High serum concentrations of growth differentiation factor-15 and their association with Crohn's disease and a low skeletal muscle index.

Sarcopenia comprises a low skeletal muscle index (SMI) and low muscle strength (MS) or low physical function. Many sarcopenia biomarkers have been reported. With Crohn's disease (CD), a low SMI is predictive of intestinal complications. Therefore, many CD studies have reported that sarcopenia is defined by SMI alone. This study investigated the sarcopenia frequency by assessing the SMI and MS of Japanese patients with CD and biomarkers predicting a low SMI. We evaluated the SMI using a bioelectrical impedance analysis, handgrip strength, and C-reactive protein, albumin, interleukin-6, tumor necrosis factor-α, growth differentiation factor (GDF)-8, and GDF-15 levels as biomarker candidates for 78 CD patients at our hospital. Sarcopenia and a low SMI were observed in 7.7% and 42.3% of the patients, respectively. There was a significant difference in the GDF-15 levels of the low SMI group and normal group according to the multivariate analysis (P = 0.028; odds ratio [OR], 1.001; 95% confidence interval [CI] 1.000-1.002). When evaluated by sex, males exhibited a negative correlation between the GDF-15 level and SMI (Pearson's r = - 0.414; P = 0.0031), and the multivariate analysis indicated a significant difference in the GDF-15 levels (P = 0.011; OR, 1.001; 95% CI 1.000-1.002). GDF-15 levels may indicate a low SMI with CD.

Significance of serum palmitoleic acid levels in inflammatory bowel disease.

Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic intestinal diseases of unknown etiology that present with variable disease extents and outcomes. The use of biomarkers for the diagnosis and management of IBDs is considered beneficial. Palmitoleic acid (PO) is an adipose tissue-derived mono-unsaturated free fatty acid that potentially serves as a lipokine in metabolic and inflammatory diseases. The aim of this study was to investigate the significance of PO levels in the serum of patients with UC and CD. The study included patients with UC (n = 22), patients with CD (n = 35), and controls (n = 22). The levels of serum PO were analyzed using gas chromatography. The association of serum PO levels with the clinical features and disease outcomes in IBD was examined. Serum PO levels were significantly higher in patients with CD than in controls, whereas no difference in these levels was observed between patients with UC and controls. Serum PO levels were significantly associated with the CD activity index. Additionally, high serum PO levels were associated with an increased risk of surgical intervention requirement during follow-up. In a pilot study with a few patients, high PO levels were observed in the mesenteric tissue in the active disease site of patients with CD (n = 7) compared with those with colon cancer (n = 6). Elevated serum PO levels might serve as a marker for local inflammation and prognosis in patients with CD.

Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study.

BACKGROUND: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD). METHODS: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn's disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn's Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC. RESULTS: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 µg/ml at week 0, 15.5 ± 7.7 µg/ml at week 12, 15.7 ± 9.6 µg/ml at week 24, and 14.5 ± 6.8 µg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426). CONCLUSIONS: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.

Use of vonoprazan for management of systemic sclerosis-related gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) in systemic sclerosis (SSc) can significantly reduce a patient's quality of life. GERD in SSc is occasionally resistant to conventional anti-acid treatment. Vonoprazan is an H+/K+-ATPase blocker that is approved in Japan for treatment of GERD. The aim of the present study was to evaluate the efficacy of vonoprazan in SSc-related GERD. The frequency scale for symptoms of GERD (FSSG) scores were collected before and after vonoprazan treatment in 15 SSc patients with GERD. Additionally, endoscopic esophagogastroduodenoscopy was performed in select patients. Conventional proton pump inhibitors or histamine-2 receptor antagonists had been previously administered in 93% (14/15) of the patients. Although the baseline esophagogastroduodenoscopy examination did not show severe erosion in the majority of patients, the mean total FSSG score before vonoprazan treatment was notably high (25.2±10.7) compared to a normal score of <8. After vonoprazan treatment, the FSSG score decreased to 9.6±7.0. The mean improvement rate of the total FSSG, acid reflux and dysmotility scores were 60.8±21.2% (P=0.0004), 67.3±24.8% (P<0.0001) and 55.4±26.0% (P=0.0022), respectively. These results suggest that vonoprazan may be a potentially effective treatment for GERD in patients with SSc.

Correction: Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.

[This corrects the article DOI: 10.1371/journal.pone.0170591.].

