Search

PurposeA prospective cohort study for pregnant women, the Maternity Log study, was designed to construct a time-course high-resolution reference catalogue of bioinformatic data in pregnancy and explore the associations between genomic and environmental factors and the onset of pregnancy complications, such as hypertensive disorders of pregnancy, gestational diabetes mellitus and preterm labour, using continuous lifestyle monitoring combined with multiomics data on the genome, transcriptome, proteome, metabolome and microbiome.ParticipantsPregnant women were recruited at the timing of first routine antenatal visits at Tohoku University Hospital, Sendai, Japan, between September 2015 and November 2016. Of the eligible women who were invited, 65.4% agreed to participate, and a total of 302 women were enrolled. The inclusion criteria were age ≥20 years and the ability to access the internet using a smartphone in the Japanese language.Findings to dateStudy participants uploaded daily general health information including quality of sleep, condition of bowel movements and the presence of nausea, pain and uterine contractions. Participants also collected physiological data, such as body weight, blood pressure, heart rate and body temperature, using multiple home healthcare devices. The mean upload rate for each lifelog item was ranging from 67.4% (fetal movement) to 85.3% (physical activity), and the total number of data points was over 6 million. Biospecimens, including maternal plasma, serum, urine, saliva, dental plaque and cord blood, were collected for multiomics analysis.Future plansLifelog and multiomics data will be used to construct a time-course high-resolution reference catalogue of pregnancy. The reference catalogue will allow us to discover relationships among multidimensional phenotypes and novel risk markers in pregnancy for the future personalised early prediction of pregnancy complications.

Aim To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. Methods A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. Results Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8–22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). Conclusion Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.

A 54-year-old male consulted a local doctor with a chief complaint of systemic convulsions and muscle stiffness and was diagnosed with Isaacs' syndrome based on positive findings for antibodies against voltage-gated potassium channels in 2009. He subsequently experienced repeated hematemesis in 2013, at which time he was taken to our hospital by ambulance. Emergent endoscopy revealed esophageal varices with spurting bleeding. The bleeding was stopped with urgent endoscopic variceal ligation. Three days later, the patient developed sudden dyspnea with stridor during inspiration under sedation with an intravenous injection of low-dose flunitrazepam prior to receiving additional treatment and was aroused with intravenous flumazenil, after which his dyspnea immediately improved. Dyspnea may be induced by muscle cramps associated with Isaacs' syndrome exacerbated by sedation. Endoscopic variceal ligation was performed safely using multiple ligation devices in an awake state following pre-medication with hydroxyzine, without sudden dyspnea. Endoscopists should be cautious of the use of sedatives in patients with diseases associated with muscle twitching or stiffness, as in the current case. In addition, it is necessary to administer endoscopic treatment in an awake state or under conscious sedation in patients with a high risk of dyspnea.

Patients with morbid obesity selected for bariatric surgery have a high prevalence of nonalcoholic steatohepatitis (NASH); however, the incidence is varied and depends on race. The prevalence of NASH in obese Japanese patients is unknown. We evaluated the prevalence of NASH in a prospective cohort of Japanese patients with morbid obesity. From October 2009 to July 2011, consecutive patients requiring bariatric surgery underwent a liver biopsy during the operation. The indications for bariatric surgery followed the guidelines of the Asia–Pacific Metabolic and Bariatric Surgery Society. One hundred two patients (55 males and 47 females, age 42.7 ± 10.7 years) were analyzed. The mean body mass index was 42.1 ± 8.2 kg/m2. Among the 102 patients, 84 patients (82.4 %) had nonalcoholic fatty liver disease and 79 patients (77.5 %) had NASH. The grading and staging of NASH by Brunt’s classification were as follows: grade 0 steatosis, one patient; grade 1 steatosis, 35 patients; grade 2 steatosis, 32 patients; grade 3 steatosis, 11 patients; stage 1 fibrosis, 25 patients; stage 2 fibrosis, 38 patients; stage 3 fibrosis, 16 patients, stage 4 fibrosis, no patients. The body weight, waist–hip ratio, visceral fat area, and aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, fasting plasma glucose, fasting plasma insulin, C peptide, hemoglobin A1c, and homeostasis model assessment insulin resistance levels were significantly elevated in the NASH group in comparison with the non-NASH group. The platelet count was significantly decreased in the NASH group. The waist–hip ratio and the alanine aminotransferase, fasting plasma glucose, and homeostasis model assessment insulin resistance levels were found to be independent predictors of NASH in a multivariate analysis. The prevalence of NASH was 77.5 % in this prospective Japanese cohort. The prevalence of NASH in Japanese morbidly obese patients was extremely high, and early intervention should be undertaken.

