative ultrasound elastography, and its relevance to POPF and histopathology was investigated. Forty-one patients (pancreatoduodenectomy, 30; distal pancreatectomy, 11) who underwent intraoperative elastography during pancreatectomy were included. The elastic ratio was determined at the pancreatic resection site (just above the portal vein) and at the remnant pancreas (head or tail). Correlations between the incidence of POPF and patient characteristics, operative variables, and the elastic ratio were examined. In addition, the relationship between the elastic ratio and the percentage of the exocrine gland at the resection stump was investigated. For pancreatoduodenectomy patients, main pancreatic duct diameter < 3.2 mm and elastic ratio < 2.09 were significant risk factors for POPF. In addition, the elastic ratio, but not main pancreatic duct diameter, was significantly associated with the percentage of exocrine gland area at the pancreatic resection stump. Pancreatic stiffness can be quantified using intraoperative elastography. Elastography can be used to diagnose "soft pancreas" and may thus be useful in predicting the occurrence of POPF.

File： Int Surg 2015 Pancreatic stiffness.pdf

DOI： 10.9738/INTSURG-D-14-00040.1

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A 36-year-old Japanese woman took over-the-counter (OTC) medication for headaches for 20 days. Subsequently, five days after discontinuing the medication, a skin rash developed over the patient's upper and lower limbs and face, in addition to a fever, brown urine and serious liver dysfunction. Drug lymphocyte stimulation tests implicated ibuprofen, a main component of the OTC drugs, which has the potential to induce this pathology, and a diagnosis of drug-induced liver injury with multiform exudative erythema was made. The patient's symptoms and liver function tests returned to normal following treatment with systemic steroids.

File： Intern Med 2015 Ibuprofen induced multiform exudative erythema.pdf

DOI： 10.2169/internalmedicine.54.3204

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：HINDAWI LTD  

Purpose. The purpose of this study was to establish the relationship between the grade of chronic pancreatitis (CP) and pancreatic blood flow as measured by contrast-enhanced transabdominal ultrasonography (CEUS) and to diagnose early CP easily. Methods. This pilot study was conducted in 8 patients with CP, 7 patients with early CP, and 6 control participants. After injecting 0.015 mL/kg of perflubutane by manual bolus, values in one region of interest (ROI) in pancreatic parenchyma and one ROI including the superior mesenteric artery (SMA) were measured. Results. The ratio of blood flow in the SMA and pancreatic parenchyma increased with grade of CP and was significantly higher in patients with CP (5.41; 2.10-11.02) than in patients with early CP (2.46; 1.41-5.05) and control participants (2.32; 1.25-3.04) (P = 0.0279, P = 0.0142, resp.). The ratio of blood flow in the SMA and pancreatic parenchyma correlated with grade of CP (rs = 0.5904, P = 0.0048). Conclusion. The ratio of blood flow correlates with grade of CP on CEUS. This safe and convenient method may be useful to diagnose early CP.

File： BioMed Research International 2015 CE-US for chronic pancreatitis.pdf

DOI： 10.1155/2015/393124

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Central blood pressure (BP) has been shown to strongly associate with cardiovascular disease and outcome. Recent studies have demonstrated a relationship between changes in body size by exercise training and peripheral BP; however, the effect on changes in central BP is unknown. The aim of this study was to assess whether changes in body size are independently related to changes in central BP in the elderly. The subjects were 11 men (mean age, 68±6 years) and 84 women (68±7 years) from a rural village. Before and at the end of the 12-week training program, metabolic variables, and first peak radial systolic BP (SBP1) and second peak radial SBP (SBP2) as estimates of central SBP, were obtained. Radial augmentation index (AI) was calculated as follows: ((SBP2-diastolic BP (DBP))/(SBP1-DBP)) × 100 (%) and we used AI corrected at heart rate 75 per min (AI@75). After the 12-week training program, weight loss correlated strongly with reduction in brachial mean arterial pressure (MAP), radial SBP1, SBP2 and AI@75. After adjusting for confounding factors, weight loss was significantly and independently associated with each reduction in brachial MAP (β=0.34, P=0.001), radial SBP1 (β=0.31, P=0.002), SBP2 (β=0.37, P<0.001) and AI@75 (β=0.36, P=0.001). These findings suggest that weight loss by a 12-week training program may be an effective strategy to improve central BP parameters among Japanese elderly persons.

File： Hypertens Res 2014 Weight loss and central systolic blood pressure.pdf

DOI： 10.1038/hr.2014.108

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Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. HCC is generally considered to spread via the bloodstream and local recurrence often occurs in the blood drainage area determined by computed tomography during hepatic arteriography (CTHA), despite complete ablation of the primary nodule. This study was conducted in order to prospectively assess the rate of local recurrence in the blood drainage area depicted by delayed-phase CTHA. The participants comprised 364 consecutive patients (260 men and 104 women; mean age, 67.4±8.6 years), enrolled between April, 2002 and December, 2011. The participants were divided into two groups, according to whether the ablation area covered the entire blood drainage area as defined by delayed-phase CTHA (group A) or not (group B). Local tumor progression was compared between the two groups. The median time to recurrence was significantly shorter for group B (434 days) compared to that for group A (1,474 days; P=0.0037). The cumulative local recurrence rates for group A were 0, 0 and 1.5% at 1, 3 and 5 years postoperatively, respectively, whereas the recurrence rates for group B were 3.8, 17.0 and 22.8% at 1, 3 and 5 years, respectively (P<0.0001). In conclusion, the safety margin for radiofrequency ablation should be defined as the blood drainage area and ablation should aim at acquiring adequate safety margins.

File： Mol Clin Oncol 2013 Local recurrence of HCC post RFA.pdf

DOI： 10.3892/mco.2013.229

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

Biliary drainage was performed in a 71-year-old man with obstructive jaundice of unknown origin; however, he died due to acute pulmonary failure. At autopsy, proliferation of adenocarcinoma cells was observed in the gallbladder mucosa transitioning from isolated signet-ring cell carcinoma (SRCC) to the subserosa and bile ducts without growth toward the gallbladder lumen. Furthermore, fibrocellular intimal proliferation, tumor emboli and organized thrombi were observed in the small pulmonary arteries. The final diagnosis was gallbladder carcinoma complicated by SRCC associated pulmonary tumor thrombotic microangiopathy (PTTM). PTTM may present as rapidly progressive dyspnea, and a high level of clinical suspicion is required to make the differential diagnosis.

File： Intern Med 2014 Signet-ring Cell Carcinoma of GB .pdf

DOI： 10.2169/internalmedicine.53.1939

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Chronic kidney disease (CKD) is a major public health problem. However, few studies have examined the significance of serum bilirubin as a risk factor for the development of CKD in the general Japanese population. The subjects comprised 413 men (mean age: 79±9 years; (range, 60-100 years) and 637 women (mean age: 81±8 years; range, 60-106 years) who visited the medical department of Seiyo Municipal Nomura Hospital. We examined the relationship between increased serum bilirubin and renal function that was evaluated by estimated glomerular filtration rate (eGFR) using CKD-EPI equations modified by a Japanese coefficient. Stepwise multiple regression analysis with eGFR as the objective variable, and adjusted risk factors as the explanatory variables, showed that serum bilirubin (β = 0.11, P<0.001) was significantly and independently associated with eGFR, in addition to gender, age, prevalence of antihypertensive medication, triglycerides, prevalence of antidiabetic medication, and serum uric acid. Compared with stages 1+2 (eGFR ≥60.0 ml/min/1.73 m2), mean multivariate-adjusted odds ratio {95% (confidence interval (CI)} for hypobilirubinemia (first quartile, <0.52 mg/dL) was 3.52 (range: 1.88-6.59). Next, to control potential confounding factors, data were further stratified by gender, age, medication (antihypertensive, antidyslipidemic, and antidiabetic agents), and prevalence of cardiovascular disease. The standardized coefficient for eGFR was significant in both groups, and there was no interaction between the groups. Our data demonstrated an independent positive association between serum bilirubin and eGFR in both genders. Low serum bilirubin level would be useful as a potential risk factor for renal function.

File： PLoS One 2014 Bilirubin and eGFR.pdf

DOI： 10.1371/journal.pone.0115294

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Serum bilirubin may have a beneficial role in preventing oxidative changes in atherosclerosis. Limited information is available on whether serum total bilirubin is an independent confounding factor for carotid atherosclerosis {for example, intima-media thickness (IMT), plaque} measured noninvasively by B-mode ultrasonography only among elderly persons. The study subjects were 325 men aged 79 ± 8 (mean ± standard deviation) years and 509 women aged 81 ± 8 years that were enrolled consecutively from patients aged ≥ 60 years in the medical department. Carotid IMT and plaque were derived via B-mode ultrasonography. Multiple linear regression analysis showed that in men age (β = 0.199, p = 0.002), smoking status (β = 0.154, p = 0.006), GGT (β = -0.139, p = 0.039), and GGT (β = -0.133, p = 0.022) were significantly and independently associated with carotid IMT, and in women age (β = 0.186, p < 0.001), systolic blood pressure (β = 0.104, p = 0.046), diastolic blood pressure (β = -0.148, p = 0.004), prevalence of antihypertensive medication (β = 0.126, p = 0.004), fasting plasma glucose (β = 0.135, p = 0.003), GGT (β = -0.104, p = 0.032), estimated glomerular filtration rate, serum bilirubin (β = -0.119, p = 0.006), and prevalence of cardiovascular disease (CVD) (β = 0.103, p = 0.017) were also independently associated with carotid IMT. The odds ratios (ORs) {95% confidence interval (CI)} of increasing serum bilirubin category were negatively associated with carotid IMT ≥ 1.0 mm and plaque in both genders. Compared to subjects with a serum bilirubin of Quartile-1, the multivariate-OR (95% CI) of carotid plaque was 0.25 (0.11-0.57) in the Quartile-4 male group, and 0.41 (0.21-0.78) in the Quartile-2 female group, 0.51 (0.26-0.98) in the Quartile-3 female group, and 0.46 (0.24-0.89) in the Quartile-4 female group. Our data demonstrated an independently negative association between serum bilirubin and carotid atherosclerosis in both genders.