Comparative efficacy of antitumor necrosis factor agents and tacrolimus in naïve steroid-refractory ulcerative colitis patients.

While retrospective studies have compared the efficacy of anti-tumour necrosis factor (TNF) agents and tacrolimus (TAC) in ulcerative colitis (UC), information regarding first-time use of these agents is limited. The aim of our study was to investigate the short- and long-term efficacy of anti-TNF agents [adalimumab (ADA) and infliximab (IFX)] and TAC in anti-TNF agent- and TAC-naïve steroid-refractory UC patients. We evaluated 150 steroid-refractory UC patients receiving anti-TNF agents (IFX: n = 30, ADA: n = 41) or TAC (n = 79) at eight institutions in Japan. Clinical response rates at 8 weeks were 73.2% and 75.9% while remission rates were 30.1% and 25.3% in the anti-TNF and TAC groups, respectively. Logistic regression analysis showed the male sex and higher C-reactive protein to be independent factors for response to anti-TNF agents and TAC, respectively. Use of TAC was an independent factor for relapse. No differences in response to the treatment or relapse were observed between IFX and ADA. In conclusion, TAC and anti-TNF agents promoted similar short-term effects, but anti-TNF agents ensured better long-term outcomes at first-time treatment of steroid-refractory UC patients.

A novel method for rapid detection of a Helicobacter pylori infection using a γ-glutamyltranspeptidase-activatable fluorescent probe.

A γ-glutamyl hydroxymethyl rhodamine green probe (gGlu-HMRG) reacts with γ-glutamyltranspeptidase (GGT) and immediately produces fluorescence, is clinically applied for real-time cancers' visualization. Since Helicobacter pylori produces GGT, this study aimed to investigate whether gGlu-HMRG can be used to detect H. pylori infections. A wild-type H. pylori strain and the ggt gene-disrupted mutant were cultured and treated with gGlu-HMRG. This fluorescent probe assay was used to quantify GGT activity of H. pylori ex vivo using gastric biopsy specimens. The H. pylori diagnostic capabilities of the assay were determined from altered fluorescence intensity (FI) values at 5 min (FIV-5) and 15 minutes (FIV-15). Distinct fluorescence was identified in wild H. pylori strain, using gGlu-HMRG, whereas no fluorescence was observed in ggt gene-disrupted mutant strain. On ex vivo imaging of gGlu-HMRG, fluorescence intensity increased markedly with time in H. pylori-positive specimens; however, the H. pylori-negative specimens displayed a slight increase in FI. FIV-5 and FIV-15 differed significantly between H. pylori-positive and -negative specimens. FIV-15 differed significantly between H. pylori-positive and -eradicated group. This assay sensitivity and specificity were 75.0% and 83.3% in the antrum and 82.6% and 89.5% in the stomach body. GGT-activatable fluorescence probe is applicable for rapid diagnosis of H. pylori.

Effect of a concomitant elemental diet with maintenance anti-tumor necrosis factor-α antibody therapy in patients with Crohn's disease: A multicenter, prospective cohort study.

BACKGROUND AND AIM: The aim of this study was to clarify the additional effect of a concomitant elemental diet (ED) for patients with Crohn's disease on maintenance anti-tumor necrosis factor-α antibody (anti-TNF). METHODS: Crohn's disease patients who received anti-TNF induction therapy were enrolled. Patients who achieved clinical response (defined as delta Crohn's disease activity index [CDAI] > 70 and CDAI < 200) at 10-14 weeks after the start of infliximab or adalimumab were included. Eligible patients took a tolerability test of ED (900 kcal/day) for 3 days. Then, patients who preferred concomitant ED and whose ED tolerance was confirmed were allocated to the ED group and given Elental 900 kcal/day or more. Other patients were allocated to the non-ED group. The primary endpoint was the cumulative remission rate at 2 years after baseline. Clinical relapse was defined as CDAI > 200 and/or need for additional treatment. Adherence to the ED was confirmed at each visit. RESULTS: Seventy-two patients were included. Thirty-seven were allocated to the ED group, and 35 were allocated to the non-ED group. The cumulative remission rate at 2 years was not significantly different between the two groups (60.9% vs 56.7%, P = 0.98). Adherence to the ED in the ED group was relatively low, and only 11 patients were maintained on an ED of 900 kcal/day. CONCLUSIONS: The addition of ED for Crohn's disease patients who responded to initial anti-TNF induction therapy was not found to improve outcomes. The efficacy of concomitant ED in other clinical settings, such as loss of response, needs to be clarified in the future (UMIN000009789).

