[show abstract][hide abstract] ABSTRACT: BACKGROUND: Genetic factors implicated in the pathogenesis of non-alcoholic fatty liver disease are poorly understood. Our aim was to characterize three genes involved in a rat model of non-alcoholic fatty liver disease and investigate the effect of rosiglitazone and bezafibrate. METHOD: Five rats were fed a chow diet (controls) and 18 a fructose-enriched diet (FED) for 5 weeks: 6 were administered rosiglitazone and 6 bezafibrate during the last 2 weeks and 6 were not treated at all. Livers were examined by reverse transcription-PCR for the genes encoding peroxisome proliferator-activated receptors (PPAR), PPAR-alpha, PPAR-gamma, and Mn superoxide dismutase2 (Mn SOD2). Western blot was used for proteins levels.Result: The FED rats showed a decrease in mRNA of MnSOD2, PPAR-alpha, and PPAR-gamma (3, 3.5 fold, and 27%, respectively) (p<0.05). The 3 genes normalized in response to rosiglitazone and bezafibrate. The proteins of MnSOD2, PPAR-alpha and PPAR-gamma in the FED rats decreased (2.5, 2, and 2.2, respectively) (p<0.05). Following administration of rosiglitazone, proteins of MnSOD2, PPAR-alpha and PPAR-gamma in the FED rats increased (reaching 1.5-fold, a 20% increase and normalization, respectively), (p<0.05). Administration of bezafibrate to the FED rats restored the proteins of 3 genes to baseline. CONCLUSION: A consistent reduction in hepatic expression of MnSOD2, PPAR-alpha and PPAR-gamma in the FED rats compared with controls was observed. Administration of either rosiglitazone or bezafibrate to the FED rats restored these genes to a pre-morbid state.
Lipids in Health and Disease 03/2013; 12(1):41. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Individuals with the metabolic syndrome (MS) and non-alcoholic fatty liver disease (NFALD) have an increased incidence of infection and infection-related mortality. Rats given fructose-enriched diet (FED) develop the MS including NAFLD. In this study, we characterized changes in splenocyte apoptosis in FED rats given medications to treat various components of the MS. Apoptosis of splenocytes may induce immunosuppression. Splenocyte apoptosis was evaluated by activated caspase-3 immunohistochemistry in the periarterial sheath (PALS), (a T-cell area), follicles (B-cell area), marginal (B-cell area) and in the red pulp zones. FED administration caused an enormous increase in splenocyte apoptosis in all of the spleen zones: PALS (+2966%), follicles (+3025%), marginal (+5228%) and red pulp (+7000%). Administration of captopril to the FED rats was associated with a further increase in the splenocyte apoptosis only in the marginal (150%), PALS (+105%) and red pulp (+67%) zones. Bezafibrate administration to the FED rats was associated with no further increase in apoptosis rates. Amlodipine administration to the FED rats was associated with almost complete amelioration of the splenoctye apoptosis that was induced by the FED diet. These pharmacological manipulations were also associated with changes in the hepatic lipids composition and oxidative milieu that did not correlate to the changes in splenocyte apoptosis. NAFLD in FED rats is associated with an increase in splenic apoptosis. Agents administered to treat components of the MS in FED rats may lead to divergent changes in the splenic histology and splenocyte apoptosis.
[show abstract][hide abstract] ABSTRACT: Ascites is the most common manifestation of decompensated liver cirrhosis. The life expectancy of cirrhotic patients developing uncomplicated ascites is 50% for 3 years. Refractory ascites, electrolyte imbalance, hepato-renal syndrome and spontaneous bacterial peritonitis may develop. Successful treatment can improve symptoms and outcomes. This article summarizes the Israeli Association for the Study of the Liver guidelines for diagnosis and management of cirrhotic ascites and its complications.
[show abstract][hide abstract] ABSTRACT: Variation in the prevalence of various types of gastric polyps worldwide may reflect different etiologies. Here, the authors report the dynamic changes in histological distribution of gastric polyps over time and by ethnicity for individuals who underwent gastroscopies between 1994 and 2009 at two hospitals in Jerusalem, Israel. During this time period, the proportion of patients receiving proton pump inhibitors (PPIs) increased while the proportion of patients infected with Helicobacter pylori (H. pylori) decreased.
Pathological reports of biopsies from 50,071 consecutive gastroscopies were reviewed.
Gastric polyps were detected in 727 individuals. The yearly prevalence of gastric polyps was ≤ 1% between 1994 and 2001 and ≥ 2% from 2004 to 2009, of which overall 66% were hyperplastic polyps and 23% fundic gland polyps (FGPs). FGPs were diagnosed exclusively in the Jewish population. From 2001 to 2004, an increase in the absolute number of newly discovered hyperplastic and FGPs per year was observed. However from 2005, a divergent trend of changes was observed: While the proportion of patients with hyperplastic polyps dropped from 0.72 during the 2001-2004 period to 0.62 during the 2005-2009 period (p = 0.02), the proportion of patients with FGPs at these time periods increased from 0.16 to 0.33 (p = 0.0001).