File： PLoS One 2014 Bilirubin Negatively Associated with Carotid Atherosclerosis.pdf

DOI： 10.1371/journal.pone.0114281

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BACKGROUND: It is not clear whether elevated uric acid is a risk factor for the onset of impaired fasting glucose after stratifying by baseline fasting plasma glucose levels. We conducted a community-based retrospective longitudinal cohort study to clarify the relationship between uric acid levels and the onset of impaired fasting glucose, according to baseline fasting plasma glucose levels. METHODS: We enrolled 6,403 persons (3,194 men and 3,209 women), each of whom was 18-80 years old and had > 2 annual check-ups during 2003-2010. After excluding persons who had fasting plasma glucose levels ≥ 6.11 mM and/or were currently taking anti-diabetic agents, the remaining 5,924 subjects were classified into quartiles according to baseline fasting plasma glucose levels. The onset of impaired fasting glucose was defined as fasting plasma glucose ≥ 6.11 mM during the observation period. RESULTS: In the quartile groups, 0.9%, 2.1%, 3.4%, and 20.2% of the men developed impaired fasting glucose, respectively, and 0.1%, 0.3%, 0.5%, and 5.6% of the women developed impaired fasting glucose, respectively (P trend <0.001). After adjusting for age, body mass index, systolic blood pressure, triacylglycerols, high density lipoprotein-cholesterol, creatinine, fatty liver, family history of diabetes, alcohol consumption, and current smoking, uric acid levels were positively associated with onset of impaired fasting glucose in men with highest-quartile fasting plasma glucose levels (adjusted hazard ratio, 1.003; 95% confidence interval, 1.0001-1.005, P = 0.041). CONCLUSIONS: Among men with high fasting plasma glucose, hyperuricemia may be independently associated with an elevated risk of developing impaired fasting glucose.

File： PLoS One 2014 Hyperuricemia & IFG.pdf

DOI： 10.1371/journal.pone.0107882

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

Subclinical hypothyroidism (SCH) has been associated with type 2 diabetes mellitus. However, it is unknown whether common complications of type 2 diabetes, such as diabetic nephropathy, are also present with SCH. Here, we investigated the association between SCH and diabetic nephropathy among Japanese patients with type 2 diabetes mellitus. In this multicenter cross-sectional study, we recruited 414 such patients who had no previous history of thyroid disease. Serum thyroid hormone levels and the urinary albumin:creatinine ratio were measured. SCH was defined as an elevated thyroid-stimulating hormone (TSH) level (>4.0 mIU/L), and diabetic nephropathy was defined as urinary albumin/creatinine ratio ≥300 mg/g. The prevalence of SCH was 8.7% (n = 36) among patients with type 2 diabetes mellitus. The SCH group had a higher prevalence of dyslipidemia (p = 0.008) and diabetic nephropathy (p = 0.014) than the euthyroid group. Multivariate analysis identified significant positive associations between diabetic nephropathy and SCH (odds ratio [OR], 3.51; 95% confidence interval [CI], 1.10-10.0; p = 0.034), hypertension (OR, 4.56; 95% CI, 1.69-14.7; p = 0.001), and smoking (OR, 3.02; 95% CI, 1.14-7.91; p = 0.026). SCH may be independently associated with diabetic nephropathy in Japanese patients with type 2 diabetes mellitus.

File： Endocr J 2014 Subclinical hypothyroidism & diabetic nephropathy.pdf

DOI： 10.1507/endocrj.EJ14-0206

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN SOC INTERNAL MEDICINE  

The present report describes a case of a patient with hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infection who was treated with tenofovir disoproxil (TDF)-based highly active antiretroviral therapy (HAART) and who achieved HBs antigen (Ag)/antibody (Ab) seroconversion. An 18-year-old Japanese man with HIV and HBV co-infection presented to our hospital. His CD4 count was decreased, and TDF-based HARRT was started. At 30 months after initiation of therapy, HBsAg was not detected. At 36 months after initiation of therapy, HBsAb was detected. We conclude that TDF-based therapy is useful for the management of patients with HBV and HIV co-infection.

File： Intern Med 2014 HBV-HIV co-infection treated with tenofovir.pdf

DOI： 10.2169/internalmedicine.53.2131

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhosis, liver failure, and complicated hepatocellular carcinoma. In addition, NAFLD is a risk factor for the development of other serious diseases, such as diabetes or cardiovascular disease. Therefore, the detection of early-stage NAFLD is important. Many studies have described the factors that predict the presence of NAFLD and its onset, and several markers have been identified. These markers have enabled the identification of high-risk patients and have improved routine medical practice. To prevent advanced disease, clinicians need to have simple markers that predict the onset of NAFLD so that interventions can be started at much earlier stages of disease. This review summarizes the current state of knowledge regarding independent factors, as reported in large studies, that predict the presence of NAFLD and its onset, especially markers that can be used in daily medical practice, such as physical measurements and blood tests.

File： J Gastroenterol Hepatol 2013 NAFLD Review.pdf

DOI： 10.1111/jgh.12251

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOMED CENTRAL LTD  

BACKGROUND: Although the outcomes of pancreatic cancer have been improved by gemcitabine, the changes in its characteristics and long-term outcomes within the gemcitabine era remain unclear. This study was conducted to identify clinical characteristics of pancreatic cancer patients within the gemcitabine era. METHODS: A retrospective chart review was performed at 10 centers for 1,248 consecutive patients who were ever considered to have a diagnosis of pancreatic cancer between 2001 and 2010. Data collected included demographics, diagnosis date, clinical stage, treatment, and outcome 1,082 patients met the inclusion criteria and were analyzed further. The chi-square test, Student's t-test, and Mann-Whitney U-test were used for statistical analysis. Outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Differences in survival analyses were determined using the log-rank test. RESULTS: The distribution of clinical stages was: I, 2.2% II, 3.4% III, 13% IVa, 27% and IVb, 55%. Chemotherapy alone was administered to 42% of patients and 17% underwent resection. The 1-, 3-, and 5-year survival rates were 39%, 13%, and 6.9%, respectively. The median survival time was 257 days, but differed considerably among treatments and clinical stages. Demographics, distribution of clinical stage, and cause of death did not differ between groups A (2001-2005, n=406) and B (2006-2010, n=676). However, group B included more patients who underwent chemotherapy (P<0.0001) and fewer treated with best supportive care (P=0.0004), mirroring improvements in this group's long-term outcomes (P=0.0063). Finally, factors associated with long-term outcomes derived from multivariate analysis were clinical stage (P<0.0001), location of the tumor (P=0.0294) and treatments (surgery, chemotherapy) (<0.0001). CONCLUSIONS: Long-term outcomes in pancreatic cancer has improved even within the gemcitabine era, suggesting the importance of offering chemotherapy to patients previously only considered for best supportive care. Most patients are still diagnosed at an advanced stage, making clinical strategy development for diagnosing pancreatic cancer at earlier stages essential.

File： BMC Gastroenterol 2013 EPOCH.pdf

DOI： 10.1186/1471-230X-13-134

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OBJECTIVE: We estimated the prevalence of nocturnal intermittent hypoxia, a surrogate marker of obstructive sleep apnoea, among type 2 diabetes mellitus (T2DM) patients and examined the association between nocturnal intermittent hypoxia and microvascular diseases. DESIGN AND METHODS: We recruited 513 Japanese patients (292 men and 221 women) with T2DM. Nocturnal intermittent hypoxia was diagnosed using the 3% oxygen desaturation index, with less than five events per hour corresponding to normal and five events or more per hour corresponding to nocturnal intermittent hypoxia. RESULTS: The prevalence of nocturnal intermittent hypoxia was 45.4% among T2DM patients. The nocturnal intermittent hypoxia group was older and had a higher BMI, greater weight change since the age of 20 years, higher smoking rate and increased prevalence of hypertension, hyperlipidaemia, microalbuminuria and macroalbuminuria. Microalbuminuria (model 1: odds ratio (OR), 3.41; 95% CI, 1.85-6.40; model 2: OR, 3.69; 95% CI, 1.85-7.59 and model 3: OR, 3.12; 95% CI, 1.45-6.95) and nephropathy (model 1: OR, 4.51; 95% CI, 1.58-15.1; model 2: OR, 7.31; 95% CI, 2.11-31.6 and model 3: OR, 5.23; 95% CI, 1.45-23.8) were derived as factors from all the three statistical models and constantly associated with nocturnal intermittent hypoxia only in women. CONCLUSIONS: Nocturnal intermittent hypoxia was highly prevalent among T2DM patients and may be an independent associated risk factor for microalbuminuria in Japanese women with T2DM.

File： Eur J Endocrinol 2013 Nocturnal intermittent hypoxia and diabetic nephropathy.pdf

DOI： 10.1530/EJE-13-0086

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：FEDERATION AMER SOC EXP BIOL  

IBDs are thought to involve uncontrolled innate and adaptive immunity against intestinal self-antigens and bacterial antigens. Mouse CA I is a major cecal bacterial antigen in fecal extracts and is implicated in the pathogenesis of IBD. We show here that oral tolerization to CA I induced antigen-specific protection from intestinal inflammation in a murine model. Oral administration of CA I but not irrelevant antigen (KLH) ameliorated CD4(+)CD25(-) T cell transfer murine colitis and DSS-induced murine colitis. Next, we investigated the mechanisms involved in the therapeutic effects of oral administration, such as induction of ALDH1a2, transcription factors, cytokines, CD103(+)CD11c(+) DCs, and generation of Tregs. Oral administration of CA I induced ALDH1a2 mRNA expression in the MLN and colon. When compared with PBS-treated mice, CA I-treated mice had higher Foxp3(+)CD4(+)CD25(+) Treg and CD103(+)CD11c(+) DC numbers in the MLN and colon; had higher TGF-β production in the MLN and colon; had lower RORγt mRNA expression in the MLN and colon; and had lower IL-17 mRNA expression and production in the MLN. These results demonstrate that oral administration of CA I induced antigen-specific immune tolerance by generating Foxp3(+)CD4(+)CD25(+) Tregs and inhibiting Th17 cells in a murine colitis model, thus suggesting that oral tolerization with CA I is an effective therapeutic strategy for IBD regulation.