Endocytoscopic classification can be predictive for relapse in ulcerative colitis.

The present study was conducted to explore the association of endocytoscopy (EC) classification with microscopic inflammatory features of ulcerative colitis (UC) and disease relapse.EC was performed for mild-to-moderate UC 32 cases from January 2010 to August 2016. EC appearance was stratified into 4 categories: EC-A, regular arrangement of round to oval pits; EC-B, irregular arrangement with/without enlarged spaces between regular pits; EC-C, deformed pits with distorted crypt lumen which are unordered in arrangement but not disrupted; and EC-D, disruptive or disappeared pits. We evaluated the association of EC classification with Mayo endoscopic subscores (MES) and the clinically active state. Microscopic features including the severity in mucosal inflammatory infiltrates the presence of crypt abscess and goblet cell depletion were assessed by an experienced pathologist who was blinded to clinical and endoscopic information. Clinical follow-up was provided for treating 22 UC patients more than 60 months after EC.There were 15 cases in EC-A, 8 in EC-B, 5 in EC-C, and 4 in EC-D. Interobserver agreement was excellent with κ value of 0.77. There were 13 patients in active disease stage, while 19 in remission. Each EC-A case was in clinically remission stage, while all the EC-C and EC-D cases were in the active stage. There were 4 and 4 EC-B cases in remission and active stage, respectively. The EC-A group consisted of 11 MES0 and 4 MES1 cases, whereas the EC-B group consisted of 2 MES0 and 6 MES1 cases. There were no cases of MES0 in the EC-C and -D groups. The EC stratification was significantly associated with pathognomonic microscopic features for UC. There were significant differences in the remission rate among the EC groups. None had relapse in the EC-A group during the follow-up period.EC stratification could be predictive for relapse in UC. Moreover, EC is reliable to assess UC specific microscopic features.

Correlation of Fecal Markers with Magnifying Endoscopic Stratification in Patients with Ulcerative Colitis Who Are in Clinical Remission.

BACKGROUND: Maintenance of mucosal healing is recommended during the treatment of ulcerative colitis (UC). However, symptoms of UC often do not reflect mucosal disease activity. Fecal markers such as calprotectin, lactoferrin, and hemoglobin have been reported to correlate well with the Mayo endoscopic subscore (MES) and are being considered alternative monitoring tools in endoscopy. Ulcerative Colitis Endoscopic Index of Severity (UCEIS) is a new and more detailed endoscopic scoring system compared to MES. Furthermore, magnifying endoscopic stratification (ME) based on alterations in the mucosal surface pit patterns is noted in UC. However, the association between fecal markers and UCIES and magnifying endoscopy is relatively unexplored. SUMMARY: This study investigated the association between the aforementioned fecal markers and MES, UCEIS, and ME in patients with UC in clinical remission. This prospective study included 60 patients with UC in clinical remission who underwent colonoscopy at the Nagasaki University Hospital between June 2015 and November 2016. A significant correlation was observed between MES and all fecal markers. Notably, the fecal markers correlated well with UCEIS (calprotectin Spearman's correlation coefficient [r] = 0.54, p < 0.0001; lactoferrin r = 0.56, p < 0.0001; and hemoglobin r = 0.43, p < 0.001). Furthermore, ME findings correlated significantly with calprotectin (r = 0.50, p = 0.0002) and lactoferrin (r = 0.46, p = 0.0006) levels and slightly with hemoglobin (r = 0.28, p = 0.043) levels. Moreover, each cutoff level of fecal calprotectin, lactoferrin, or hemoglobin had a high sensitivity and specificity for the detection of MES = 0, UCEIS = 0, ME = A, for predicting mucosa healing. Key Messages: Fecal markers correlated not only with MES but also with UCEIS and ME and should be useful for monitoring patients with UC in clinical remission.

A case of combined Morgagni and esophageal hiatal hernias successfully repaired by endoscopy and laparoscopy.

