Shlomo Brill

Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure.

ObjectiveTo test the efficacy of the molecular adsorbent recycling system (MARS) in patients with acute exacerbation of chronic liver disease. DesignA prospective case analysis. SettingA university-affiliated tertiary medical center. Patients and Methods We applied MARS to treat a consecutive series of eight patients with acute exacerbation of chronic liver disease. ResultsThe overall survival rate was 62.5%. All patients demonstrated improvement with regard to their degree of encephalopathy. In three patients, intracranial pressure and jugular bulb oxygen saturation decreased and cerebral perfusion pressure increased after treatment institution. Patients’ hyperdynamic state was attenuated, as demonstrated by elevation of systemic vascular resistance, mean arterial pressure, and parallel reduction in cardiac index. A prompt reduction in serum ammonia, bilirubin, and lactate levels was observed. There were no complications during the treatment period. ConclusionsApplying MARS treatments to patients with acute exacerbation of chronic liver disease can detoxify blood, improve cerebral circulation, and reduce brain edema, as reflected by the reduction in intracranial pressure and jugular bulb oxygen saturation values in our patients. A partial reversal of the characteristic hyperdynamic circulation was also achieved. Despite our encouraging results, further testing is needed to determine the reliability of the system.

Proton pump inhibitors reduce cell cycle abnormalities in Barrett's esophagus.

Neoplastic progression in Barretts esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barretts esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27kip1 protein, but did not display appreciable nuclear staining for p16kip4, p21cip1 or cyclins D1 and E. Barretts metaplastic specimens displayed increased expression levels of p16kip4 (74%), p21cip1 (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16kip4 and cyclin E, and p21cip1 and p27kip4 with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barretts esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.

Gliotoxin Ameliorates Development of Fibrosis and Cirrhosis in a Thioacetamide Rat Model

Activation of hepatic stellate cells causes most of the pathological changes in cirrhosis. The fungal metabolite gliotoxin was shown to induce apoptosis of hepatic stellate cells in vitro. We examined whether gliotoxin may prevent or reverse liver fibrosis in a rat model of thioacetamide-inducedcirrhosis, and whether gliotoxin administration in vivo causes apoptosis of activated stellate cells. Gliotoxin treatment resulted in a significant decrease in liver fibrosis in rats, but did not improve liver functions. We observed a significant reduction in the numbers of activated hepatic stellate cells in the gliotoxin-treated rats. Gliotoxin administration also resulted in parenchymal apoptosis of hepatocytes and hepatic stellate cells. In conclusion, gliotoxin reduces hepatic fibrosis, an effect accompanied by reduction of the numbers of activated hepatic stellate cells in the liver.

Stromal extracellular matrix reduces chemotherapy-induced apoptosis in colon cancer cell lines

Several studies have shown that extracellular matrix reduces chemotherapeutic drugs-induced apoptosis in small cell lung cancer cells, myelomas and gliomas. We have investigated the protective effect of defined extracellular matrix components and of extracellular matrix from different cell types (fibroblasts, hepatocytes and intestinal epithelial cells) on the toxicity of three types of chemotherapeutic drugs on colon cancer cells. Human colon cancer cell lines LS174T and LiM6 were plated on plastic, on hepatocyte-derived ECM or on stromal ECM and in the presence of the antimetabolite 5-fluorouracil (5-FU), the topoisomerase I inhibitor camptothecin and the topoisomerase II inhibitor etoposide. We determined IC50 for the drugs for each of these culture conditions. We also determined the expression of the anti-apoptotic proteins bcl-2 and bcl-x (L) under these culture conditions. We found that stromal ECM protected LiM6 cells from the toxicity of etoposide and LS174T, but not LiM6 cells, from the toxicity of camptothecin. Collagen I, fibronectin and fibroblast-derived ECM rendered LiM6 cells, but not LS174T, more sensitive to the harmful effect of 5-FU. Both colon cell lines had increased expression of anti-apoptotic proteins bcl-2 and bcl-x(L) when cultured on the various ECMs and with the drugs, but there was no correlation between a protective ECM effect and expression of the anti-apoptotic proteins. Stromal-derived ECM may protect colon cancer cells from etoposide and camptothecin-induced apotosis, through a mechanism that is not bcl-2 or bcl-x(L) dependant.

