Efficacy and tolerability of a novel galactomannan-based formulation for symptomatic treatment of gastroesophageal reflux disease: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: Proton Pump Inhibitors (PPIs) and traditional antacids are the common standard set of therapy for the management of gastroesophageal reflux disease (GERD) symptoms. The aim of the current study was to evaluate efficacy and safety of a novel galactomannan-based liquid formulation in reducing typical GERD symptoms in patients not taking PPIs. PATIENTS AND METHODS: This was a single-center, randomized, double-blind, placebo-controlled study. Sixty patients met the eligibility criteria and were treated either with the investigational product (RefluG™) or placebo, one sachet three times per day for 14 consecutive days. Symptom intensity/frequency and quality of life were assessed over the course of the study by Reflux Disease Questionnaire (RDQ) and GERD-Health related Quality of life (HRQL) Questionnaire, respectively. The primary endpoint was to determine the number of subjects with at least 30% symptoms reduction from baseline to day 14 compared to placebo. RESULTS: RefluG™ was statistically superior to placebo (p <0.001) as 100% of subjects experienced at least 30% symptoms reduction at the end of the study while none achieved a 30% reduction in the placebo group. For all domains both after 7 and 14 days of treatment, significant improvement in HRQL was seen in the active group in comparison to placebo. Tolerability and safety were good and comparable between groups. CONCLUSIONS: The investigational product was safe and effective as mono-therapy in providing early resolution of troublesome GERD symptoms as well as for improving quality of life.

Impedance-based drug-resistance characterization of colon cancer cells through real-time cell culture monitoring.

Interest in impedance-based cellular assays is rising due to their remarkable advantages, including label-free, low cost, non-invasive, non-destructive, quantitative and real-time monitoring. In order to test their potential in cancer treatment decision and early detection of chemoresistance, we devised a new custom-made impedance measuring system based on electric cell-substrate impedance sensing (ECIS), optimized for long term impedance measurements. This device was employed in a proof of concept cell culture impedance analysis for the characterization of chemo-resistant colon cancer cells. Doxorubicin-resistant HT-29 cells were used for this purpose and monitored for 140 h. Analysis of impedance-based curves reveal different trends from chemo-sensitive and chemo-resistant cells. An impedance-based cytoxicity assay with different concentrations of doxorubicin was also performed using ECIS. The obtained results confirm the feasibility of ECIS in the study of drug resistance and show promises for studies of time-dependent factors related to physiological and behavioral changes in cells during resistance acquisition. The methodology presented herein, allows the continuous monitoring of cells under normal culture conditions as well as upon drug exposure. The ECIS device used, sets the basis for high-throughput early detection of resistance to drugs, administered in the clinical practice to cancer patients, and for the screening of new drugs in vitro, on patient-derived cells.

Severe ulcerative colitis: predictors of response and algorithm proposal for rescue therapy.

BACKGROUND: There is no agreeing if rescue therapy can avoid short-term colectomy in patients treated for severe steroid-refractory ulcerative colitis. AIMS: The aim of our study was to identify predictors of response to infliximab and cyclosporine A. METHODS: In this cross-sectional study, 49 patients with severe ulcerative colitis were included. Response to therapy was defined as three or more point reductions in Mayo score after 6 months of treatment and avoidance of colectomy after 1 year. The predictors analysed were gender, age, time from ulcerative colitis diagnosis, months of steroid or/and azathioprine therapy before onset of the severe phase, smoking habits, extension of the disease, laboratory analyses and Mayo score. RESULTS: Patients treated with infliximab showed a statistically significant higher response rate in case of moderate Mayo score (P = 0.04). Ex-smokers had very low chance of response to infliximab (P = 0.03). In the group treated with cyclosporine A, patients with C-reactive protein >3 mg/L had a response rate significantly higher than those with C-reactive protein <3 mg/L (P = 0.03); those with negative C-reactive protein and moderate Mayo score did not responded to therapy, while in the ones with elevated C-reactive protein and/or severe Mayo score, 15 versus 4 responded (P = 0.008). CONCLUSIONS: Our data suggest that cyclosporine A is advisable in ex-smokers. In never smokers or active smokers, infliximab can be prescribed in case of Mayo score ≤10 and/or negative CRP, while cyclosporine A is indicated in case of Mayo score >10 and positive CRP.

Endoscopic ultrasound in the preoperative staging of gastric cancer: key messages for surgeons.

Gastric cancer (GC) remains a frequent and important cause of cancer mortality worldwide. Many factors affect the prognosis of GC, but invasion and metastasis are the leading causes of death. Due to the various stage-oriented therapies available, after the diagnosis of GC it is important to determine the staging preoperatively in order to choose the appropriate management. GC staging is the workhorse of endoscopic ultrasound (EUS). EUS can distinguish the different wall layers of the gastrointestinal tract as well as assess regional lymph nodes. Furthermore, samples of suspicious lesions or lymph nodes can be obtained by means of EUS-guided fine-needle aspiration (EUS-FNA). In this narrative review, we highlight the current status of the usefulness of EUS for GC staging, with focus on early GC that still remains a diagnostic and therapeutic challenge. In particular, the possibility to ameliorate the accuracy of EUS, in this context, by using instruments with increased ultrasound frequency is emphasized.

