Elevated expression of ISY1, APOA-1, SYNE1, MTG1, and MMP10 at HCC initiation: HCC specific protein network involving interactions of key regulators of lipid metabolism, EGFR signaling, MAPK, and splicing pathways.

Identification of molecular regulators of hepatocellular carcinoma (HCC) initiation and progression is not well understood. We chemically induced HCC in male Wistar rats by administration of diethyl nitrosamine (DEN) and 2-acetylaminofluorene (2-AFF). Using 2D-electrophoresis and MALDI-TOF-MS/MS analyses, we characterized differentially expressed proteins in liver tissues at early stage of HCC progression. Using RT-PCR analysis, we quantified the mRNA expression of the characterized proteins and validated the transcript expression with tumor tissues of clinically confirmed HCC patients. Using bioinformatic tools, we analyzed a network among the introduced proteins that identified their interacting partners and analyzed the molecular mechanisms associated with signaling pathways during HCC progression. We characterized a protein, namely, pre-mRNA splicing factor 1 homolog (ISY1), which is upregulated at both transcriptome and proteome levels at HCC initiation, progression, and tumor stages. We analyzed the interacting partners of ISY1, namely, APOA-1, SYNE1, MMP10, and MTG1. Real-time PCR analysis confirmed elevated expression of APOA-1 mRNA at HCC initiation, progression, and tumor stages in animals undergoing tumorigenesis. The mRNA expression of the interacting partners was validated with tumor tissues of clinically confirmed liver cancer patients; the analysis revealed significant elevation in expression of transcripts. The transcriptome and proteome analyses complement each other and dysregulation in mRNA and protein expression of these regulators may play critical role in HCC initiation and progression.

Diet and nutrition in the management of inflammatory bowel disease.

The role of diet and its manipulation in the management of inflammatory bowel disease (IBD) is gradually acquiring central stage. Certain dietary factors have been identified as putative triggers in IBD as some other factors are found to be protective. The dietary manipulation as part of comprehensive IBD care should be done by the clinician in conjunction with a skilled dietitian. Nutritional deficiencies are common in patients with IBD and can have long-term effects on disease course and quality of life in these patients. So, early identification and correction of these deficiencies along with proper nutritional supplementation should be addressed routinely as a part of IBD management. Oral nutritional supplementation is sufficient for most patients, but in some sick patients, tube feeding may be necessary. Diet needs to be individualized based on the nutritional deficiencies and dietary triggers in a specific patient. Multiple specific diets, with elimination of components that trigger inflammation or addition of components that alter gut microbes in a favorable way, are now appearing as a treatment option in IBD, but more evidence is required before their universal recommendation. Though enteral nutrition (EN) (both exclusive enteral nutrition [EEN] and partial enteral nutrition [PEN]) have proven therapeutic role in pediatric IBD, their uses and role are now expanding in adult IBD patients as well.

Effect of lactase on symptoms and hydrogen breath levels in lactose intolerance: A crossover placebo-controlled study.

BACKGROUND AND AIM: The absence of lactase in the intestinal villi due to mucosal injury or genetic factors causes undigested lactose to reach the colon where it is fermented. Lactose intolerance is diagnosed based on clinical symptoms like bloating, abdominal pain and flatulence, lactose hydrogen breath test (HBT), and lactose tolerance test. No Indian studies are available on the use of lactase supplements. The aim was to study the effect of lactase chewable tablets on clinical symptoms and hydrogen breath excretion in patients with lactose intolerance. METHODS: This was a randomized, double-blind, crossover placebo-controlled trial to study the effect of lactase tablets on symptoms and hydrogen breath levels in adults with lactose intolerance, confirmed by Lactose HBT. Clinical symptom severity was recorded using a visual analog scale, and HBT was performed every 30 min for 180 min. As it was a crossover design, the same patients were tested with both lactase and placebo, acting as their own controls with a washout period of 1 week between visits. RESULTS: Forty-seven patients (mean age 33.6 years; 30 males) with lactose intolerance formed the study group. Clinical symptoms, mean clinical score (P < 0.05), and mean hydrogen breath levels (P < 0.05) were improved when the patients were given lactase. Reduction in cumulative hydrogen breath level over 180 min was 55% when patients received lactase compared to placebo. CONCLUSIONS: Orally supplemented lactase enzyme significantly reduced the clinical symptoms and hydrogen breath excretion in patients with lactose intolerance.