The role of fetal and adult hepatocyte extracellular matrix in the regulation of tissue-specific gene expression in fetal and adult hepatocytes.

We explored the effect of extracellular matrix (ECM) produced by fetal and adult hepatocytes on tissue-specific gene expression and proliferation of fetal and adult hepatocytes. Adult hepatocytes ECM strongly induced expression of both albumin and HNF-4 in adult hepatocytes. In contrast, fibroblast ECM reduced the expression of mRNAs for albumin and alpha-fetoprotein in fetal hepatocytes. Adult hepatocytes ECM also increased the activity of liver-specific enzymes of adult hepatocytes (DPP IV and glucose-6-phosphatase) in both fetal and adult hepatocytes, while fetal hepatocyte-derived ECM increased activity of the fetal hepatocyte enzyme GGT in fetal hepatocytes. Fibroblast ECM was inhibitory for the activity of all enzymes assayed. Removal of heparin chains from the various matrices by pretreatment of the ECM with heparinase resulted in reduction of glucose-6-phosphatase and DPP IV in adult hepatocytes. Removal of chondroitin sulfate chains from fetal hepatocyte-derived ECM resulted in loss of induction of GGT in the fetal cells. Fetal hepatocytes proliferated best on adult hepatocyte-derived ECM. Adult hepatocytes showed only modest proliferation on both fetal and adult hepatocytes ECM and their growth was inhibited by fibroblast ECM. In conclusion, adult hepatocyte ECM better supports the expression of adult genes, whereas fetal hepatocyte ECM induced expression of fetal genes. Fibroblast derived-ECM was inhibitory for both proliferation and tissue-specific gene expression in fetal and adult hepatocytes. The data support a role for heparan sulfate being the active element in adult ECM, and chondroitin sulfate being the active element in fetal ECM.

One-Week Triple Therapy With Omeprazole, Clarithromycin, and Nitroimidazole for Helicobacter pylori Infection in Children and Adolescents

Background. Resolution ofHelicobacter pylori infection is important in the management of peptic ulcer disease and reduces peptic ulcer recurrence in both adults and children. Various anti-H pyloritreatment regimens have been proposed, reflecting the incomplete clinical success of each. A combination of omeprazole, clarithromycin, and tinidazole, given for 1 week, has been shown to be highly tolerable and effective, achieving a success rate of >90% in the adult population. Objective. The aim of this study was to evaluate this short-term regimen in pediatric and adolescent populations. Methods. The study group consisted of 35 children referred for evaluation of dyspeptic symptoms. They all underwent upper gastrointestinal endoscopy, in which H pylori infection was confirmed by rapid urease test and/or histologic staining. They were given omeprazole (20 mg twice daily), clarithromycin (250 mg twice daily), and tinidazole or metronidazole (500 mg twice daily) for 1 week. The patients were divided into two groups: those who received the first course of anti-H pylori therapy during this study (group 1) and those who had previously received standard metronidazole and bismuth combination therapies that failed to eradicate H pylori (group 2). Therapeutic efficacy was assessed by a13C-urea breath test performed 4 weeks after completion of treatment. Results. The 35 study patients had a mean age of 15.9 years (range, 10 to 19) and included 19 males and 16 females, of whom 22 were born in Israel and 13 were immigrants from the former USSR. There were 27 patients (77.1%) in group 1 and 8 patients (22.9%) in group 2. Endoscopic findings were nodular gastritis (14), gastritis (11), gastric ulcer (1), duodenal ulcer (5), and duodenitis (4).H pylori resolution was significantly higher in group 1 patients (24/27, 88.9%) than in group 2 patients (1/8, 12.5%). There was no difference between patients with nodular gastritis and those with nonnodular gastritis, and between Israeli-born patients and patients born in the former USSR. Compliance in both groups was equally good, and no major side effects were recorded. Conclusions. One-week omeprazole/clarithromycin/tinidazole triple therapy is highly tolerable and effective for treating H pylori in the pediatric age group, but previous treatment failure diminishes the likelihood of success with this regimen.