Endocrine manifestations of chronic HCV infection.

Chronic hepatitis C virus (HCV) infection has been associated with a great number of extra-hepatic manifestations (EHMs), including several endocrine disorders. Currently available epidemiological, clinical and experimental data do not show a link between HCV and all EHMs. Thyroid disorders (TD) and type 2 diabetes, for example, are the most frequent endocrine alterations in patients with chronic HCV infection, but there are only weak evidences that HCV could be involved in hypothalamic-pituitary axis perturbation, bone metabolism alteration and sexual dysfunctions induction. Thus, this issue needs further investigation. Prospective studies have also shown that interferon (IFN)-based therapy for chronic HCV infection can induce or worsen EHMs. In particular, IFN has been associated with development of autoimmunity and/or TD in up to 40% of chronic HCV infected patients. Hence, a careful monitoring of thyroid function should be performed in such patients. The recent approval of direct-acting antiviral agents in IFN-free regimens for chronic hepatitis C treatment will dramatically reduce not only liver-related mortality but also morbidity due to EHMs.

MicroRNAs in HBV-related hepatocellular carcinoma: functions and potential clinical applications.

Hepatitis B virus (HBV) infection is still a relevant problem worldwide and many cases of hepatocellular carcinoma (HCC) are related to HBV. The prognosis of HBV-related HCC is poor, particularly for advanced stage diagnosis. Although follow-up strategies were adopted for patients at risk, there is need for an optimal early biomarker for the screening purpose. MicroRNAs (miRNAs) are small non-coding RNAs, tightly connected to cell type and differentiation status and act as genetic regulator which can be involved in oncogenic processes. The alteration in miRNA expression pattern may represent a new opportunity for HBV-related HCC diagnosis and therapies. Some studies focused on miRNA polymorphism responsible for HCC susceptibility; others found several miRNAs deregulated by HBV X protein as well as miRNAs altered in HBV-related HCC tissue and cells. A high variability among results emerged, probably due to different techniques employed, biological substrates, experimental procedures, criteria of miRNAs selection and ethnic provenience of the included patients. Interestingly, circulating miRNAs have been studied as potential HCC-biomarkers but the reported accuracy is still not convincing, particularly in distinguishing patients with HCC from patients with cirrhosis. Hence, the use of miRNAs remains in an experimental phase and more studies are required to define their role in the clinical practice.

Serum adipokine levels in overweight patients and their relationship with non-alcoholic fatty liver disease.

AIM: Non-alcoholic fatty liver disease (NAFLD) is a relevant public health matter in Western countries. The pathogenetic link between visceral fat, insulin resistance (IR) and NAFLD has been reported in literature. However, there are contradictions on the changes of adipokine levels in serum related to the presence of NAFLD. The aim of the present study was to evaluate the serum concentrations of a selected set of adipokines, that is, adiponectin, leptin, resistin and the pro-inflammatory cytokine interleukin-6 (IL-6) in overweight patients, and to clarify their relationship with NAFLD. METHODS: Fasting serum levels of adipokines were determined in 42 consecutive overweight patients and in 25 lean controls. The degree of ultrasound (US) liver steatosis was graded according to the Hamaguchi score. RESULTS: Liver steatosis was detected in 33 patients (78%) by US examination. Twelve patients with elevated transaminases levels showed significantly higher values of IR, leptin and resistin levels (P<0.05). Patients with steatosis presented a significantly higher leptin and a lower adiponectin levels (P<0.05) than controls. A significant inverse correlation was found between US steatosis progression and adiponectin and resistin levels (p<0.05). Considering the multiple logistic regression, adiponectin and leptin were good predictors to detect the presence of steatosis (p<0.05). CONCLUSION: Our data support the concept that adipokine level changes are closely linked with IR. In addition, serum adiponectin and leptin levels may be used as diagnostic markers to determine the presence of NAFLD in overweight patients.

Helicobacter pylori infection and dementia: can actual data reinforce the hypothesis of a causal association?

Helicobacter pylori (H. pylori) is involved in the development of several gastroduodenal diseases. Since the latest decade, several studies have reported on the link between chronic H. pylori infection and a variety of extragastric manifestations, including dementia. To identify the publications on the association between H. pylori and dementia, a MEDLINE search was conducted. Although case-control studies reported controversial data, a recent longitudinal population-based cohort study found that after 20 years of follow-up, 28.9% of H. pylori-positive versus 21.1% of H. pylori-negative subjects developed dementia. After correction for confounding factors, the infection was significantly associated with higher risk of developing dementia (P=0.04). Moreover, in another study evaluating the effect of H. pylori eradication on the progression of dementia in Alzheimer's disease patients with peptic ulcer, the cure of the bacterium was associated with a decreased risk of dementia progression compared to persistent infection. To date, defining H. pylori as a target for prevention or treatment of dementia remains a topic with much controversy but of essence, as any relationship would reduce, due to the cost-effectiveness of the therapy, a burden on the National Health Care budget. The need for extensive studies with appropriate epidemiological and clinical approaches is crucial to investigate a potential causal relationship.