Diet and inflammatory bowel disease: The Asian Working Group guidelines.

INTRODUCTION: These Asian Working Group guidelines on diet in inflammatory bowel disease (IBD) present a multidisciplinary focus on clinical nutrition in IBD in Asian countries. METHODOLOGY: The guidelines are based on evidence from existing published literature; however, if objective data were lacking or inconclusive, expert opinion was considered. The conclusions and 38 recommendations have been subject to full peer review and a Delphi process in which uniformly positive responses (agree or strongly agree) were required. RESULTS: Diet has an important role in IBD pathogenesis, and an increase in the incidence of IBD in Asian countries has paralleled changes in the dietary patterns. The present consensus endeavors to address the following topics in relation to IBD: (i) role of diet in the pathogenesis; (ii) diet as a therapy; (iii) malnutrition and nutritional assessment of the patients; (iv) dietary recommendations; (v) nutritional rehabilitation; and (vi) nutrition in special situations like surgery, pregnancy, and lactation. CONCLUSIONS: Available objective data to guide nutritional support and primary nutritional therapy in IBD are presented as 38 recommendations.

Correction to: Diet and inflammatory bowel disease: The Asian Working Group guidelines.

The recommendations 31 which recommend "VSL#3®", refer only to the product used in the cited literature and equivalent products independent from the present product labelings. This product is now known by the generic name "De Simone Formulation".

Management of acute severe ulcerative colitis.

The management strategy of acute severe ulcerative colitis has evolved over the past decade from being entirely restricted to twin choices of intravenous steroids or colectomy to include colon rescue therapies like cyclosporin as well as infliximab. However it still remains a medical emergency requiring hospitalization and requires care from a multidisciplinary team comprising of a gastroenterologist and a colorectal surgeon. The frame shift in management has been the emphasis on time bound decision making with an attempt to curtail the mortality rate to below 1%. Intravenous corticosteroids are the mainstay of therapy. Response to steroids should be assessed at day 3 of admission and partial/non-responders should be considered for alternative medical therapy/surgery. Medical rescue therapies include intravenous cyclosporin and infliximab. Cyclosporin is administered in a dose of 2 mg/kg per day and infliximab is administered as a single dose intravenous infusion of 5 mg/kg. Approximately 75% patients have short term and 50% patients have long term response to cyclosporin. Long term response to cyclosporin is improved in patients who are thiopurine naïve and are started on thiopurines on day 7. Infliximab also has a response rate of approximately 70% in short term and 50% in long term. Both cyclosporin and infliximab are equally efficacious medical rescue therapies as demonstrated in a recent randomized control trial. Patients not responding to infliximab or cyclosporin should be considered for colectomy.

A randomized, open-label, non-inferiority study of intravenous iron isomaltoside 1,000 (Monofer) compared with oral iron for treatment of anemia in IBD (PROCEED).