An 87-year-old woman with a 4-month history of postprandial gastrointestinal obstruction was admitted to our facility after suddenly vomiting black matter. Computed tomography and esophagogastroduodenoscopy revealed gastric prolapse and prolapse of the duodenum and transverse colon. Morgagni hernia combined with esophageal hiatal hernia was diagnosed. Gastric and duodenal obstructions were successfully repaired by endoscopy, followed by laparoscopic repair. Endoscopic repair helped the patient avoid fasting before surgery. The patient had a history of several chest bruises, which were detected by chest X-rays and suspected to be the cause of the hernias over time.

MicroRNA-130a is highly expressed in the esophageal mucosa of achalasia patients.

Esophageal achalasia is considered as a risk factor of esophageal cancer. The etiologies of esophageal achalasia remain unknown. Peroral endoscopic myotomy (POEM) has recently been established as a minimally invasive method with high curability. The aims of the present study were to identify the microRNAs (miRs) specific to esophageal achalasia, to determine their potential target genes and to assess their alteration following POEM. RNA was extracted from biopsy samples from middle esophageal mucosa and analyzed using a microarray. Differentially expressed miRs in achalasia patients compared with control samples were identified and analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Correlations between specific miR expression levels and the patients' clinical background were also investigated. In addition, alterations of selected miR expression levels before and after POEM were analyzed. The results of RT-qPCR analysis demonstrated that the miR-130a expression levels were significantly higher in patients with achalasia (P<0.0001). In addition, miR-130a expression was significantly correlated with male sex and smoking history in patients with achalasia. However, no significant change in miR-130a expression was observed between before and after POEM. In conclusion, miR-130a is highly expressed in the esophageal mucosa of patients with achalasia and may be a biomarker of esophageal achalasia.

Expression of coproporphyrinogen oxidase is associated with detection of upper gastrointestinal carcinomas by 5-aminolevulinic acid-mediated photodynamic diagnosis.

BACKGROUND: 5-Aminolevulinic acid is a precursor of photosensitizing protoporphyrin IX and has been applied for photodynamic diagnosis of brain and bladder tumors with few side effects. Although most upper gastrointestinal tumors can be detected during photodynamic diagnosis, some tumors containing signet-ring cells cannot be visualized. Here, we aimed to assess whether proteins involved in the absorbance, activation, and turnover of protoporphyrin IX altered the fluorescence signal in gastric cancer. METHODS: Aminolevulinic acid-mediated photodynamic diagnosis was performed in 23 lesions from 20 patients using an endoscope equipped with a blue laser light that caused red fluorescence emission of photosensitizing protoporphyrin IX. Red fluorescence signal and intensity was assessed during photodynamic diagnosis procedures. Lesions were resected by endoscopic and/or laparoscopic surgery, and specimens were immunostained and assessed for the expression of ATP-binding cassette sub-family G member 2, oligopeptide transporter-1, and coproporphyrinogen oxidase. RESULTS: Photodynamic diagnosis was negative in four cases (17.4%). Three cases of photodynamic diagnosis-negative lesions were signet-ring cell carcinomas, and only one case was differentiated adenocarcinoma (intestinal type). Twenty intestinal type, photodynamic diagnosis-positive lesions showed high expression of coproporphyrinogen oxidase, whereas signet-ring cell carcinomas were all negative. Oligopeptide transporter-1 immunoreactivity was significantly higher in tumors of intestinal type. ATP-binding cassette sub-family G member 2 expression tended to be higher in luminal surface tumors than in intestinal type tumors. CONCLUSION: Aminolevulinic acid-mediated photodynamic diagnosis provided good detection of upper gastrointestinal tumors of intestinal type but not diffuse type tumors, such as signet-ring cell carcinomas, possibly owing to coproporphyrinogen oxidase expression.

Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.

BACKGROUND AND AIMS: A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. METHODS: Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. RESULTS: Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. CONCLUSIONS: The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans.

Glucose fluctuations reduce quality of sleep and of life in patients with liver cirrhosis.