Triiodothyronine and interleukin‐6 (IL‐6) induce expression of HGF in an immortalized rat hepatic stellate cell line

Abstract: Background/Aims: Despite its being considered a primary mitogen for hepatocytes, triiodothyronine (T3) has no effect on the proliferation of hepatocytes in vitro, and in our studies, induces significant in vivo hepatocyte proliferation only during liver injury. We hypothesized that T3 may affect hepatocytes proliferation indirectly, by inducing other cells in the liver to secrete hepatic mitogens.

Diagnostic yield of routine push enteroscopy with a graded-stiffness enteroscope without overtube

BACKGROUND Push enteroscopy has become a standard procedure for evaluation of small intestinal disorders. Its diagnostic yield and acceptability, however, has been hampered by the use of an overtube, which is both inconvenient and potentially hazardous. This study assessed the clinical value of enteroscopy with a graded-stiffness videoenteroscope without an overtube. METHODS A total of 121 consecutive patients (mean age 59 years, range 12-89 years) underwent diagnostic enteroscopy. All procedures (n = 126) were performed with a push-type graded-stiffness videoenteroscope without an overtube. Indications were the following: unexplained iron deficiency anemia (45%), GI bleeding (29%), abdominal pain (6%), malabsorption (5.5%), imaging abnormality (5.5%), diarrhea (4%), intestinal obstruction (3%), and vomiting (2%). RESULTS The mean depth of instrument insertion distal to the pylorus was 121 cm. A diagnosis was made in 40% of all procedures. The findings included ulcerations or erosions in 43%, angioectasia in 35%, inflammation in 14%, tumors in 6%, and varices in 2%. In all cases of a positive enteroscopic diagnosis, therapeutic maneuvers were performed, and no patient needed a further diagnostic procedure. Patient comfort was good. No complications were observed. CONCLUSIONS Routine enteroscopy with a graded-stiffness enteroscope without an overtube is safe and comfortable for the patient and the endoscopist, and has a clinical efficacy comparable with that reported for enteroscopy with use of an overtube. A prospective, randomized study is warranted to assess the exact role of this form of enteroscopy in patient care.

Heparin-derived disaccharides modulate proliferation and Erb-B2–mediated signal transduction in colon cancer cell lines

Organ‐specific extracellular matrix (ECM) determines metastasis formation by regulating tumor cell proliferation. Hepatocyte‐derived ECM enhances proliferation of colon cancer cell lines by increasing expression of tyrosine kinase receptors of the erb‐B family. The active components in the ECM are the heparan sulfates, which are highly heterogenous in their chemistry and size. We determined the effect of heparan sulfate disaccharides, of defined chemistry and present in high amounts in the liver heparan sulfate chains, on the proliferation of colon cancer cell lines and investigated the mechanism involved. The low‐metastatic cell line KM12 was stimulated to proliferate by a highly sulfated disaccharide, found in the highest amounts in hepatocyte‐derived heparan sulfate. Growth of the highly metastatic cell line KM12SM was inhibited by the second most common disaccharide in hepatocyte‐derived heparan sulfate. The effect of both disaccharides was not accompanied by changes in the expression of erb‐B1, erb‐B2, erb‐B3 or heregulin‐α. We determined whether the disaccharides modified the signal‐transduction pathways mediated by the erb‐B receptors. The erb‐B2‐specific tyrosine kinase inhibitor AG825 abolished the enhancement of KM12 cell proliferation by the stimulatory disaccharide. This disaccharide increased tyrosine phosphorylation of erb‐B1 and erb‐B2 receptors, effects that were abolished by AG825. Moreover, the disaccharide caused increased expression of cyclin D1 and of activated MAP kinase, again reduced in the presence of the inhibitor AG825. The growth‐inhibitory disaccharide reduced phosphorylation of erb‐B1, but not of erb‐B2, receptors in KM12SM cells. In conclusion, not only hepatocyte‐derived heparan sulfate but also disaccharide molecules derived from heparan sulfate can affect colon cancer cell proliferation. Their effect is mediated by modulation of the erb‐B signal transduction.

The Efficacy of Omeprazole‐Based Short‐Term Triple Therapy in Helicobacter pylon‐Positive Older Patients with Dyspepsia

OBJECTIVE: To evaluate the efficacy of 1‐week triple therapy with omeprazole, clarithromycin, and tinidazole (OCT) in Helicobacter pylori‐positive older patients with dyspepsia.