The aim of this study was to assess the long-term prognosis, efficacy, and safety of combination therapy using ursodeoxycholic acid (UDCA) and bezafibrate (BF) for primary biliary cirrhosis (PBC) patients exhibiting dyslipidemia.We performed a prospective, randomized, controlled, multicenter study to compare the long-term clinical results between combination therapy and UDCA monotherapy for patients refractory to UDCA monotherapy. Twenty-seven consecutive PBC patients were enrolled.The median treatment period in the UDCA and UDCA+BF groups was 107 and 110 months, respectively. The serum alkaline phosphatase (ALP) levels and the Mayo risk score in the combination therapy group (mean 290 IU/l and 0.91, respectively) were significantly lower than those in the UDCA monotherapy group (mean 461 IU/l and 1.42, respectively) at 8 years after the beginning of the study (P0.05). The serum creatinine levels in the combination therapy group (mean 0.94 mg/dl) were significantly higher than those in the UDCA monotherapy group (mean 0.56 mg/dl) at 8 years after the beginning of the study (P0.05). However, the survival rate was not significantly different between the groups. We observed dose reduction or discontinuation of the administration of BF, but not UDCA, due to renal dysfunction or muscle pain.Long-term combination therapy significantly improved the serum ALP levels and the Mayo risk score. However, the survival rate was not significantly different between the groups. In addition, long-term combination therapy significantly increased the serum creatinine levels. We should pay close attention to adverse events during this long-term combination therapy.

Atypical progeroid syndrome (APS), including atypical Werner syndrome (AWS), is a progeroid syndrome involving heterozygous mutations in the LMNA gene encoding the nuclear protein lamin A/C. We report the first Japanese case of APS/AWS with a LMNA mutation (p.D300N). A 53-year-old Japanese man had a history of recurrent severe cardiovascular diseases as well as brain infarction and hemorrhages. Although our APS/AWS patient had overlapping features with Werner syndrome (WS), such as high-pitched voice, scleroderma, lipoatrophy and atherosclerosis, several cardinal features of WS, including short stature, premature graying/alopecia, cataract, bird-like face, flat feet, hyperkeratosis on the soles and diabetes mellitus, were absent. In immunofluorescence staining and electron microscopic analyses of the patient's cultured fibroblasts, abnormal nuclear morphology, an increase in small aggregation of heterochromatin and a decrease in interchromatin granules in nuclei of fibroblasts were observed, suggesting that abnormal nuclear morphology and chromatin disorganization may be associated with the pathogenesis of APS/AWS.

Aims Optimization of the duration of peginterferon-α/ribavirin therapy in patients with hepatitis C virus (HCV) genotype 2 and high viral loads remains to be established. We sought to prospectively optimize the treatment duration based on their virological responses. Methods Serum HCV RNA levels of less than 50 IU/mL at weeks 2 and 4, and of 50 IU/mL or more at week 4, were defined as a super-rapid virological response (SRVR), rapid virological response (RVR) and late virological response (LVR), respectively. Treatment for 12, 24 or 48 weeks was assigned to the patients with an SRVR, RVR or LVR, respectively. However, patients with an LVR who expressed a desire to receive the standard therapy duration were given the 24-week therapy. Results The overall sustained virological response (SVR) rate was 78.1% (118/151). The SVR rate in the SRVR group was 93.8% (15/16), which was comparable to the 93.0% (66/71) SVR rate in the RVR group. In the LVR patients, the 48-week treatment slightly increased the SVR rate to 76.5% (13/17) compared with the 51.1% (24/47) SVR rate in LVR patients who underwent the standard 24-week treatment. The relapse rate in LVR patients was significantly decreased in patients treated for 48 weeks compared with patients treated for 24 weeks. Multivariate analysis identified the predictive factors for SVR as RVR, prior interferon therapy and total peginterferon-α-2b adherence in patients treated for 24 weeks. Conclusion Response-guided therapy may be effective and useful for optimization of the treatment duration.