The yearly prevalence of gastric polyps in Jerusalem has recently doubled. This occurred mainly due to the increasing prevalence of FGPs. The changing epidemiology of gastric polyps is probably related to the interaction between genetic factors and fluctuating environmental factors like H. pylori infection rates and exposure to PPIs.
Scandinavian journal of gastroenterology 05/2012; 8-9(47):907-13. · 2.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Breastmilk specimens from three women with acute hepatitis A virus (HAV) infection were studied. Anti-HAV immunoglobulin M and immunoglobulin G antibodies were detected in serum and breastmilk specimens of the three women. The three women also had serum HAV RNA. However, HAV RNA was detected only in two of the three breastmilk specimens. It is interesting that none of the three infants contracted clinical HAV infection. Furthermore, mothers with HAV infection should not be encouraged to discontinue breastfeeding.
Breastfeeding Medicine 04/2012; 7:313-5. · 1.65 Impact Factor
[show abstract][hide abstract] ABSTRACT: An increase in serum ferritin levels during combined interferon-ribavirin treatment in chronic patients infected with hepatitis C virus (HCV) can occur. A study was conducted to determine whether observing the kinetics of serum ferritin levels during antiviral therapy, may assist in predicting the rate of sustained virological response. The kinetics of serum ferritin levels during antiviral therapy in treatment-naive, adherent patients with chronic HCV who had early virological response were characterized. Thirteen patients achieved sustained virological response (group 1) while eight patients did not (group 2). Pre-treatment serum ferritin levels were higher in group 2 patients. During antiviral therapy, serum ferritin levels increased in both groups. On treatment, the median increase (compared to baseline) and the calculated rate of the increase in serum ferritin levels was higher in group 1 patients (874% vs. 272%, P < 0.05, 63%/week vs. 13%/week, P = 0.024, respectively). Red blood cell lysis did not contribute to the increase in serum ferritin level. Post-treatment (1st month) serum ferritin levels in group 1 patients were lower than in group 2 patients. In addition, the degree of decline in the 1st month serum ferritin levels (from peak levels) in group 1 patients was higher (76% vs. 49%, P = 0.039). Measuring serum ferritin levels during antiviral therapy in HCV patients who had an early virological response may assist in predicting sustained virological response.
Journal of Medical Virology 07/2011; 83(7):1262-8. · 2.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: Sulphonylurea (SU) agents continue to be a cornerstone of the therapy of type 2 diabetes mellitus (T2DM). Hypoglycemia is the most dangerous side effect of SU. Identifying the characteristics of patients with SU-induced hypoglycemia (SUIH) may help in reducing its frequency.
All consecutive admissions of patients with SUIH, between 2000 and 2008, were retrospectively reviewed.
Over the study period, 4702 patients with type 2 diabetes mellitus were admitted to the department of medicine. Of these, 155 patients were admitted because of SUIH. Most of these patients were elderly, had multiple comorbid situations, and were taking multiple medications. Almost a third of the patients had a history of recent changes in the use of their medications. Various infectious complications (urinary, lung, skin, and peritoneal) occurred in 43% of patients. Renal failure was a frequent finding at admission (44% of patients had creatinine plasma levels > 120 μmol/L). Poor oral intake before admission was reported by 31% of patients. Markers of malnutrition (low serum levels of albumin, iron, vitamin B-12, and folic acid) were frequently found in most patients. Mean hemoglobin A1C levels were in the low abnormal levels. A major vascular event during hospitalization co-occurred in 11% of patients. Three patients died during the hospital admission for SUIH.
Elderly fragile patients with multiple comorbid situations including renal failure and tight glycemic control are prone to develop SUIH. Sulphonylurea agents should be avoided in such patients. An episode of SUIH should be considered as an alarming prognostic marker.
Journal of the American Medical Directors Association 10/2010; 13(3):234-8. · 5.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Controversy exists as to whether rats after bile duct ligation (BDL) are more susceptible to gastric mucosal damage (GMD) induced by irritants. In the present study we characterize GMD after intragastric instillation of either ethanol or hydrochloric acid (HCL), 3 and 21 days after the surgical procedure.
Bile duct ligation and sham operated (SO) rats were studied.