BACKGROUND: Sleep disturbance and decreased health-related quality of life (HRQOL) are significant complaints in patients with liver cirrhosis. Although the etiology of these complications is unclear, we propose that glucose intolerance may be a predisposing factor. Therefore, our aim was to investigate the relationship between glucose intolerance and these complications. METHODS: We assessed continuous glucose monitoring in 43 patients with chronic liver disease. Among these patients, 36 completed the Pittsburgh Sleep Quality Index (PSQI), the 36-Item Short-form Health Survey (SF-36), and the Neuropsychological Test (NPT). We also assessed the change in glucose fluctuations between preoperative periods and 1 year after liver transplantation in 13 patients. RESULTS: Standard deviation (SD) of blood glucose was 24.15 ± 13.52. SD values correlated to glucose metabolism measures, including HbA1c and glycoalbumin. SD values also correlated to markers of liver fibrosis, including type IV collagen. Twenty-one patients (58.3 %) were classified as "poor" sleepers, with a global PSQI score ≥6. Glucose fluctuations correlated with the global PSQI score (r = 0.456, p = 0.008) and the SF-36 score (r = 0.434, p = 0.013). Multivariate regression analysis identified SD values as an independent risk factor for sleep disturbance (r = 0.12, p = 0.039) and decreased HRQOL (r = -0.32, p = 0.024). SD values did not correlate with the NPT. SD values were also improved in 11 (84.6 %) patients 1 year after liver transplantation. CONCLUSION: Abnormal glucose fluctuations are a risk factor for sleep disturbance and decrease of HRQOL in patients with cirrhosis.

Prevalence of Restless Legs Syndrome in Patients with Inflammatory Bowel Disease.

BACKGROUND AND AIM: There has been increased interest in sleep disorders in patients with inflammatory bowel disease (IBD). Studies in North America and Europe reported that the prevalence of restless legs syndrome (RLS) is much higher in patients with Crohn's disease (CD) than in the general population. The aim of this study was to reveal the prevalence and clinical features of RLS in Japanese patients with IBD and investigate the influence of RLS on sleep quality and quality of life (QOL). METHODS: The study included 80 outpatients with IBD who visited Nagasaki University Hospital between December 2012 and July 2014. All patients completed the international RLS study group rating scale, a validated measure of the presence of RLS. Sleep quality was assessed using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI), and health-related QOL was assessed using the Japanese version of the 36-item short form healthy profile (SF-36) version 2. RESULTS: The prevalence of RLS in patients with IBD was 20%, including rates of 21.7% in patients with ulcerative colitis (UC) and 17.6% in patients with CD. Among patients with CD, the proportion of women and serum level of CRP were higher in the RLS group than in the non-RLS group. Among those with UC, there were no differences in clinical characteristics between the RLS and non-RLS groups. Patients in the RLS group slept significantly less well than those in the non-RLS group (PSQI > 5; 62.5 vs. 34.4%, P < 0.05). No significant relationships were observed between QOL indices and the presence of RLS (SF-36 physical score, 46.8 vs. 50.1; mental score, 43.8 vs. 45.7; role/social score, 48.1 vs. 49.2). CONCLUSIONS: RLS occurs frequently in Japanese patients with UC as well as CD. RLS affects sleep quality but not QOL, and it should be considered one of the causes of sleep disturbance in patients with IBD.

Elevated Fasting Plasma Glucose before Liver Transplantation is Associated with Lower Post-Transplant Survival.

BACKGROUND The risk of liver cirrhosis is higher among individuals with diabetes mellitus, and a cirrhotic patient with diabetes may have a poorer prognosis after liver transplantation compared to a patient without diabetes. Thus, we evaluated whether fasting plasma glucose prior to receiving a liver transplant was a prognostic factor for post-transplant survival. MATERIAL AND METHODS Ninety-one patients received a living donor liver transplant between November 2005 and December 2012. Patients were considered diabetic if they were prescribed diabetes medications or had impaired glucose tolerance as measured by an oral glucose tolerance test. Each patient was monitored through December 31, 2013, to evaluate prognosis. RESULTS Fasting plasma glucose of at least 100 mg/dL significantly decreased survival following transplant (52% in the high FPG group compared to 78% in the control group, p=0.04), while postprandial hyperglycemia had no effect on survival. Additionally, overall mortality and the incidence of vascular disease were significantly higher among patients with uncontrolled plasma glucose. Impaired fasting plasma glucose was significantly and inversely associated with overall survival in the univariate and multivariate analyses, while creatinine (at least 1 mg/dL) was inversely associated with survival in the univariate analysis. CONCLUSIONS Elevated fasting plasma glucose prior to liver transplantation was inversely associated with post-transplant survival. This effect may be due to underlying microangiopathy as a result of uncontrolled diabetes before transplantation. Our data demonstrated the importance of controlled blood glucose prior to liver transplantation.