Gastric cancer as a stem-cell disease: data and hypotheses.

The main function of gastric stem cells is to maintain the integrity of the gastrointestinal epithelium and replenish all the mature cell lineages. In order to accomplish this, gastric stem cells proliferate and self-renew, giving rise to transient amplifying cells which replace the constantly renewing epithelium, especially after injury induced by long-term inflammation. Gastric cancer (GC) remains the fourth most common cancer and the second leading cause of death for cancer in the world. The most accepted model of gastric carcinogenesis provides a multifactorial and multistep pathogenesis, involving a number of initiators and other continuator agents. Helicobacter pylori infection is recognized as a necessary but insufficient cause of GC. Recent advances in gastric stem cell biology point out to two hypotheses. In the first, it is postulated that resident stem cells may, in a chronically inflamed environment, as in the case of Helicobacter pylori-induced gastritis, accumulate over time a series of genetic and epigenetic changes that lead to the emergence of GC stem cells. Alternatively, the setting of chronic inflammatory stress may lead to loss of the indigenous gastric stem cells from their niches, followed by recruitment and engraftment of bone marrow derived stem cells (BMDCs) into the gastric epithelium. In the mouse model, increasing evidence supports the hypothesis that BMDCs are important cellular source of Helicobacter-induced GC. This review highlights data and hypotheses about GC as a model of stem-cell disease.

Liver steatosis in celiac disease: the open door.

Non-alcoholic fatty liver disease (NAFLD) is a common disease of unknown origin characterized by histological features similar to alcoholic-like liver injury but in the absence of significant alcohol intake. Non-alcoholic fatty liver disease refers to a spectrum of diseases of the liver ranging from simple steatosis (i.e., fatty infiltration of the liver) to nonalcoholic steatohepatitis (i.e., steatosis with inflammation and hepatocyte necrosis) to cirrhosis. Non-alcoholic fatty liver disease is frequently associated with disorders such as insulin resistance, obesity, type 2 diabetes mellitus, hyperlipidemia and protein-calorie malnutrition. However, in a subgroup of NAFLD patients, the true relevant cause remains undetermined. Celiac disease (CD) is a common immune-mediated disorder and develops in genetically susceptible subjects after the ingestion of gluten proteins. Celiac disease has been found in about 10% of patients with unexplained abnormal liver tests, and in about 3.5% of patients with NAFLD as the only manifestation of the disease. The frequency of subclinical or silent presentations in older children and adults highlights the importance of CD screening in patients with unexplained chronic abnormal liver function tests and NAFLD without any specific etiology. The pathogenesis of liver steatosis in CD is uncertain. The aims of this review are to describe the possible mechanisms involved in the occurrence and progression of liver steatosis in CD patients.

Epilepsy and celiac disease: review of literature.

Celiac disease (CD) is a chronic, immune-mediated disorder, characterized by small intestinal malabsorption of nutrients after the ingestion of gluten by genetically susceptible individuals. The discovery of the wide variations in the nature and intensity of clinical presentation of CD has transformed its status, long considered a rare disease, to that of a common health problem. As patients with CD get older, they tend to present with complaints not directly referable to the gastrointestinal tract. Neurologic symptoms, caused by lesions of the central or peripheral nervous system occasionally occur in patients with CD and are poorly understood. This review focalizes on the present knowledge of the potential relationship between CD and epilepsy. The prevalence of CD among patients with epilepsy is not homogeneously distributed, probably because epilepsy encompasses a heterogeneous group of disorders. In fact, the clinical spectrum of epilepsy related to CD ranges from benign syndromes to intractable epilepsy. The precise mechanism of the potential association between CD and epilepsy is also still under discussion.

Molecular findings on Helicobacter pylori: update for clinicians.

Helicobacter pylori (H. pylori) is a gram-negative bacterium which is responsible for a wide range of disorders of the stomach, from chronic gastritis to peptic ulcers to gastric cancer which, however, occurs in a lower percentage of subjects. The difference in the clinical course of infection seems to be correlated both to the typical pathogenicity of the bacterium and to factors related to the host. The reasons underlying these observations include differences in bacterial pathogenicity as well as in host susceptibility. Numerous studies published in the last year have provided new insights into H. pylori virulence factors, their interaction with the host and the relative consequences in the pathogenesis. In this review, we have set ourselves the target of summarising the latest progress made in understanding the molecular aspects of H. pylori infection of notable importance for the physician.