File： J Leukoc Biol 2013 Carbonic anhydrase Iameliorates murine experimental colitis.pdf

DOI： 10.1189/jlb.1212612

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PURPOSE: B cell-activating factor (BAFF) is expressed in adipocytes and affects lipogenesis and insulin sensitivity. In addition, the BAFF receptor is expressed in visceral adipose tissue and liver. The aim of this study was to analyze serum BAFF levels in patients with nonalcoholic steatohepatitis (NASH) and simple steatosis (SS) and to compare their respective clinical and histological findings. METHODS: A total of 96 patients with nonalcoholic fatty liver disease (20 with SS and 76 with NASH) were enrolled and their serum BAFF levels were analyzed. Comprehensive blood chemistry analysis and histological examination of liver samples were also conducted. RESULTS: Serum BAFF levels were higher in patients with NASH than in those with SS (p = 0.016). NASH patients with ballooning hepatocytes and advanced fibrosis had higher levels of BAFF in sera (p = 0.016 and p = 0.006, respectively). In addition, the prevalence of NASH increased significantly as the serum BAFF level increased (p = 0.004). Higher serum BAFF levels were found to be an independent risk factor for development of NASH (OR 1.003, 95% CI 1.0003-1.006; p = 0.047). CONCLUSIONS: Nonalcoholic steatohepatitis patients had higher levels of serum BAFF than patients with SS, and higher levels were associated with the presence of hepatocyte ballooning and advanced fibrosis. The serum BAFF level may be a useful tool for distinguishing NASH from SS.

File： Hepatol Int 2013 BAFF in NAFLD.pdf

DOI： 10.1007/s12072-012-9345-8

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The motilin receptor belongs to a family of Class I G protein-coupled receptors, and is an important endogenous regulator of gastrointestinal motor function. Motilin and erythromycin, two chemically distinct full agonists of the motilin receptor, are known to bind to distinct regions of this receptor, based on previous systematic mutagenesis of extracellular regions that dissociated the effects on these two agents. The action of these different chemical classes of agonists likely yields a common activation state of the cytosolic face of this receptor that is responsible for interaction with its G protein. In the current work, we studied the predicted transmembrane (TM) domains of this receptor for functional responses to motilin and erythromycin. Motilin receptor constructs were prepared in which each residue in the TM domains was mutated to alanine or valine. Each construct was expressed in COS cells and characterized for motilin and erythromycin binding and intracellular calcium responses stimulated by both agonists. Constructs with mutations of residues, Asp94, Leu95, Arg97 and Trp99 in TM2, Ser169 in TM4, and Tyr321 and Glu325 in TM6, were responsible for the negative impact on biological activity stimulated by erythromycin, but had no effect on motilin responses. On the other hand, constructs with mutations of residues, Leu113 in TM3, Pro172 in TM4, Trp250 and Tyr255 in TM5, and Gln334 in TM7, were negatively responsive to both erythromycin and motilin. These data support important roles of new regions in the TM domains of the motilin receptor for erythromycin action, suggesting differential mechanisms of actions by peptidyl and non-peptidyl ligands.

File： Reg Pep 2012 Utsunomiya.pdf

DOI： 10.1016/j.regpep.2012.10.003

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B cell-activating factor (BAFF) is a cytokine belonging to the tumor necrosis factor (TNF) superfamily. It has been reported that BAFF is elevated in patients with autoimmune pancreatitis and contributes to the malignant potential of blood cancers and solid tumors. In this study, clinical evidence of increased BAFF levels in patients with pancreatic ductal adenocarcinoma (PDAC) was obtained, and the roles and mechanisms of BAFF in PDAC were clarified in human tissues of PDAC and from in vitro data of PDAC cell lines. Serum levels of BAFF in patients with PDAC were significantly higher than in healthy subjects (p = 0.0121). Patients with UICC stage IV PDAC (T1-4, N0-1, M1) had significantly higher levels of serum BAFF compared to patients with PDAC (p = 0.0182). BAFF was remarkably expressed in infiltrating B lymphocytes surrounding pancreatic cancer in human pancreatic tissues, suggesting that BAFF may play a role in progression of pancreatic cancer. PDAC cell lines were cultured with human recombinant BAFF, and morphology and gene expression were analyzed; pancreatic cancer cells changed to a fibroblast-like morphology, and showed altered gene expression of E-cadherin, vimentin and Snail. These BAFF-induced changes reflect enhanced cell motility and invasion. BAFF-R-overexpressing cell clones confirmed the association between these BAFF-induced changes and epithelial-mesenchymal transition (EMT)-related genes. BAFF was elevated in patients with metastatic advanced PDAC and induced alterations in PDAC cells via regulation of EMT-related genes. Elucidation of the precise role and mechanism of control of BAFF may lead to new therapeutic approaches with the aim of improving pancreatic cancer survival.

File： PLoS One 2013 BAFF & Pancreatic Cancer.pdf

DOI： 10.1371/journal.pone.0071367

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Authorship：Last author,　Corresponding author   Language：English  

Primary biliary cirrhosis (PBC) is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver. It is a rare disease with prevalence of less than one in 2000. Its prevalence in developing countries is increasing presumably because of growth in recognition and knowledge of the disease. PBC is thought to result from a combination of multiple genetic factors and superimposed environmental triggers. The contribution of the genetic predisposition is evidenced by familial clustering. Several risk factors, including exposure to infectious agents and chemical xenobiotics, have been suggested. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The prognosis of PBC has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.

File： Hepatic Medicine 2012 PBC review.pdf

DOI： 10.2147/HMER.S25998

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER HEIDELBERG  

Hepatitis C virus (HCV) infection alters fatty acid synthesis and metabolism in association with HCV replication. The present study examined the effect of serum fatty acid composition on interferon (IFN)-based therapy. Fifty-five patients with HCV were enrolled and received IFN-based therapy. Patient characteristics, laboratory data (including fatty acids), and viral factors that could be associated with the anti-HCV effects of IFN-based therapy were evaluated. The effects of individual fatty acids on viral replication and IFN-based therapy were also examined in an in-vitro system. Multivariate logistic regression analysis showed that the level of serum palmitic acid before treatment and HCV genotype were significant predictors for rapid virological response (RVR), early virological response (EVR), and sustained virological response (SVR). High levels of palmitic acid inhibited the anti-HCV effects of IFN-based therapy. HCV replication assays confirmed the inhibitory effects of palmitic acid on anti-HCV therapy. The concentration of serum palmitic acid is an independent predictive factor for RVR, EVR, and SVR in IFN-based antiviral therapy. These results suggest that the effect of IFN-based antiviral therapy in patients with HCV infection might be enhanced by treatment that modulates palmitic acid levels.

File： Lipids 2012 Palmitic Acid & IFN-based therapy for HCV.pdf

DOI： 10.1007/s11745-012-3716-8

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The motilin receptor (MR) belongs to a family of Class I G protein-coupled receptors that also includes growth hormone secretagogue receptor (GHSR). Their potentially unique structure and the molecular basis of their binding and activation are not yet clear. We previously reported that the perimembranous residues in the predicted extracellular loops and amino-terminal tail of the MR were important for responses to the natural peptide ligand, motilin, and the transmembrane domains of the MR were important for a non-peptidyl ligand, erythromycin. We also reported that the perimembranous residues in the second extracellular loop of the GHSR were critical for natural ligand ghrelin binding and activity. The MR is 52% identical to GHSR, with 86% sequence identity in the transmembrane domains. In the current work, to gain insight into a relationship between MR and GHSR, we studied functional responses to motilin, erythromycin and ghrelin of expression cells of chimeric constructs of MR and GHSR and co-expression cells of both MR and GHSR. We also generated human MR transgenic mice, and clarified a relationship between motilin and ghrelin. MR(1-62)/GHSR(68-366) construct responded only to ghrelin, MR(1-102)/GHSR(108-366) responded to ghrelin and erythromycin, and MR(1-129)/GHSR(135-366) and MR(1-178)/GHSR(184-366) responded to erythromycin, while GHSR(1-183)/MR(179-412) responded to neither motilin, erythromycin nor ghrelin. MR and GHSR co-expression cells have no additional responses to these ligands. Motilin or erythromycin administration to human MR transgenic mice resulted in a decrease of serum acyl-ghrelin levels, while MR and GHSR mRNA expression in the gastrointestinal tracts were not changed. These data suggested that in species expressing both motilin-MR and ghrelin-GHSR, there is a compensatory relationship in vivo.

File： Reg Pep 2012 Nunoi.pdf

DOI： 10.1016/j.regpep.2012.03.001

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER MASSON  

A lesion was discovered in the tail of the pancreas by ultrasonography performed during a health checkup for a 59-year-old Japanese man. Abdominal contrast-enhanced computed tomography (CE-CT) revealed strong enhancement in a 4-cm tumor in the pancreatic tail and in a 1-cm tumor in the pancreatic body. Serum glucagon levels were elevated to 54,405 pg/mL and a preoperative diagnosis of glucagonoma was made. The pancreatic tail and spleen were resected en bloc, along with a protruding tumor in the pancreatic body. However, histopathological evaluation revealed diffuse glucagonoma throughout the pancreas. When we retrospectively reviewed abdominal CE-CT after the operation, the entire pancreas was seen to be enlarged and diffusely enhanced by strong spots. Immunohistochemical examination using anti-CD31 demonstrated rich microvessels in two solid glucagonomas as well as microglucagonoma throughout the entire pancreas, indicating hypervascularity. Enlarged pancreas and diffuse enhancement of the pancreas by strong spots may be characteristic features of diffuse glucagonoma on abdominal CE-CT. (C) 2011 Elsevier Masson SAS. All rights reserved.

