Effect of losartan on early liver fibrosis development in a rat model of nonalcoholic steatohepatitis

BACKGROUND AND AIM: Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver that may evolve into fibrosis or cirrhosis. Recent studies have shown reduction of experimental liver fibrosis with the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists. The aim of this study was to determine whether losartan can influence the early phase of fibrogenesis in an animal model of NASH. METHODS: To induce NASH, a choline-deficient diet (CDD) was given to Sprague-Dawley rats for 12 weeks. These animals were then compared with a control group receiving choline-supplemented diet (CSD) and a group fed a CDD plus losartan (10 mg/kg/day). Biochemical (serum levels of alanine aminotransferase and aspartate aminotransferase) and histological evaluation of fatty liver was performed by conventional techniques. Hydroxyproline content in liver tissue was assayed by spectrophotometry. In addition, mRNA levels of procollagen I and transforming growth factor (TGF)-beta were assessed by semiquantitative RT-PCR and stellate cell activation by alpha-actin immunofluorescence stain. RESULTS: After 12 weeks CDD induced a marked elevation of serum aminotranferases, a severe fatty liver infiltration with mild histological inflammation and fibrosis. These findings correlated with a significant increase in mRNA levels of both procollagen I and TGF-beta and significant increased liver hydroxyproline content. No differences were seen between rats receiving CDD alone and rats receiving CDD plus losartan with regard to the biochemical, morphological or molecular alterations induced by the CDD. CONCLUSION: Losartan does not seem to influence liver injury and fibrogenic events in the CDD model of NASH.     

Early motherhood in rats is associated with a modification of hippocampal function

The transition to motherhood results in a number of hormonal, neurological and behavioral changes necessary to ensure offspring survival. However, little attention has been paid to changes not directly linked to reproductive function in the early mother. In this study, we demonstrate that spatial performances during the learning phase were impaired after the delivery in rats, while spatial retention ability was improved 2 weeks later. In addition, we also report that early motherhood reduced the cell proliferation in the dentate gyrus of the hippocampus without inducing a decrease in the newborn cells 2 weeks later. The decrease of estradiol levels and high levels of glucocorticoids after delivery could in part explain the changes in the hippocampal function. In summary, our findings suggest that early postpartum period is associated with a modification of hippocampal function. This may reflect a homeostatic form of hippocampal plasticity in response to the onset of the maternal experience.     

Double trouble (McArdle's disease and myasthenia gravis): How can exercise help?

We report a 29-year-old patient with McArdle's disease and myasthenia gravis. She had been debilitated with McArdle's disease since childhood (with marked rhabdomyolysis) and was obese. Myasthenia gravis was diagnosed at 24 years of age. After 3 months of aerobic exercise training, her exercise capacity increased significantly and she regained the ability to live independently. We conclude that even patients with profound neuromuscular diseases may benefit from carefully prescribed exercise training.     

Endoplasmic reticulum-associated degradation of the NR1 but not the NR2 subunits of the N-methyl-D-aspartate receptor induced by inhibition of the N-glycosylation in cortical neurons

The N-methyl-D-aspartate receptor (NMDAR) is fundamental to normal and pathological functioning of neurons. The receptor subunits are N-glycosylated proteins synthesized in the endoplasmic reticulum (ER) that fold, mature, and oligomerize as they transit through the secretory pathway. Although the early processes of biogenesis are fundamental to NMDAR expression and function, our knowledge of them is nevertheless limited. Additionally, the investigation of NMDAR synthesis is highly relevant, in that ER dysfunction, frequently associated with acute and degenerative brain diseases, might alter this process. We characterize here the effect of ER stress produced by inhibition of N-glycosylation on NMDAR synthesis and function. We use first heterologous systems of NMDAR expression in which NR1 and NR2A subunits are synthesized in nonneuronal cells. The function of these NMDARs as Ca2+ channels is repressed by tunicamycin, because of the inhibition of NR1, but no NR2A, synthesis. The regulation of NR1 is relevant to the central nervous system, in that a dramatic decrease in synthesis of this subunit and assembly of NMDARs is observed in cortical neurons treated with tunicamycin. The inhibition of NR1 synthesis is not due to changes in levels of mRNA but associated with the earliest stages in NMDAR biogenesis. The inhibition of N-glycosylation activates ER-specific stress responses in neurons, which include the ER-associated degradation (ERAD) mechanism responsible for differential and extremely efficient degradation of nonglycosylated NR1 by the proteasome after ubiquitination. Because this is an obligatory NMDAR component, the significant sensitivity of NR1 to ER stress will have important consequences on receptor function.     