Three days after surgery, BDL rats exhibited a reduction in gastric mucosal nitric oxide synthase (NOS) activity but an increase in ethanol-induced GMD. Twenty-one days after surgery gastric mucosal prostaglandin (PG) E(2) generation in BDL rats was increased while NOS activity in both groups was similar. Ethanol-induced GMD in SO rats was higher. Pretreatment with NG-nitro-L-arginine methyl ester, prior to ethanol administration was associated with an increase in gastric mucosal PGE(2) generation: (147% in SO and 104% in BDL rats) and in GMD (176% in SO and 303% in BDL rats). HCL induced GMD was of similar magnitude in both groups in both time periods.
The gastric resistance to damage by irritants in rats with BDL is not a static phenomenon. This may result from sequential changes that occur in the gastric mucosal defense mechanisms during the evolution of liver disease.
Journal of Gastroenterology and Hepatology 06/2010; 25(6):1170-5. · 3.33 Impact Factor
[show abstract][hide abstract] ABSTRACT: Rats given fructose-enriched diet develop many characteristics of the human metabolic syndrome and non-alcoholic fatty liver disease. In this study, we characterized the hepatic effects of rosiglitazone in fructose-enriched diet rats. Rats were randomly divided into three groups. One group was maintained on standard rat chow diet for 6 weeks, whereas the other two groups were given fructose-enriched diet for 6 weeks. Four weeks after the initiation of fructose-enriched diet, one of the fructose-enriched diet groups was also given rosiglitazone (10 mg/kg/day) for an additional 2 weeks. Rosiglitazone administration to the fructose-enriched diet rats was associated with decreases in the following parameters: blood pressure (-17%), plasma triglycerides (-62%), hepatic total lipids (-19%), hepatic triglycerides (-61%), hepatic malondialdehyde (-88%), glutathione reductase activity (-84%). An increase in adiponectin plasma levels (+329%), hepatic phospholipids (+46%), hepatic alpha-tocopherol concentrations (+24%) and hepatic paraoxonase activity (+68%) was observed. Rosiglitazone caused a decrease in hepatic macrovesicular steatosis score but no change in hepatic fibrosis. Administration of rosiglitazone, to rats with the metabolic syndrome has limited hepatic favourable effects: it improves hepatic lipid metabolism, decreases macrovesicular steatosis and improves some of the hepatic oxidative-anti-oxidative milieu but has no effect on hepatic fibrosis.
[show abstract][hide abstract] ABSTRACT: We aimed to demonstrate the involvement of 5-HT(1A) receptors in the therapeutic effect of cannabidiol, a non-psychoactive constituent of Cannabis sativa, in a model of hepatic encephalopathy induced by bile-duct ligation (BDL) in mice.
Cannabidiol (5 mg x kg(-1); i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight-arm maze and the open field tests respectively. Hippocampi were analysed by RT-PCR for expression of the genes for tumour necrosis factor-alpha receptor 1, brain-derived neurotrophic factor (BDNF) and 5-HT(1A) receptor. N-(2-(4-(2-methoxy-phenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide (WAY-100635), a 5-HT(1A) receptor antagonist (0.5 mg x kg(-1)), was co-administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin.
Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor-alpha receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5-HT(1A) expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY-100635, indicating 5-HT(1A) receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL.
The behavioural outcomes of BDL result from both 5-HT(1A) receptor down-regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti-inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5-HT(1A) receptor expression or liver function. BDNF up-regulation by cannabidiol does not seem to account for the cognitive improvement.
British Journal of Pharmacology 02/2010; 159(4):950-7. · 5.07 Impact Factor
[show abstract][hide abstract] ABSTRACT: The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease.
CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL.
Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-alpha-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor.
The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.
Journal of Hepatology 06/2009; 51(3):528-34. · 9.86 Impact Factor
[show abstract][hide abstract] ABSTRACT: Portal hypertension (PHT) often leads to collateralization of blood flow through variceal vessels that shunt blood from the portal to the systemic circulation. Life-threatening bleeding from esophageal and ectopic varices often complicates severe PHT. Increase in PHT occurs during the last stages of the second trimester of pregnancy and is associated with increased risk of PHT bleeding in the later stages of pregnancy. In this report, we present two rare cases of pregnant women with PHT, who had postpartum bleeding from very uncommon sites. The first had a rupture of an intra-abdominal varix and the second had two episodes of bleeding from abdominal wall varices, after two emergent cesarean sections, in two consecutive pregnancies. On the basis of a literature review, we constructed an algorithm that includes instructions on how to handle women with PHT during the various stages of pregnancy and labor.
European journal of gastroenterology & hepatology 03/2009; 21(9):1086-91. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Safety data of statins have been collected from diverse ethnic populations. Drug effects, including adverse reactions, may depend on genetics and environment. We investigated liver enzymes in relation to statin treatment in a northeast Jerusalem Jewish community.