File： Clin Res Hepatol Gastroenterol 2012 Diffuse glucagonoma.pdf

DOI： 10.1016/j.clinre.2011.12.003

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

BACKGROUND: The manner in which ribavirin (RBV) enhances the antiviral effects of interferon (IFN) against hepatitis C virus (HCV) remains unknown. We investigated whether RBV modifies IFN-stimulated genes (ISGs) in vivo and in vitro. METHODS: We measured the messenger RNA (mRNA) levels of ISGs in T lymphocytes from patients with HCV infection who were receiving IFN-α therapy with or without RBV. We added RBV and/or IFN-α to a plasmid-based HCV replication system containing a full-length HCV genotype 1a sequence in HepG2 and Huh7 cell lines and the JFH-1 HCV genotype 2a sequence in Huh7 cell lines and measured levels of ISGs and autocrine IFN-β. RESULTS: The expression of protein kinase R and myxovirus resistance A mRNA was enhanced more with IFN-α and RBV than by IFN-α alone in assays in vivo and in vitro. Such enhancement depended on autocrine IFN-β being enhanced by RBV. RBV upregulated interleukin 8 (IL-8) in the absence of IFN-α. The IL-8 upregulation induced by RBV was responsible for the activation of activator protein 1 (AP-1). CONCLUSIONS: Ribavirin augments the anti-HCV effects of IFN-α induced by ISGs through enhancing autocrine IFN-β. Moreover, RBV can enhance IL-8 through activating AP-1. Improved understanding of ISG modulation by RBV would help to establish a means of eliminating HCV.

File： J Infect Dis 2012 HCV IFN mechanism.pdf

DOI： 10.1093/infdis/jis025

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

Inflammatory bowel disease (IBD), which is characterized by a dysregulated intestinal immune response, is postulated to be controlled by intestinal self-antigens and bacterial Ags. Fecal extracts called cecal bacterial Ag (CBA) have been implicated in the pathogenesis of IBD. In this study, we identified a major protein of CBA related to the pathogenesis of IBD and established a therapeutic approach using Ag-pulsed regulatory dendritic cells (Reg-DCs). Using two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry, carbonic anhydrase I (CA I) was identified as a major protein of CBA. Next, we induced colitis by transfer of CD4(+)CD25(-) T cells obtained from BALB/c mice into SCID mice. Mice were treated with CBA- or CA I-pulsed Reg-DCs (Reg-DCs(CBA) or Reg-DCs(CA1)), which expressed CD200 receptor 3 and produced high levels of IL-10. Treatment with Reg-DCs(CBA) and Reg-DCs(CA1) ameliorated colitis. This effect was shown to be Ag-specific based on no clinical response of irrelevant Ag (keyhole limpet hemocyanin)-pulsed Reg-DCs. Foxp3 mRNA expression was higher but RORγt mRNA expression was lower in the mesenteric lymph nodes (MLNs) of the Reg-DCs(CA1)-treated mice compared with those in the MLNs of control mice. In the MLNs, Reg-DCs(CA1)-treated mice had higher mRNA expression of IL-10 and TGF-β1 and lower IL-17 mRNA expression and protein production compared with those of control mice. In addition, Reg-DCs(CBA)-treated mice had higher Foxp3(+)CD4(+)CD25(+) and IL-10-producing regulatory T cell frequencies in MLNs. In conclusion, Reg-DCs(CA1) protected progression of colitis induced by CD4(+)CD25(-) T cell transfer in an Ag-specific manner by inducing the differentiation of regulatory T cells.

File： J Immunol 2012 IBD.pdf

DOI： 10.4049/jimmunol.1100559

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPAN ENDOCRINE SOC  

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral hypoglycemic agents for the management of diabetes that elevate the plasma concentration of active glucagon-like peptide-1 via inhibition of DPP-4. They effectively lower not only glycosylated hemoglobin levels, but also fasting and postprandial plasma glucose levels. Patients with diabetes occasionally consume an overdose of oral hypoglycemic agents in suicide attempts: the prevalence of depression is high in patients with diabetes, and depression is a strong risk factor for suicide. We encountered an 86-year-old woman with type 2 diabetes and depression, who was transferred to the emergency room 4h after ingestion of 1,700 mg of the DPP-4 inhibitor sitagliptin (1,700 mg is 17 times greater than the approved maximum dose). Upon arrival, she was fully conscious, plasma glucose was 124 mg/dL, and serum immunoreactive insulin level was 5.81 µU/mL. Thereafter, the plasma concentration of sitagliptin rose to 3,793 nM, which is 4.5 times higher than the value found under regular treatment with the maximum dose. The patient did not suffer from hypoglycemia, suggesting that a single oral overdose of sitagliptin is unlikely to cause hypoglycemia. A literature review of oral anti-diabetic agents revealed that overdose of biguanides is occasionally fatal when immediate intensive care is not provided. In summary, sitagliptin is a good treatment option for diabetic elderly patients or patients with psychiatric disorders who are suicidal and do not require insulin.

File： Endocr J 2012 Sitagliptin overdose.pdf

DOI： 10.1507/endocrj.EJ11-0390

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.51.7578

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：LIPPINCOTT WILLIAMS & WILKINS  

OBJECTIVES: Overexpression of B Cell-activating factor (BAFF) is involved in autoimmunity, but little is known about its role in autoimmune pancreatitis (AIP). The aim of this study was to investigate the role of BAFF in the diagnosis and pathogenesis of AIP. METHODS: Patients with AIP (n = 19) were compared with 2 disease control groups (chronic pancreatitis [n = 17] and pancreatic cancer [n = 15]) and a healthy subject group (n = 19). Serum BAFF levels were assessed using an enzyme-linked immunosorbent assay. The expressions of BAFF and BAFF receptor in the pancreatic tissue of patients with AIP were estimated using immunohistochemistry. RESULTS: Mean serum BAFF levels were higher in the patients with AIP than in the patients with chronic pancreatitis, the patients with pancreatic cancer, and the healthy subjects (P < 0.0001 for all groups). Using the cutoff value of 1389 pg/mL, the sensitivity and specificity to differentiate AIP from disease and healthy controls were 89.5% and 92.2%, respectively. Glucocorticoid therapy decreased serum BAFF levels below 1389 pg/mL in all patients with AIP (P < 0.0001). B Cell-activating factor and BAFF receptor were expressed on cells infiltrating the pancreas of patients with AIP. CONCLUSIONS: B Cell-activating factor could be a novel marker for diagnosis and treatment response in AIP and may contribute to its pathogenesis.

File： Pancreas 2011 AIP.pdf

DOI： 10.1097/MPA.0b013e3182143b10

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BACKGROUND: A few reports suggest that the emergence of double balloon endoscopy (DBE) has likely changed the clinical picture of small bowel tumors (SBTs). AIM: To further clarify the characteristics of SBTs detected by DBE. METHODS: A retrospective chart review was conducted in 227 patients who had undergone DBE. RESULTS: The SBT group contained more symptomatic patients than the non-SBT group (90% vs. 49%, P<0.0005) with a significantly higher rate of gastrointestinal symptoms at presentation (72% vs. 33%, P<0.005). Twenty patients (8.8%) were eventually diagnosed with SBT, and their indications for DBE were obscure gastrointestinal bleeding (n=5), abdominal pain (n=5), abdominal fullness (n=5), vomiting (n=2), and diarrhea (n=1). Tumors were located in the jejunum in 14 patients (70%) and in the ileum in 6 (30%). A final histological diagnosis was assigned to all 20 patients: primary adenocarcinoma (n=8, 40%), malignant lymphoma (n=5, 25%), metastatic cancer (n=4, 20%), gastrointestinal stromal tumor (n=1, 5%), carcinoid tumor (n=1, 5%) and inflammatory fibroid polyp (n=1, 5%). Stenosis or ulceration were the most frequently observed endoscopic findings (n=13, 65%). All primary adenocarcinomas and three of four (75%) metastatic cancers showed stenosis or ulceration. Three of five (60%) malignant lymphomas showed multiple lymphomatous polyps. All patients but one underwent surgical resection or chemotherapy or both. CONCLUSION: DBE is a safe and useful procedure that enables a precise diagnosis of SBTs.

File： Dig Dis Sci 2011 DBE & SBT.pdf

DOI： 10.1007/s10620-011-1741-8

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A 77-year-old man with hypertension, diabetes mellitus, ischemic heart disease and a smoking habit presented at our hospital with sudden abdominal pain. Computed tomography indicated edematous swelling and pneumatosis of the intestinal wall in a localized area of the ascending colon with inflamed adipose tissue. Acute mesenteric ischemia was diagnosed. Abdominal angiography showed stenosis of the mesenteric arteries. Virtual histology-intravascular ultrasound imaging indicated a fibrous change in the superior mesenteric artery with a necrotic core. Endovascular treatment with stent placement after percutaneous transluminal angioplasty was effective. Surgery would usually be considered as the first choice for treating patients with acute mesenteric ischemia; however, when this condition is complicated with metabolic diseases, stenotic changes in the mesenteric arteries that would normally be found in patients with chronic mesenteric ischemia need to be considered to ensure optimal treatment.