Chemoembolization of hepatocellular carcinoma with drug eluting beads: efficacy and doxorubicin pharmacokinetics

BACKGROUND/AIMS: This study assesses the safety, pharmacokinetics and efficacy of transarterial chemoembolization using drug eluting beads (DEB), an embolizing device that slowly releases chemotherapy to decrease systemic toxicity. METHODS: Twenty-seven Child-Pugh A cirrhotics (76% male, 59% HCV) with untreated large/multifocal HCC received chemoembolization with doxorubicin loaded DEBs at doses adjusted for bilirubin and body surface (range: 47-150 mg). Clinical and analytical data were recorded at 24 and 48 h, 7, 14 and 30 days after first and second TACE. Response rate was assessed by CT at 6 months. Blood samples were obtained in 13 patients at 5, 20, 40, 60, 120 min, 6, 24, 48 and 168 h to determine doxorubicin Cmax and AUC. RESULTS: DEB-TACE was well tolerated with an acceptable safety profile. Two cases developed liver abscess, one leading to death. Response rate was 75% (66.6% on intention-to-treat). Doxorubicin Cmax and AUC were significantly lower in DEB-TACE patients (78.97+/-38.3 ng/mL and 662.6+/-417.6 ng/mLmin) than in conventional TACE (2341.5+/-3951.9 ng/mL and 1812.2+/-1093.7 ng/mLmin, p=0.00002 and p=0.001, respectively). After a median follow-up of 27.6 months, 1- and 2-year survival is 92.5% and 88.9%, respectively. CONCLUSIONS: Chemoembolization using DEBs is an effective procedure with a favorable pharmacokinetic profile.     

Adhesion molecules in chronic ulcerative colitis

Background and aims The adhesion molecule expression in colonic mucosa is pivotal for transition from quiescent to active stage of ulcerative colitis (UC). The aim of the present study is to reveal the adhesion molecule profile of colonic mucosa in the active stage of UC and in remission. Materials and methods Biopsy specimens obtained from 14 patients with UC (seven with active disease and seven with UC in remission) and from seven controls were used. Immunohistochemistry was performed with antibodies against ICAM-1, VCAM-1, E-selectin, LFA-1, Mac-1, and VLA-4. Results In controls, slight ICAM-1 positivity was observed on thety endothelium of blood vessels of the mucosal and submucosal layer and only single ICAM-1-, Mac-1-, and LFA-1-positive cells were found. In all patients with UC, the endothelium of venules in the edematous mucosal and submucosal layers was ICAM-1-, VCAM-1-, and E-selectin-positive. Numerous ICAM-1- and LFA-1-positive and less VCAM-1-, Mac-1-, and VLA-4-positive inflammatory cells were detected in mucous layers of acute UC. In specimens of UC in remission, the inflammatory cells positive for the studied adhesion molecules were significantly less in number in the mucosa and submucosa (p < 0.05). Conclusions Based on the increased expression of ICAM-1, VCAM-1, and their ligands LFA-1 and VLA-4 in patients with UC, we can conclude that these adhesion molecules play a key role in the adherence of lymphocytes and macrophages to endothelial cells maintaining the chronic inflammation. Presence of E-selectin on endothelial cells of venules could be a sign of relapse after remission in UC.     

Effects of an intrahospital exercise program intervention for children with leukemia

PURPOSE: The purpose was to investigate the effect of a 16-wk intrahospital supervised conditioning program including both resistance and aerobic training and a 20-wk detraining period on measures of aerobic fitness, muscular strength, functional mobility, ankle range of motion, and quality of life (QOL) in children receiving treatment for acute lymphoblastic leukemia (ALL). METHODS: Seven children (four boys, three girls; age: 5.1 +/- 1.2 yr, body mass: 24.0 +/- 5.8 kg, height: 114.6 +/- 7.7 cm) in the maintenance phase of treatment against ALL performed three sessions per week for 16 wk of resistance (one set of 8-15 repetitions of 11 exercises) and aerobic training (30 min at > 70% HRmax) followed by 20 wk of detraining where no structured exercise program was performed. Before training, after training, and after detraining, a treadmill test determining .VO2peak and ventilator threshold (VT), muscular strength (6RM), functional mobility (timed up and down stairs test, time up and go 3-m and 10-m tests), passive and dynamic ankle range of motion, and self-reported quality of living were determined. RESULTS: After training, significant increases in .VO2peak, VT, upper- and lower-body muscular strength, and all measures of functional mobility were shown (P < 0.05). Muscular strength was well maintained (significantly greater than before training and no significant decrease from after training) during detraining, whereas .VO2peak, VT, and functional mobility (not significantly different from before training but no significant decrease from after training) were only partially retained. CONCLUSION: Young children in the maintenance phase of treatment against ALL can safely perform both aerobic and resistance training. Training results in significant increases in measures of aerobic fitness, strength, and functional mobility. During detraining, strength and functional mobility are well maintained, whereas .VO2peak and VT are partially maintained.     

Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis

There is a renewed interest in the ultimate role of fatty acid synthase (FASN)--a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids--in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.     

Role of the HLA-DQ locus in the development of chronic gastritis and gastric carcinoma in Mexican patients

~~Role of the HLA-DQ locus in the development of chronic gastritis and gastric carcinoma in Mexican patients@Roberto Herrera-Goepfert$Department of Pathology, Institute Nacional de Cancerologia (INCan), Mexico City, Mexico @Jesús K Yamamoto-Furusho$Dep…