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.

We devised an extended 72-wk peginterferon-α-2a/ribavirin therapy regimen for the retreatment of highly intractable cases, i.e., 48-wk peginterferon-α-2b/ribavirin therapy-intractable cases. Although 2 cases achieved a rapid virological response to 72-wk peginterferon-α-2a/ribavirin therapy, 1 case failed to achieve a sustained virological response. Although the reason for this difference in the effectiveness of 72-wk peginterferon-α-2a/ribavirin therapy between the cases was unclear, the rebound phenomenon of serum transaminase after 48-wk peginterferon-α-2b/ribavirin therapy and the resultant lower viral load compared to that before 48-wk peginterferon-α-2b/ribavirin therapy might have influenced the treatment outcome. Thus, it may be beneficial to consider the rebound phenomenon of serum transaminase and the changes in viral load resulting from previous interferon-based therapy and then cautiously determine the indication and the timing of the administration of 72-wk peginterferon-α-2a/ribavirin in highly intractable cases. Further studies should be performed to confirm this strategy.

The role that transforming growth factor-α (TGF-α) has in chronic pancreatitis and pancreatic cancer has not been fully elucidated. We evaluated the effects of TGF-α on the human pancreatic stellate cell (PSC) line RLT-PSC and primary human PSCs, and the expression levels of TGF-α and metalloproteinase-1 (MMP-1) in human chronic pancreatitis and pancreatic cancer tissues. TGF-α stimulated the proliferation and migration of PSCs. Although the mRNA expression levels of tissue inhibitor of metalloproteinase-1 and α1(I) collagen were unchanged, the mRNA expression levels of MMP-1 increased concomitant with increases in MMP-1 protein levels and collagenase activity. TGF-α-stimulated migration of RLT-PSC cells was partially blocked by tissue inhibitor of metalloproteinase-1 protein and MMP-1 small interfering RNA. MMP-1 was also observed to stimulate the migration of PSCs. TGF-α-induced MMP-1 expression was completely blocked by gefitinib in PSCs. The Ras-ERK and PI3/Akt pathways appear to be involved in the activation of MMP-1 in PSCs. Immunohistochemical analyses showed that MMP-1 expression was significantly increased in the pancreatic interstitial tissues in case of chronic pancreatitis or pancreatic cancer compared with those in case of normal pancreas. In conclusion, TGF-α increased proliferation and migration of PSCs. TGF-α-induced migration of cells may be partly due to upregulation of MMP-1. TGF-α and MMP-1 upregulation may contribute to the pathogenesis of chronic pancreatitis and pancreatic cancer.

Radiation-induced gastroduodenitis is a well-known but rare disorder causing uncontrollable hemorrhage and has not been reported as a complication of proton beam therapy in radiation treatment. Argon plasma coagulation (APC) has been shown to be effective and safe in the management of radiation-induced hemorrhagic gastroduodenitis. We describe a case of hemorrhagic gastroduodenitis after proton beam radiation therapy for pancreatic cancer with multiple hemorrhagic risk factors, which was treated successfully with APC. A 62-year-old man was diagnosed as having early pancreatic cancer that was incidentally detected on computed tomography when screening for hepatocellular carcinoma. He opted to receive radical proton beam radiation for pancreatic cancer but not surgery because he had multiple risk factors such as liver cirrhosis due to hepatitis C virus and chronic renal failure that required hemodialysis. Three months later, however, he developed hemorrhagic gastroduodenitis induced by proton beam radiation although the cancer had been eradicated. Initially, he required frequent blood transfusions, but his disease condition improved dramatically after several endoscopic treatments using APC. The patient has been free of relapse after pancreatic cancer for >2 years.