OBJECTIVES: In the largest head-to-head comparison between an oral and an intravenous (IV) iron compound in patients with inflammatory bowel disease (IBD) so far, we strived to determine whether IV iron isomaltoside 1,000 is non-inferior to oral iron sulfate in the treatment of iron deficiency anemia (IDA). METHODS: This prospective, randomized, comparative, open-label, non-inferiority study was conducted at 36 sites in Europe and India. Patients with known intolerance to oral iron were excluded. A total of 338 IBD patients in clinical remission or with mild disease, a hemoglobin (Hb) <12 g/dl, and a transferrin saturation (TSAT) <20% were randomized 2:1 to receive either IV iron isomaltoside 1,000 according to the Ganzoni formula (225 patients) or oral iron sulfate 200 mg daily (equivalent to 200 mg elemental iron; 113 patients). An interactive web response system method was used to randomize the eligible patient to the treatment groups. The primary end point was change in Hb from baseline to week 8. Iron isomaltoside 1,000 and iron sulfate was compared by a non-inferiority assessment with a margin of -0.5 g/dl. The secondary end points, which tested for superiority, included change in Hb from baseline to weeks 2 and 4, change in s-ferritin, and TSAT to week 8, number of patients who discontinued study because of lack of response or intolerance of investigational drugs, change in total quality of life (QoL) score to weeks 4 and 8, and safety. Exploratory analyses included a responder analysis (proportion of patients with an increase in Hb ≥2 g/dl after 8 weeks), the effect of regional differences and total iron dose level, and other potential predictors of the treatment response. RESULTS: Non-inferiority in change of Hb to week 8 could not be demonstrated. There was a trend for oral iron sulfate being more effective in increasing Hb than iron isomaltoside 1,000. The estimated treatment effect was -0.37 (95% confidence interval (CI): -0.80, 0.06) with P=0.09 in the full analysis set (N=327) and -0.45 (95% CI: -0.88, -0.03) with P=0.04 in the per protocol analysis set (N=299). In patients treated with IV iron isomaltoside 1,000, the mean change in s-ferritin concentration was higher with an estimated treatment effect of 48.7 (95% CI: 18.6, 78.8) with P=0.002, whereas the mean change in TSAT was lower with an estimated treatment effect of -4.4 (95% CI: -7.4, -1.4) with P=0.005, compared with patients treated with oral iron. No differences in changes of QoL were observed. The safety profile was similar between the groups. The proportion of responders with Hb ≥2 g/dl (IV group: 67%; oral group: 61%) were comparable between the groups (P=0.32). Iron isomaltoside 1,000 was more efficacious with higher cumulative doses of >1,000 mg IV. Significant predictors of Hb response to IV iron treatment were baseline Hb and C-reactive protein (CRP). CONCLUSIONS: We could not demonstrate non-inferiority of IV iron isomaltoside 1,000 compared with oral iron in this study. Based on the dose-response relationship observed with the IV iron compound, we suggest that the true iron demand of IV iron was underestimated by the Ganzoni formula in our study. Alternative calculations including Hb and CRP should be explored to gauge iron stores in patients with IBD.

Oxidative stress in chronic pancreatitis: pathophysiological relevance and management.

SIGNIFICANCE: Chronic pancreatitis (CP) is a progressive, inflammatory disease of the pancreas leading to slow destruction of pancreatic parenchyma and progressive fibrosis. The pathophysiological mechanism of CP is not well understood. RECENT ADVANCES: A pathophysiologic role of oxidative stress in CP has, however, been suggested in recent years. Pancreatic acinar cells contain phase I cytochrome P450 (CYP 450) biotransforming enzymes and phase II conjugation reactions for the metabolism of xenobiotics. The oxidative stress in the acinar cell may result from generation of free radicals through CYP induction, concurrent exposure to a chemical that undergoes bioactivation, and insufficiency of micronutrients that are required to sustain antioxidant (AO) capacity. CRITICAL ISSUES: Studies have shown that there is indeed a state of oxidative stress as evidenced by increased levels of products of oxidative stress and reduced AO capacity in patients with CP. A recent randomized, controlled trial has shown beneficial effect of AO therapy in CP; a combination of AOs (0.54 g ascorbic acid, 9000 IU ß-carotene, 270 IU α-tocopherol, 600 µg organic selenium, and 2 g methionine per day in divided doses) led to significant reductions in pain and oxidative stress in patients with CP. FUTURE DIRECTIONS: Similar studies from other centers and multicenter studies should confirm that oxidative stress plays an important role in the pathophysiology of CP and supplementation with AOs leads to significant pain relief in patients with this disease.

Inflammatory bowel disease in the Asia-Pacific area: a comparison with developed countries and regional differences.

The Asia-Pacific region has been marked as an area with a low incidence of inflammatory bowel disease (IBD), although confusion always existed as to whether this low incidence was a result of low diagnostic awareness, a high incidence of infective diarrhoea and its diagnostic overlap or a true low incidence. As epidemiological studies from this region are being made available it is clear that the incidence and prevalence rates of IBD in Asia-Pacific region are low compared with Europe and North America. They are however, increasing rapidly. There are substantial variations in the incidence and prevalence rates of IBD in various ethnic groups in Asia. The highest incidence rates are recorded from India, Japan and the Middle East and there exists a genetic predisposition of South Asians (Indians, Pakistanis and Bangladeshis) to ulcerative colitis (UC). It appears that certain racial groups are more prone than others to develop IBD. For instance, Indians in South-East Asia have higher rates than Chinese and Malays. While there is a host genetic predisposition, environmental factor(s) may be responsible for this difference. The clinical phenotypes and complication rates of Asian IBD resemble those of the Caucasian population in general, but some heterogeneity is observed in different regions of Asia. There is no evidence of a north-south or an east-west divide in the Asia-Pacific region. The available studies suggest an increasing incidence of UC in the Asia-Pacific region and hence it is an appropriate time to launch well-designed epidemiological studies so that etiopathogenetic factors can be identified. There is a male predominance in Crohn's disease in the Asian population. The NOD2/CARD15 gene is not associated with CD in the Japanese, Korean, Chinese and Indian population.