File： Clin J Gastroenterol 2011 Acute mesenteric ischemia.pdf

DOI： 10.1007/s12328-011-0236-7

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

AIM:   There is an ongoing need for predictors of long-term outcomes for patients with primary biliary cirrhosis (PBC). Biochemical response to ursodeoxycholic acid (UDCA) has been introduced to predict development of symptoms by our group (Ehime criteria) and to predict long-term outcomes in Western countries (Paris, Barcelona and Rotterdam criteria). The aim of this study was to evaluate whether these criteria are also useful to predict long-term outcomes in Japanese patients with PBC. METHODS:   A retrospective chart review was conducted for 227 Japanese patients with PBC. Patients taking UDCA with an observation period of more than 6 months were included in the study. Data collection included demographics, biochemical and serological markers, and histological stage. Four different criteria regarding biochemical response to UDCA were compared and evaluated. RESULTS:   In total, 138 patients met the inclusion criteria and underwent analysis. Using the Ehime criteria, the transplant-free survival rate was significantly higher in responders than in non-responders (P = 0.010). The Paris criteria also predicted long-term outcomes in our population (P = 0.003), whereas the Barcelona and Rotterdam criteria showed no such association (P = 0.282 and P = 0.553, respectively). CONCLUSION:   Good biochemical response to UDCA according to the Ehime and Paris criteria is associated with long-term outcome in Japanese patients with PBC and allows identification of non-responders who may benefit from further trials. Finally, Ehime criteria should be validated in a different patient cohort.

File： Hepatol Res 2011 Biochemical response in Japanese PBC.pdf

DOI： 10.1111/j.1872-034X.2011.00782.x

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Hypoglycemia caused by insulin-like growth factor II is difficult to control. A 77-year-old woman was diagnosed with gastric cancer and multiple liver metastases in September 2006 and underwent chemotherapy; however, at that time there were no symptoms of hypoglycemia. From January 2007 onwards, hypoglycemic comas and symptoms of hypoglycemia began to appear frequently. Her serum level of insulin was normal; thus, we suspected the presence of big insulin-like growth factor II was causing the hypoglycemia. This was proven by Western immunoblotting and we diagnosed non-islet cell tumor hypoglycemia associated with gastric cancer. Overnight nutrition provided via a central venous catheter port to prevent hypoglycemia allowed the patient to become ambulant and to remain free of hypoglycemic coma at follow-up until her death 7 months later.

File： Clin J Gastroenterol 2011 Insulin-like growth factor in gastric cancer.pdf

DOI： 10.1007/s12328-010-0200-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: Fine-powder cisplatin has recently been developed, allowing the easy manufacture of high-density cisplatin-lipiodol suspensions. The aim of this study is to evaluate the efficacy and toxicity of transcatheter arterial chemoembolization (TACE) with fine-powder cisplatin and lipiodol suspension against advanced hepatocellular carcinoma (HCC).
Methodology: We prospectively analyzed 20 patients (16 men, 4 women) with inoperative advanced HCC without extrahepatic metastases who underwent TACE with fine-powder cisplatin and lipiodol suspension in our hospital between August 2006 and December 2008. All patients were administered a suspension of fine-powder cisplatin at 10mg/1cm of tumor diameter.
Results: Partial response was seen in 10 cases, with stable disease in 7 cases and progressive disease in 3 cases. Overall response rate was 50%. The 1-year survival rate was 90%. Adverse effects (&gt;= grade 3) occurred in 40%, with vomiting in 5%, thrombocytopenia in 15%, elevated serum bilirubin in 20%, decreased serum albumin in 5%, fever in 65%, general fatigue in 15% and anorexia in 30%. However, no other life-threatening, adverse events were observed.
Conclusion: TACE with fine-powder cisplatin suspended in lipiodol provides better therapeutic efficacy, suggesting the potential usefulness of this agent in the treatment of advanced HCC.

File： Hepatogastroenterology 2011 HCC Cisplatin-Lp.pdf

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.50.5203

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DOI： 10.2169/internalmedicine.50.5919

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.50.5340

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Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic liver disease of autoimmune etiology, characterized by injury of the intrahepatic bile ducts that may eventually lead to cirrhosis and liver failure. Evidence suggests cardinal roles for both environmental factors and genetic susceptibility. Nevertheless, the absolute etiology of PBC is unclear, despite recent well-designed case-control studies that reported environmental risk factors, including infectious agents, for PBC. Of the reported infectious agents, some of them are not reproducible and remain controversial. However, infection is no doubt one of the major risks among the environmental factors. This is supported by the fact that infectious agents in autoimmune diseases express antigens resulting in molecular mimicry and xenobiotics that play a role in breaking tolerance. Taken together, recent findings from genome wide assays as well as novel animal models may enable us to better understand the mechanism of pathogenesis responsible for this disease.

DOI： 10.3233/DMA-2010-0747

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

AIM: Hepatocellular carcinoma (HCC) nodules close to the liver surface exhibit high recurrence compared to those in distal parts of the liver. Moreover, when nodules remain adjacent to the gastrointestinal tract or gallbladder, severe complications such as perforation of those organs may occur due to invasive therapy. Percutaneous radiofrequency ablation (PRFA) with artificial ascites or laparoscopic radiofrequency ablation (LRFA) are used to treat these patients to avoid complications. The purpose of the present study was to assess the efficacy and safety of these two methods. METHODS: Subjects comprised 74 patients (48 men, 26 women; mean age, 68.5 +/- 8.0 years; range, 46-89 years) with 86 HCC nodules. PRFA with artificial ascites was carried out for 37 patients (44 nodules) and LRFA was used for 37 patients (42 nodules). Clinical profiles were compared between groups. RESULTS: No significant differences in clinical profiles were found between patients treated by PRFA or LRFA. Mean number of treatments was significantly lower for LRFA (1.0 +/- 0.0) than for PRFA (2.1 +/- 1.0, P < 0.001). Mean number of PRFA treatments was 2.2 +/- 1.0 in patients with HCC nodules >2 cm in diameter, whereas all tumors were completely ablated with only one session of LRFA. The safety margin was significantly wider for LRFA than for PRFA. CONCLUSION: LRFA is a better treatment option for ablation of HCC nodules >2.0 cm in diameter.

File： Dig Endosc 2009 Laparoscopic RFA vs RFA with artificial ascites.pdf

DOI： 10.1111/j.1443-1661.2009.00836.x

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1186/1750-1172-3-1

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Other Link： http://link.springer.com/article/10.1186/1750-1172-3-1/fulltext.html

Authorship：Lead author   Language：English  

A 56-year-old gentleman with benign recurrent intrahepatic cholestasis (BRIC) suffered from recurrent episodes of pruritus for over 40 years. The treatment prescribed, namely cholestyramine, was minimally effective. However, rifampin 150 mg b.i.d promptly and completely relieved his severe pruritus. The diagnosis of BRIC, being a rare condition, may go unrecognized. The severity of the lifelong episodes of intermittent cholestasis with pruritus in BRIC may be extremely distressing to the affected patient. Administration of rifampin during the acute episode of severe pruritus led to a marked improvement in his quality of life.

File： Clin J Gastroenterol 2008 Rifampin in BRIC.pdf

DOI： 10.1007/s12328-008-0027-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS  

OBJECTIVE: Transcatheter arterial embolization (TAE) with gelatin sponge particles and iodized oil often yields poor results when used to treat unresectable multifocal hepatocellular carcinoma (HCC). The present study retrospectively investigated the utility of a novel combination chemotherapy regimen for treating multifocal HCC resistant to TAE. METHODS: Thirteen consecutive patients with unresectable multifocal HCC and resistance to TAE were treated with combination chemotherapy consisting of arterial chemoembolization with degradable starch microspheres (DSM) (150-4500 mg on Day 1), mitomycin-C (4-8 mg on Day 1), continuous arterial infusion of 5-fluorouracil (1250 mg/120 h), cisplatin (25-50 mg/120 h) and l-leucovorin (125 mg/120 h) for 10-19 weeks. RESULTS: The response rate was 84.6%, with complete response in one patient and partial response (PR) in 10 patients. In four of 10 patients with PR, the tumor was not observable, although the tumor marker did not completely decline to the normal range. The 1-, 2- and 3-year survival rates were 100, 28.9 and 9.6% in all, and 100, 33.3 and 0% in six patients with portal vein tumor thrombosis (PVTT). The median survival was 22.1 months in all and 17.1 months in six patients with PVTT. Thrombocytopenia of Grade III or higher was observed in eight patients. Laparoscopic splenectomy was performed before therapy in four patients with platelet counts of <70,000/mm(3), and during therapy in five patients with severe thrombocytopenia. CONCLUSIONS: This novel chemotherapy regimen achieved favorable results and may be useful in treating patients with unresectable multifocal HCC resistant to TAE.

File： Jpn J Clin Oncol 2008 Chemotherapy for HCC.pdf

DOI： 10.1093/jjco/hyn076

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Authorship：Lead author   Language：English   Publisher：WILEY  

Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.

File： Hepatol Res 2008 New Insights into AILD.pdf

DOI： 10.1111/j.1872-034X.2008.00366.x

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Language：English   Publisher：WILEY  

Most care of liver disease is in the ambulatory setting, and therefore the clinical needs of patients represent those of any other chronic illness. Emphasis must be given to preventative strategies such that liver lifetime (including pre-emptive strategies related to potential allograft survival) is maximised through timely intervention and avoidance of side effects. This review addresses the pertinent practical clinical concerns faced by clinicians as they manage adult patients with chronic liver disease, with an emphasis on preventing and managing symptoms and complications directly and indirectly related to the underlying disease.

File： Liver Int 2008 Preventative hepatology.pdf

DOI： 10.1111/j.1478-3231.2008.01816.x

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：W B SAUNDERS CO-ELSEVIER INC  

Primary biliary cirrhosis is a slowly progressive, cholestatic, and chronic liver disease in which the epithelium of the intrahepatic biliary tree is destroyed by a chronic inflammatory process. The origin of this disease, which mainly affects middle-aged women, is unknown but has characteristics favoring an autoimmune etiology. This article reviews the presentation and diagnosis of PBC in the 21st century.