Non-alcoholic steatohepatitis (NASH) is characterised by steatosis, liver cell injuries, the presence of a mixed inflammatory lobular infiltrate, and variable degrees of fibrosis. Werner syndrome (WS) is a rare autosomal recessive disease characterised by the premature onset of multiple age-related disorders. Central obesity and insulin resistance are common symptoms of both NASH and WS. Three cases were studied to evaluate the association between WS and NASH. NASH was diagnosed by liver biopsies and imaging studies following the exclusion of alcohol consumption, viral disease or autoimmune liver disease. Liver histology was compatible with NASH in all cases. Liver dysfunction, hyperlipidaemia, insulin resistance and regional increase of intra-abdominal fat even though the body mass indices were all normal or low, were observed. Metabolic disorders due to WS may complicate and cause NASH. Hence, the observed clinical association between WS and NASH suggests that patients with WS should also be screened for NASH.

A S L D A b st ra ct s were included in the study. Hemoglobin less than 14.0g/dl at W1 and W2 of treatment was associated with subsequent decrease in ribavirin dose (p = 0.0005 and 0.0002, respectively), and addition of erythropoietin (p = 0.0145 and 0.0001, respectively). Drop in hemoglobin of.2g/dl from baseline atW2was also significantly associated with addition of erythropoietin (p = 0.0005). Hemoglobin at W1 or W2 was not associated with requirement for blood transfusion or with extended rapid virological response (eRVR), end of therapy response (ETR) or sustained virological response (with 4, 12 and 24 week follow-up; SVR4, SVR12 and SVR24 respectively). Undetectable viral load at W2 was associated with eRVR (p = 0.0025), ETR (p = 0.027), SVR4 (p = 0.037) and SVR12 (p = 0.0007). Undetectable viral load at W1 was not significantly associated with eRVR (p = 0.08), ETR or SVR4, SVR12 and SVR24. Conclusions In patients being treated with P, R, PI for CHC, undetectable viral load at W2 is associated with eRVR, ETR, SVR4 and SVR12. Early anemia (at W1 or W2) is associated with subsequent ribavirin dose reduction and addition of erythropoietin. Early monitoring of hemoglobin at W1 and W2 and of HCV RNA at W2may be helpful in patient management.

Background: Hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) has been increasingly reported as the concept of NASH has received wide acceptance among clinicians in the intervening years. Moreover incidence of NASH itself is expected to increase reflecting age of gluttony. However it does not make sense from a cost-effectiveness point of view to screen HCC frequently in all patients with NASH because patients with NASH make up around 1% in overall Japanese population. Aim: This study was designed to assess risk factors for HCC in patients with NASH to develop effective screening methods. Patients and Methods: Our study included all the patients who were consecutively diagnosed at Gunma University Graduate School of Medicine and its affiliated hospitals as having NASH between 2000 and 2006, were followed up for at least 24 months. We evaluated incidence of HCC to date. We compared clinicopathological features (physical findings, laboratory findings, histological features and complications) between patients with HCC (HCC group) and patients without HCC (non-HCC group). The criteria for the diagnosis of NASH were compatible liver histology. We confirmed the diagnosis of HCC by ultrasonographic scanguided tumor biopsy except the treatment-resistant ascites or absence of informed consent in which an angiography or computed tomography showed typical characteristics of HCC. Results: The overall sample included 79 patients (26 men and 53 women, median age 63 years). The follow-up period ranged from 30 to 138 months with an average of 52 months. Fourteen patients (9 men and 5 women, median age 63 years) developed HCC. As for histological stage due to Blunt's classification, 1 and 16 had stage 1, 2 and 23 had stage 2, 3 and 12 had stage 3, and 8 and 14 had stage 4 in HCC group and non-HCC group, respectively. All cases accompanied either obesity or diabetes mellitus. Univariate analysis showed age, sex, histological stage, prothrombin time, serum total cholesterol level, and serum uremic acid level were significant different between HCC group and non-HCC group. Multiple logistic analysis showed male sex (odds ratio: 44.09, 95% Confidence interval: 3.564-545.4, p=0.032) and elder age (odds ratio: 1.134, 95% Confidence interval: 1.0181.265, p=0.029) were significant risk factors for HCC in patients with NASH. Conclusions: Though preliminary results, male sex and elder age were significant risk factors for HCC in patients with NASH and these patients have to be regularly monitored for early detection of HCC. At the same time, we should increase the sample size and follow-up periods and confirm our hypothesis in the near future.