The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis.

BACKGROUND & AIMS: Probiotics can maintain ulcerative colitis (UC) in remission effectively, but little is known of their ability to induce remission. We conducted a multicenter, randomized, double-blind, placebo-controlled trial of a high-potency probiotic, VSL#3, for the treatment of mild-to-moderately active UC. METHODS: Adult patients with mild-to-moderate UC were assigned randomly to groups that were given 3.6 x 10(12) CFU VSL#3 (n = 77) or placebo (n = 70), twice daily for 12 weeks. The primary end point was a 50% decrease in the Ulcerative Colitis Disease Activity Index (UCDAI) at 6 weeks. The secondary end points included remission by 12 weeks and reduction in total individual UCDAI parameters from baseline at 12 weeks. Intention-to-treat analysis was performed. RESULTS: At week 6, the percentage of patients with an improvement in UCDAI score that was greater than 50% was significantly higher in the group given VSL#3 (25; 32.5%) than the group given placebo (7; 10%) (P = .001). At week 12, there were 33 patients given VSL#3 (42.9%) who achieved remission, compared with 11 patients given placebo (15.7%) (P < .001). Furthermore, significantly more patients given VSL#3 (40; 51.9%) achieved a decrease in their UCDAI that was greater than 3 points, compared with those given placebo (13; 18.6%) (P < .001). The VSL#3 group had significantly greater decreases in UCDAI scores and individual symptoms at weeks 6 and 12, compared with the placebo group. CONCLUSIONS: VSL#3 is safe and effective in achieving clinical responses and remissions in patients with mild-to-moderately active UC.

A randomized controlled trial of antioxidant supplementation for pain relief in patients with chronic pancreatitis.

BACKGROUND & AIMS: Oxidative stress has been implicated in the pathophysiology of chronic pancreatitis (CP). We evaluated the effects of antioxidant supplementation on pain relief, oxidative stress, and antioxidant status in patients with CP. METHODS: In a placebo-controlled double blind trial, consecutive patients with CP were randomized to groups that were given placebo or antioxidants for 6 months. The primary outcome measure was pain relief, and secondary outcome measures were analgesic requirements, hospitalization, and markers of oxidative stress (thiobarbituric acid-reactive substances [TBARS]) and antioxidant status (ferric-reducing ability of plasma [FRAP]). RESULTS: Patients (age 30.5+/-10.5 years, 86 male, 35 alcoholic, and 92 with idiopathic CP) were assigned to the placebo (n=56) or antioxidant groups (n=71). After 6 months, the reduction in the number of painful days per month was significantly higher in the antioxidant group compared with the placebo group (7.4+/-6.8 vs 3.2+/-4, respectively; P< .001; 95% CI, 2.07, 6.23). The reduction in the number of analgesic tablets per month was also higher in the antioxidant group (10.5+/-11.8 vs 4.4+/-5.8 respectively; P= .001; 95% CI, 2.65, 9.65). Furthermore, 32% and 13% of patients became pain free in the antioxidant and placebo groups, respectively (P= .009). The reduction in the level of TBARS and increase in FRAP were significantly higher in the antioxidant group compared with the placebo group (TBARS: placebo 1.2+/-2.7 vs antioxidant 3.5+/-3.4 nmol/mL; P= .001; 95% CI 0.96, 3.55; FRAP: placebo -5.6+/-154.9 vs antioxidant 97.8+/-134.9 microMFe(+2) liberated, P= .001, 95% CI 44.98, 161.7). CONCLUSIONS: Antioxidant supplementation was effective in relieving pain and reducing levels of oxidative stress in patients with CP.