File： Clinics in Liver Diseases 2008 PBC review.pdf

DOI： 10.1016/j.cld.2008.02.014

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

OBJECTIVE: This study was aimed at investigating the efficacy and safety of minimally invasive laparoscopic splenectomy in patients with hypersplenism secondary to cirrhosis. BACKGROUND: While advances have been made in the treatment of liver cancer and chronic hepatitis, certain treatments such as radio frequency ablation (RFA) must often be discontinued due to thrombocytopenia caused by hypersplenism. Laparoscopic splenectomy is performed to treat diseases as idiopathic thrombocytopenic purpura, but is contraindicated for hypersplenism in many institutions. Few studies have thus examined the safety and efficacy of this approach. METHODS: Efficacy and safety were retrospectively analyzed for laparoscopic splenectomies starting from January 2003. Relationships between postoperative increases in platelet count and thrombopoietin, platelet-associated immunoglobulin, excised spleen weight, and serum parameters were examined. Perioperative data of open splenectomies starting from January 1990 were compared with those of laparoscopic splenectomies. RESULTS: No laparoscopic cases were converted to open surgery in this series. Mean operative times of open and laparoscopic splenectomy were 205 and 173 min respectively. Mean blood losses were 750 and 359 ml (P < 0.05) and the mean weights of excised spleen were 460 and 525 g respectively. Postoperatively, no changes in liver function were noted, and platelet and leukocyte counts were significantly increased. Compared with preoperative platelet count, degree of increase at 2 weeks postoperatively did not correlate with preoperative thrombopoietin levels, but significantly correlated with levels of platelet-associated immunoglobulin and spleen volume (P < 0.05). Postoperative portal or splenic vein thrombosis (PSVT) was seen in 3 patients and these patients did not exhibit any clinical symptoms. CONCLUSIONS: Laparoscopic splenectomy is a safe technique for the treatment of hypersplenism and contributes to postoperative increases in platelet counts. Postoperative increases in platelet count seem to depend on platelet-associated immunoglobulin level and spleen weight, which may be valuable prognosticators.

File： World J Surg 2007 Laparoscopic splenectomy.pdf

DOI： 10.1007/s00268-006-0504-8

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

A 63-year-old man was admitted to hospital in 2003 for treatment of a hepatocellular carcinoma (HCC). He was negative for HBs antigen (HBsAg) and anti-HCV antibody, and positive for anti-HBs. He had a past history of chronic hepatitis B. In 1986, HBsAg had become negative with the development of anti-HBs. In 2003, an HCC was detected and liver resection was carried out. Histological examination revealed moderately differentiated HCC and slightly fibrotic liver. It is suggested that a diagnosis of HCC, combined with negativity for HBsAg and anti-HCV antibody, may include cases of past recovery from chronic hepatitis B, such as this case.

DOI： 10.2169/internalmedicine.46.1586

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING  

OBJECTIVE: Contrast-enhanced computed tomography (CECT) is regarded as the gold standard for assessing the efficacy of radiofrequency ablation (RFA) against hepatocellular carcinoma (HCC). We evaluated the efficacy of virtual ultrasonography (VUS) with contrast-enhanced ultrasonography (CEUS) vs. CECT for assessing the response to RFA. MATERIALS AND METHODS: Study 1: The therapeutic responses in 22 patients with 26 HCC nodules were assessed by CEUS with VUS as well as by CECT. The efficacy of treatment was based on whether the safety margin was greater than 5 mm after RFA. Study 2: In seven patients with seven HCC nodules, the nodules were treated by RFA and the therapeutic efficacy was assessed by CEUS with VUS. The number of RFA sessions was assessed. RESULTS: Compared with CECT, CEUS with VUS had a specificity of 77%, a sensitivity of 91.6%, and an accuracy of 84%. When the therapeutic response to RFA was analyzed by CECT only, 1.86 +/- 0.69 assessments (mean) were required, while when response was assessed by CEUS with VUS, 1.14 +/- 0.38 CECT assessments were required (P = 0.03). CONCLUSION: CEUS with VUS is effective in assessing the therapeutic response to RFA of HCC. Moreover, the number of CECT scans required is reduced by this approach.

File： Liver Int 2006 Virtual US.pdf

DOI： 10.1111/j.1478-3231.2006.01367.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER TOKYO  

BACKGROUND: Esophageal varices (EV), one feature of portal hypertension, have been regarded as a late complication of liver diseases. However, accumulating evidence indicates that EV sometimes develop early during the course of primary biliary cirrhosis (PBC). The prognosis is usually poorer for patients with symptomatic PBC than for those with asymptomatic PBC. Nevertheless, the clinical features and prognosis of patients with PBC whose initial symptoms are EV have not been clarified. METHODS: The clinical features and the prognosis of patients who initially developed EV without other symptoms (v-PBC) were retrospectively investigated in 54 patients with symptomatic PBC. RESULTS: The leukocyte and platelet counts were lower in patients with v-PBC than in those with PBC accompanied by other symptoms (s-PBC). Liver function tests, autoantibodies, and histological stage did not differ between patients with v-PBC and those with s-PBC. Although the prognosis did not differ, the incidence of hepatocellular carcinoma was significantly higher in v-PBC than in s-PBC (P = 0.0037). CONCLUSIONS: These data indicate that v-PBC is a hypercarcinogenic state and constitutes a new subgroup of PBC.

File： J Gastroenterol 2006 PBC&Varix.pdf

DOI： 10.1007/s00535-006-1914-y

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Publishing type：Research paper (scientific journal)   Publisher：American Roentgen Ray Society  

DOI： 10.2214/ajr.04.1252

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AIM: To retrospectively evaluate the prognosis of patients with hepatocellular carcinoma (HCC) with or without a history of therapy for HCC following transcatheter arterial embolization (TAE). METHODS: One hundred and twenty-one patients with HCC treated with TAE from 1992 to 2004 in our hospital were enrolled in this study. Eighty-four patients had a history of treatment for HCC, while 37 did not. At the time of entry, patients with extra-hepatic metastasis, portal vein tumor thrombosis, or Child-Pugh class C were excluded. TAE was repeated when recurrence of HCC was diagnosed by elevated tumor markers, or ultrasonography or dynamic computed tomography findings. RESULTS: Tumor size was larger and the number of tumors was fewer in patients without past treatment (P<0.01). However, there were no differences in tumor node metastasis (TNM) stage or survival rate between the 2 groups. A bilobular tumor and high level of alpha-fetoprotein (AFP) (>100 ng/mL) were factors related to a poor prognosis in patients with a history of HCC. CONCLUSION: The prognosis following TAE is similar between HCC patients with and without past treatment. Early diagnosis of HCC or recurrent HCC and obtaining good local control against HCC before entry to a repeated TAE course can improve prognosis.

DOI： 10.3748/wjg.v12.i13.2075

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BACKGROUND: α-Fetoprotein (AFP) is a useful marker of hepatocellular carcinoma (HCC), and protein induced by vitamin K absence or antagonist II (PIVKA-II) and fucosylated AFP (AFP-L3) are specific tumor markers. OBJECTIVE: The aim of this article was to report a case of intrahepatic cholangiocarcinoma (CC) with high levels of expression of AFP, AFP-L3, and PIVKA-II. METHODS: A 70-year-old man weighing 66 kg with a diagnosis of intrahepatic CC presented with a liver tumor 4.0 cm in diameter and elevated concentrations of carbohydrate antigen 19-9 (575 U/mL), PIVKA-II (379 mAU/mL), and AFP (497 ng/mL; AFP-L3, 88.1%). On extended medial hepatic segmentectomy, microscopy showed that the tumor was a CC without HCC. The patient subsequently underwent immunohistochemical assessments using cytokeratin-19, epithelial membrane antigen (EMA), hepatocyte paraffin-1 (HP-1), PIVKA-II, and AFP. RESULTS: In all specimens, desmoplasia was observed. However, results of immunohistochemistry showed positive results for cytokeratin-19 and EMA; HP-1 results were negative. Results of PIVKA-II and AFP testing in the tumor were positive. CONCLUSIONS: The case presented here showed characteristics of CC and HCC, whereas the histologic expression of the tumor suggested CC. Based on the literature search, this is the first known report of a case of a CC expressing AFP and PIVKA-II confirmed on immunohistochemical staining. This case is interesting with regard to the ability of the progenitor cells to differentiate HCC and CC.

File： Current theurapeutic research 2005 HCC&CCC.pdf

DOI： 10.1016/j.curtheres.2005.12.004

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Dendritic cells (DCs), the most potent antigen-presenting cells in vivo, are now used for cancer immunotherapy during which they are usually administered to the blood of patients with cancer. However, the route of administration of DCs affects the magnitude of immune responses. This study was conducted to assess the safety of the direct administration of DCs into cancer nodules. DCs were generated by culturing peripheral blood mononuclear cells with granulocyte-macrophage colony-stimulating factor and interleukin-4 for 7 days. After confirming the phenotype and function, one hundred thousand DCs were injected directly into the cancer nodules of 4 patients with hepatocellular carcinoma (HCC) under ultrasonography guidance 48 h after the administration of 100% ethanol. All patients were monitored for any alteration in generalized condition, signs of inflammation, and liver and kidney function for the next 14 days. In addition, the final assessment of the safety of the administration of DCs into cancer nodules was performed 6 months after therapy commencement. The injection of 100% ethanol disrupted the HCC nodules in all 4 patients. DCs were distributed uniformly in the cancer nodules as assessed by ultrasonography. The administration of DCs into cancer nodules was well tolerated by all patients and there were no immediate or delayed side effects. The tumor marker decreased in one patient after the direct administration of DCs. Direct administration of DCs into the cancer nodules of patients with HCC was safe.