A long-term laboratory follow-up of liver enzymes prestatin and poststatin introduction was conducted. Records of participants who received statins were reviewed. Prestatin and poststatin liver enzymes were compared by various statistical models.
Two-hundred and sixty participants had mean follow-up of 25 months prestatin, and 26 months poststatin introduction. Sixty-six percent had hypertension, and 48% were diabetic. The frequency of liver enzyme abnormalities varied widely with time. Altogether, during pretreatment and posttreatment follow-up, 18.4 and 13.4% of measurements revealed abnormal (either cholestatic and/or hepatocellular) liver enzymes, respectively (P<0.01). Hyperlipidemia (positive correlation) and administration of renin-angiotensin antagonists (inverse correlation) predicted on-treatment liver enzyme abnormalities in men, whereas diabetes predicted abnormalities in women.
A substantial proportion of patients who need statins had elevated 'background' liver enzymes. The profile of elevated liver enzymes was not augmented by statin therapy; moreover, statin administration was associated with a decreasing frequency of liver enzyme abnormalities. Physicians should not refrain from prescribing statins solely on the basis of liver enzyme abnormalities.
European journal of gastroenterology & hepatology 11/2008; 20(10):1002-5. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Changes in tissue levels of 2-arachidonoylglycerol (2-AG), an endocannabinoid, during the evolution of bile duct ligation (BDL) may indicate that endocannabinoids have a role in the hemodynamic changes that occur in this condition.
2-AG levels, in various organs and vascular beds of BDL rats, 2 and 4 weeks post surgery, were determined. Untouched and sham-operated (SO) rats were used as controls.
2-AG content of a specific organ was not a static finding and depended on the rat's age, the time from the surgical procedure and the type of procedure. The most pronounced changes were observed in BDL rats 4 weeks post surgery. In these rats, hepatic, pulmonary, cardiac and renal medullary and papillary 2-AG levels were highest observed. No changes in splenic, aortic and renal cortical 2-AG levels were observed. In addition a stepwise increase in 2-AG levels from the cortex to the papilla was detected and was followed by a decrease in creatinine clearance.
2-AG probably has a role in the pathophysiologic changes in the liver, heart, lung and kidney that follows BDL.
[show abstract][hide abstract] ABSTRACT: Colonic cytomegalovirus reactivation rarely occurs in adults without inflammatory bowel disease or a known immunosuppressive state.
To describe our experience with such patients.
All consecutive admissions of patients with possible cytomegalovirus colitis, between 1995 and 2006, were reviewed retrospectively.
Nineteen patients were studied. Most of the patients were elderly with multiple co-morbidities. Three main forms of disease presentation were recognized: acute diarrhoea, chronic diarrhoea and lower gastrointestinal bleeding. Colonic mucosal intranuclear inclusion bodies were found in 12 patients. Thirteen patients had cytomegalovirus viraemia (either by polymerase chain reaction and/or by white blood cell-cytomegalovirus antigenaemia test). Ganciclovir therapy was given to only eight patients; only five of these patients survived. The other subgroup of 11 patients received only supportive therapy. Most of the patients from this subgroup had a prolonged and complicated hospital course; only nine patients survived. Follow-up colonoscopies were performed only in five patients (out of the 14 patients who survived). In four of these patients, chronic mucosal inflammatory changes were noted.
Cytomegalovirus colitis occurs rarely in adult individuals. The disease may have various and multiple acute and/or chronic clinical manifestations. Clinical awareness of this condition is needed.
[show abstract][hide abstract] ABSTRACT: Oxidative stress may initiate significant hepatocyte injury in subjects with fatty liver. We characterized changes in hepatic oxidative anti-oxidative parameters in rats given a fructose-enriched diet (FED) with and without medications to reduce blood pressure or plasma triglycerides. FED rats had an increase in malondialdehyde (MDA) concentration, a reduction in alpha-tocopherol concentration, a reduction in paraoxonase (PON) activity, an increase in glutathione peroxidase (GSH-Px), and glutathione reductase (GSSG-R) activity. Amlodipine increased PON and GSH-Px, but decreased GSSG-R activity and alpha-tocopherol concentration. Captopril decreased MDA concentration and the activity of both GSH-Px and GSSG-R, but increased alpha-tocopherol concentration and PON activity. Bezafibrate increased alpha-tocopherol concentration and PON activity, but decreased the activity of GSSG-R. Animals with fatty liver exhibit an increase in peroxidative stress but also a defect in anti-oxidative pathways. Drugs administered to treat hypertension and hypertriglyceridemia could lead to a variety of changes in the hepatic oxidative, anti-oxidative milieu.
Digestive Diseases and Sciences 04/2008; 53(3):777-84. · 2.26 Impact Factor