File： Oncol Rep 2005 DC therapy for HCC.pdf

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OBJECTIVE: We quantified cytochrome P-450 (CYP) 3A4 mRNA in the blood and liver of patients with viral liver diseases to determine whether CYP 3A4 expression is related to disease progression. DESIGN AND METHODS: Total RNA was extracted from 10 mL of blood from 12 normal volunteers, from 6 patients with acute hepatitis, 17 with chronic hepatitis, 12 with liver cirrhosis, and 16 with hepatocellular carcinoma. Total RNA from 1 mg of liver tissue was extracted simultaneously in 10 patients. CYP 3A4 mRNA was quantified by competitive reverse-transcription polymerase chain reaction and expressed as log copies/microliter. RESULTS: The CYP 3A4 mRNA titer in blood correlated with that of the liver (r = 0.65, P < 0.05). The CYP 3A4 mRNA titer was 1.6 +/- 0.4 in normal controls, 1.0 +/- 0.5 in acute hepatitis, 0.7 +/- 0.2 in chronic hepatitis, 0.5 +/- 0.2 in liver cirrhosis, 0.5 +/- 0.2 in hepatocellular carcinoma, and decreased with progression of liver disease (P < 0.05). CONCLUSION: These data suggest that the CYP 3A4 mRNA level in blood relates to progression of liver disease.

File： Clin Biochem 2005 p-450 in viral liver disease.pdf

DOI： 10.1016/j.clinbiochem.2005.01.005

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The prognosis for patients with decompensated hepatitis B virus (HBV) related liver cirrhosis (LC-B), especially for those with LC-B complicated with hepatocellular carcinoma (HCC), is poor. We investigated the effects of lamivudine in patients with decompensated LC-B, with and without HCC. Decompensated LC-B patients (n=55) with Child-Pugh classification scores (CPS) >7 points were enrolled. All were admitted to the hospitals of the authors between January 1997 and December 2004. Decompensated cases due to a severe exacerbation of hepatitis with CH-B and patients with HCC showing an extra hepatic metastasis or portal vein tumor thrombus were excluded. Some 19 cases (including 5 cases complicated with HCC at the start of therapy) were treated with lamivudine at 100 mg/day (L group), and 36 (including 7 cases with HCC at time of admittance) were treated without lamivudine (non-L group). The median of CPS points in the L group was higher than that of non-L group (11 points versus 9 points, p<0.02). Prothrombin time (%), albumin, ascites, CPS, and HBV-DNA quantity were each significantly improved after 6 months in the L group (p<0.05). A mutation in the YMDD motif was observed in 5 patients in the L group, however liver function did not deteriorate. Further, the survival rate was significantly higher in the L group (p<0.05). HCC was found in 3 L group and 4 non-L group patients during the study. In the L group, all patients complicated with HCC were treated repeatedly or until cured, whereas 91% of those in the non-L group could not be treated (p<0.01). Our results suggest that lamivudine is a useful and important therapy for patients with decompensated LC-B with and without HCC, as well as those who are restricted from having liver transplantation.

File： Oncol Rep 2002 HCC RFA.pdf

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：H G E UPDATE MEDICAL PUBLISHING S A  

Background/Aims: The usefulness of the diagnostic criteria of the International Consensus Meeting (criteria A) has been previously reported. However, these criteria are not clinically adaptable in Japan where allergic reaction is one of the major etiologies of drug-induced liver injury and thus it was revised and reported in the Digestive Disease Week-Japan of 2002 as DDW-J criteria (criteria B). It remains controversial whether the revised criteria can exclude drugs not causing liver injury.
Methodology: Two new diagnostic criteria (criteria C and D) were designed to supplement the DDW-J criteria. Usefulness and limitations of the four criteria were retrospectively examined using cases of drug-induced liver injury experienced in 8 hospitals.
Results: It was confirmed that the sensitivity of criteria B is excellent for diagnosis of drug-induced liver injury. However, diagnostic criteria B were found to be disadvantageous in relation to specificity, while diagnostic criteria D were disadvantageous in relation to sensitivity. Sensitivity of diagnostic criteria C was a little superior to that of diagnostic criteria A.
Conclusions: On the basis, the significant sensitivity of criteria B was confirmed again, however, modification should be done for increasing specificity. Criteria C appear to be the best for their sensitivity and specificity.

File： Hepatogastroenterology 2005 Drug induced liver injury.pdf

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BACKGROUND: Three-dimensional (3D) images can be generated using thin sections from multi-detector row computed tomography (CT) and computer software, simulating images obtained using conventional ultrasonography (US). This software allows easy diagnosis of abdominal lesions and subsequent treatment of focal liver lesions such as hepatocellular carcinoma (HCC). The present study used newly developed virtual US software for diagnose and treatment of hepatobiliary disease. METHODS: The software was used to create virtual US images in 10 subjects. Radiofrequency ablation (RFA) was performed by virtual US in seven patients with HCC. RESULTS: Slices were easily reconstructed from various angles, and each slice was continuously animated as with conventional US in all subjects. Moreover, when seven patients with HCC were examined using virtual US, HCC nodules were visualized and could be treated with RFA. CONCLUSIONS: Virtual US should prove useful for visualization of HCC nodules that cannot be seen under conventional US. Virtual US is a useful tool for US-guided treatment of HCC.

File： Eur J Radiol 2005 Virtual US.pdf

DOI： 10.1016/j.ejrad.2004.03.026

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.44.212

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.44.794

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DOI： 10.2169/internalmedicine.44.439

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BACKGROUND: Low incidence of reversal blood flow at the portal vein has been reported by measurement in larger and extrahepatic blood vessels but not in intrahepatic blood vessels in patients with liver cirrhosis. Moreover, there is little information regarding the incidence of reversal blood on the basis of the cause of liver cirrhosis. The aim of this study was to measure the reversal blood flow in the portal vein including intrahepatic branches in patients with alcoholic and viral cirrhosis. METHODS: The blood flow in the portal vein and existence of portosystemic shunt were studied in 52 and 27 patients with alcoholic and viral cirrhosis, respectively, by Doppler ultrasonography. The parameters of liver function test and the prevalence of ascites and esophageal varices were compared between patients with and without reversal blood flow. RESULTS: Reversal blood flow at the portal vein was found only in patients with only alcoholic cirrhosis (17 of 52 patients) but not in any patients with viral cirrhosis (0 of 27 patients; p < 0.05). The incidence of portosystemic ascites and red color of esophageal varices was also higher in patients with alcoholic cirrhosis with reversal blood flow in the portal vein compared with patients without reversal blood flow (p < 0.05). CONCLUSIONS: Reversal blood flow in the portal vein is a characteristic feature of alcoholic cirrhosis. The presence of reversal blood flow indicates severe liver diseases, and this feature may have prognostic importance for patients with alcoholic cirrhosis.

File： Alcohol Clin Exp Res 2004 Alcohol & portal flow.pdf

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Two hundred and eighty seven Japanese cases of drug induced liver injury were assessed by the diagnostic scale of the International Consensus Meeting (ICM). They were classified to the hepatocellular (55%), mixed (24%) and cholestatic (22%) type according to the type of liver injury. Five cases were diagnosed as 'unrelated', since the reaction occurred more than 15 days after stopping the drug. The remaining 282 cases were classified to 69 cases of 'highly probable', 170 cases of 'probable', 39 cases of 'possible', and four cases of 'unlikely'. The cases with positive drug-lymphocyte stimulation test (DLST) and with eosinophilia distributed to higher scores. Although the diagnostic scale of the ICM was found to be also useful for Japanese cases, the modification of the scale including the data of DLST and eosinophilia together with some other modifications were recommended in the view of the present status of Japan. Using the modified diagnostic scale, the 287 cases were classified to 173 cases of 'highly probable', 102 cases of "probable', 11 cases of 'possible', and one case of 'unlikely'. Although the modified diagnostic scale seems better than the original one, further assessment of the modified scale using many Japanese cases is needed for the further improvement of the scale.

File： Hepatol Res 2003 Drug induced liver injury.pdf

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Antigen-presenting dendritic cells (DC), loaded in vitro with tumor associated antigens (TAAs), are now used for antitumor therapy. However, little is known about the interaction between DC and TAAs within tumor microenvironment. This study was conducted to evaluate if antitumor immunity can be induced by injecting immature DC into necrotized tumor tissues. A mouse model of colon cancer was established by subcutaneous injection of CMT-93 (a murine colon cancer cell) in the flank of C57BL/6 mice. When the tumors became about 10 mm in diameter, a portion of the tumor nodules was necrotized by injecting 100 micro l of 100% ethanol. Bone marrow-derived immature DC from syngenic mice were injected into the tumors, 48 h after ethanol injection. The size of the tumor and the survival time of the mice were studied. Immunohistochemical methodology was employed to detect injected DC and to evaluate the levels of maturation of DC. Tumor-bearing mice injected with ethanol plus DC survived for longer duration compared to untreated mice (p<0.05). Three weeks after therapy, the sizes of the tumor nodules were reduced compared to untreated mice. Forty-eight hours after injection, the injected DC were detected in the spleen. The stimulatory capacity of spleen DC isolated from mice treated with ethanol plus DC were significantly higher compared to that of untreated mice (p<0.05). Mature DC expressing CD86 were detected in cancer nodule after injecting ethanol plus DC, however, these were almost absent in tumor-bearing mice in situ. Taken together, direct administration of ethanol plus DC in the tumor nodules represents a new therapeutic approach for antitumor immunotherapy.

File： Int J Oncol 2003 DC based cancer immunotherapy.pdf

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

Eighty-five Japanese patients with drug-induced liver injury were assessed by criteria of Consensus Meetings in Europe on causality assessment of drug-induced liver injury. Histopathological investigation was performed for all patients to confirm the diagnosis. We divided these patients into two groups by the date of disease onset. Cases before 1989 were defined as past cases, and those after 1990 as recent cases, because the clinical-pathological characteristics of drug-induced liver injury have changed due to the ability to diagnose hepatitis C virus infection since 1990. Fifty-seven patients with drug-induced liver injury were enrolled as past cases, and 28 as recent cases. For past cases, the results of assessment by the criteria of Consensus Meetings in Europe were as follows: 'very likely': 14 patients (25%), 'likely': 23 patients (40%), 'possible': 15 patients (26%), 'dubious': five patients (9%), and 'unlikely': none (0%). For recent cases, the results were as follows: 'very likely': six patients (22%), 'likely': 14 patients (42%), 'possible': six patients (22%), 'dubious': two patients (7%), and 'unlikely': none (0%). There were no differences between the past and recent cases in distribution of assessment. More than 90% of patients were assessed as 'possible' or more, and the remaining seven patients were assessed as 'dubious'. No patients were assessed as 'unlikely'. Five of seven patients assessed as 'dubious' had long-term cholestasis, and two had alcohol consumption. These results indicated that the criteria of Consensus Meetings in Europe were useful for diagnosing drug-induced liver injury in Japanese patients.

File： Hepatol Res 2003 Drug Danan.pdf

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A 42-year-old Japanese man was admitted to our hospital for investigation of abnormal liver function tests. He had no history of drug use, and drank little alcohol. Body mass index was 30. Serum was negative for viral markers and autoantibodies. Laparoscopy revealed diffuse small nodules on the liver surface. Liver biopsy revealed small nodules with pericellular fibrosis and macrovesicular fat deposition throughout the acini. Some inflammatory changes were observed. Liver cirrhosis due to non-alcoholic steatohepatitis (NASH) was diagnosed. NASH displays similar histological and laparoscopic characteristics to alcoholic liver diseases.

File： Dig Endosc 2003 NASH Laparoscopic finding.pdf

DOI： 10.1046/j.1443-1661.2003.00292.x

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We report a case of peliosis hepatis associated with placental site trophoblastic tumor (PSTT) of the uterus. A 46-year-old woman was admitted to our hospital with complaints of leg edema, pleural effusion and ascites, complicated with esophageal varices. Peritoneoscopy did not show any evidence of liver cirrhosis and liver biopsy revealed peliosis hepatis. Later, uterine tumor was detected and, after a hysterectomy, peliosis hepatis and esophageal varices were dramatically improved. We suggest that the uterine tumor caused peliosis hepatis with fibrosis and that portal hypertension developed as a consequence of these lesions. The present case is of interest because esophageal varices were improved without ordinary treatment.

File： Dig Endosc 2003 Peliosishepatis.pdf

DOI： 10.1046/j.1443-1661.2003.00218.x

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Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Internal Medicine  

DOI： 10.2169/internalmedicine.42.1104

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PROFESSOR D A SPANDIDOS  

Radiofrequency ablation (RFA), a new local therapy, has recently been developed for hepatocellular carcinoma (HCC). In this study, we have checked for the factors influencing the recurrence of HCC following RFA. We gave special emphasis to complete coagulation. The study population was comprised of 47 patients (80 tumors) with HCC with tumor size of &lt;3 cm in maximal diameter. The patients were observed for a period of 2-3 years (average 865 days). The local recurrence rate was 19% at the end of 1 year, and 21% by the end of 2 years. The patients with local recurrence received significantly fewer RFA sessions (P&lt;0.05) compared to patients with no recurrence. The frequencies of complete coagulation were significantly less (P&lt;0.05) in patients with local recurrence than patients without local recurrence. The distant recurrence rate was 38% at 1 year, and 60% at 2 years. Patients with distant recurrence had significantly increased number of tumors (2.0+/-1.4) (P&lt;0.05) compared to patients without distant recurrence (1.2+/-0.4). In conclusion, obtaining complete coagulation is an important factor to prevent local recurrence and the number of tumors predicted the distant recurrence in patients with HCC undergoing RFA.

File： Oncol Rep 2002 HCC RFA.pdf

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Language：English  

A 38-year-old Japanese woman with no past history of liver disease developed liver dysfunction associated with fever, anorexia, and general malaise following the prolonged administration of saridon. A liver biopsy demonstrated multiple noncaseating epithelioid granulomas within hepatic lobules, with an inflammatory cell infiltrate of the lobular parenchyma and portal tracts. Viral markers and autoantibodies were negative. Lymphocyte stimulation tests for saridon and for isopropylantipyrine, one of the constituents of saridon, were positive, and therefore a diagnosis of drug-induced hepatitis due to administration of saridon was made. Her symptoms resolved and liver function test results returned to normal following discontinuation of the drug. The possibility of drug-induced hepatitis must be considered when liver dysfunction or systemic symptomatology develops during saridon therapy.

File： J Gastroenterol 2002 Saridon Hepatic granuloma.pdf

DOI： 10.1007/s005350200180

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Language：English   Publishing type：Research paper (scientific journal)  

The number of patients with autoimmune hepatitis with histological features of acute hepatitis (AIH-AH) has been increasing recently. Here, the clinical features of patients with AIH-AH have been compared with those of patients with AIH with histological findings of chronic hepatitis (AIH-CH) and liver cirrhosis (AIH-LC). The levels of total serum bilirubin (P<0.05) and serum transaminases (P<0.05) were significantly higher in patients with AIH-AH than in patients with AIH-CH and AIH-LC. However, the serum levels of gamma-globulin (P<0.05) and immunoglobulin G (P<0.05) were significantly lower in AIH-AH than in patients with AIH-CH and AIH-LC. The aggregate score according to the criteria of the International Autoimmune Hepatitis Group in 1999 was also significantly lower in AIH-AH patients than in patients with AIH-CH and AIH-LC (P<0.05). Eleven patients with AIH-AH were treated with corticosteroids, however, the clinical response was insignificant in three patients. In summary, it is difficult to diagnose of patients with AIH-AH using the criteria of the International AIH scoring system. We wish that this scoring system would be modified in the near future.

File： Hepatol Res 2001 Features of acute AIH.pdf

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI IRELAND LTD  

The levels of macrophage migration inhibitory factor (MIF), a proinflammatory and carcinogenic cytokine, were significantly higher in the sera from patients with hepatocellular carcinoma (HCC 25.6 +/- 15.3 ng/mi, n=55) and liver cirrhosis (LC; 18.9 +/- 10.7 ng/ml, n=26) compared with sera from patients with gastrointestinal cancer (6.8 +/-7.5 ng/ml, n=29) and normal controls (5.6 +/-1.2 ng/ml, n=45; P&lt;0.01). Hepatocytes from patients with LC and HCC but not from chronic hepatitis, expressed very high levels of MIF A possible association between overexpression of MIF and hepatocarcinogenesis is suggested. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

File： Cancer Lett 2001 HCC MIF.pdf

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Objectives: To study the role of macrophage migration inhibitory factor (MIF) in the pathogenesis of alcoholic liver diseases.
Design and Methods: The levels of MIF in the sera were estimated by an enzyme-linked immunosorbent assay in 13 patients with alcoholic hepatitis (ALH), 9 patients with alcoholic cirrhosis ALC and 26 normal controls, MIF was localized in the liver specimens by immunohistochemistry.
Results: The mean levels of MIF in the sera were significantly higher in ALH and ALC compared with the normal controls (P &lt; 0.05). Serial observations revealed a relationship between serum MIF levels and the serum transaminase levels. MIF was expressed by the hepatocytes and by the infiltrating cells around the site of accumulation of neutrophils and ballooned hepatocytes in ALH.
Conclusions: This is the first report on MIF in human alcoholic liver diseases, and the data suggest that MIF may be related to abnormal cytokine homeostasis in ALH. (C) 2001 The Canadian Society of Clinical Chemists. All rights reserved.

File： Clin Biochem 2001 Alcohol MIF.pdf

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Award type：Award from Japanese society, conference, symposium, etc. 

The Eldest Female Case of Myasthenia Gravis with an Unusual Presentation: Aspiration Pneumonia as the Initial Manifestation

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Author：Other 

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Author：Myself 

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感染症患者への対応を競う大会

新型コロナウイルスの感染拡大が続く中、感染症の患者に対応する技術を身につけてもらおうと、愛媛大学医学部でトーナメント形式で感染症医療の技術を競う大会が行われました。

この大会は新型コロナの感染拡大に伴い病棟で実習を行うことが難しくなっていることから学生たちに競い合いながら感染症の患者への対応技術を身につけてもらうと愛媛大学医学部が開きました。
参加した１００人あまりの学生は７人ずつのチームに分かれ、新型コロナに感染した男性が運ばれてきたという想定でどう対応するのかトーナメント形式で披露しました。
学生たちは互いに声をかけあいながら検査のために鼻に綿棒を入れて粘液を拭ったり、肺に空気を送るために患者の口に異物がないかを確認したあと、気管に管を挿入したりしていました。
一方、教員らは正しい手順で粘液の採取や管の挿入ができているかなどを細かくチェックしながら採点していました。
参加した男子学生は「新型コロナが流行する中、迅速に患者に対応できるよう実践力を身につけたい」と話していました。
愛媛大学医学部の熊木天児教授は「実習で現場に踏み込むことができなかったコロナの医療がどのように行われているのか経験してもらいたい。研修医となってからも今回の経験を活かして欲しい」と話していました。

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医師を目指す学生が参加して新型コロナの患者への対応力を競い合う大会が、愛媛大学医学部でトーナメント形式で行われ、学生たちが習得した技術を披露しました。

大会はコロナ禍の影響で実習の機会が少なかった医学部の学生に感染症の患者への対応力を身につけてもらおうと、愛媛大学が開きました。
参加したおよそ１２０人の学生は１８のチームに分かれ、新型コロナに感染して自宅療養していた高齢男性が緊急搬送されたという想定で、適切に対応できるかトーナメント形式で競いました。
学生たちは人体模型のシミュレーターを使って、制限時間内に検査のために鼻に綿棒を入れて粘液を拭ったり、肺に空気を送るため、気管に管を挿入したりして、授業などで習得した技術を披露していました。
参加した男子学生は「授業は教えてもらうのが基本ですが、きょうは主体的に実践できるいい機会となりました」と話していました。
愛媛大学医学部付属病院の熊木天児総合臨床研修センター長は「新型コロナの影響で学生たちも実習現場に立ち入れなかった時期がありましたが、こうした機会を通じて対応力を向上させられればいいです」と話していました。

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Author：Myself 

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