Increased hepatocyte CYP2E1 expression in a rat nutritional model of hepatic steatosis with inflammation

BACKGROUND & AIMS: Nonalcoholic steatohepatitis is morphologically identical to alcoholic hepatitis and has multiple etiologic associations and an unknown pathogenesis. The present study used a rat nutritional model of hepatic steatosis with inflammation to test the hypothesis that induction of the alcohol-inducible hepatic cytochrome P450 (CYP) 2E1 is associated with production of steatohepatitis. METHODS: Rats received a diet devoid of methionine-choline. CYP2E1 protein was detected in liver sections by immunohistochemistry and in hepatic microsomal fractions by immunoblotting; CYP2E1 activity was detected by N-demethylation of N,N-dimethylnltrosamine (NDMA). CYP2E1 messenger RNA was analyzed by Northern blotting and slot blot hybridization. RESULTS: After 4 weeks of methionine-choline devoid diet, macrovesicular steatosis and an inflammatory infiltrate were prominent in hepatic acinar zone 3. CYP2E1 immunostaining was increased and had a more extensive acinar distribution corresponding to that of the steatosis. Microsomal CYP2E1 protein, NDMA activity, and hepatic CYP2E1 messenger RNA levels were all correspondingly increased. CONCLUSIONS: CYP2E1 is induced, partly at a pretranslational level, in this experimental form of steatohepatitis. The finding of biochemical and histological similarities between this nutritional model of hepatic steatosis with inflammation and alcoholic hepatitis indicates possible clues to common pathogenetic mechanisms. The relevance of this finding to human nonalcoholic steatohepatitis remains uncertain and requires further investigation of human liver specimens. (Gastroenterology 1996 Dec;111(6):1645-53)     

Primary gastric lymphoma versus gastric carcinoma: endoscopic US evaluation

Endoscopic ultrasonography (US) enables high-resolution imaging of the stomach and can demonstrate the different layers of the gastric wall. It has therefore been proposed for use in evaluating the extension of gastric neoplasms. It was performed in nine patients with primary gastric non-Hodgkin lymphoma and in 36 with gastric carcinoma. The US and pathologic findings were correlated in three surgical specimens of gastric lymphoma. Three different US patterns were found in gastric lymphomas: a polypoid pattern (two cases), localized (two cases) or extended (five cases) hypoechoic infiltration, and thickening with superficial ulcerations. Infiltration was confined to the second and third layers of the gastric wall in six cases and was transmural in three. The study of the gastric lymphoma specimens confirmed the accuracy of US in demonstrating the extent of infiltration. Gastric carcinomas had a more echogenic pattern and a different trend of diffusion, with no extended longitudinal hypoechoic infiltration of the superficial layers or extended hypoechoic transmural infiltration.     

Monocyte-derived recruiting activity: kinetics of production and effects of endotoxin

Cultured monocytes release a factor, monocyte-derived recruiting activity (MRA), which stimulates fibroblasts, endothelial cells, and T lymphocytes to produce colony-stimulating activity (CSA). We studied the kinetics of MRA production using a technique in which MRA levels were measured in a two stage bioassay. We used umbilical vein endothelial cells as the MRA-responsive (CSA-producing) cells, and normal colony-forming unit granulocyte-macrophage (CFU-GM)-enriched bone marrow cells (T lymphocyte- and monocyte-depleted, low density bone marrow cells) as the CSA-responsive cells. MRA stimulated a 30- fold increase in CSA production by endothelial cells. MRA production was detected in supernatants from as few as 10(3) monocytes per milliliter, required the presence of fetal calf serum, and was inhibited by cycloheximide (10 to 100 micrograms/mL) and puromycin (10 to 50 micrograms/mL). Production was detectable after 24 hours of monocyte incubation, was maintained for three days, and fell to undetectable levels by seven days. With the addition of bacterial endotoxin (lipopolysaccharide [LPS]) (50 micrograms per 10(6) cells), MRA was detectable after only three hours of incubation, and levels peaked at 24 hours. Further, maximum MRA levels in the supernatants of LPS-stimulated monocytes were up to ten times greater than peak levels in the supernatants of unstimulated monocytes. Endotoxin augmented monocyte production of MRA to a greater extent than it did CSA production, indicating that the stimulation of CSA production by endotoxin may be at least partly indirect. The responsiveness of MRA production to endotoxin in vitro is consistent with the notion that MRA may be a biologically relevant regulator of CSA production by cells of the hematopoietic microenvironment.     

Thrombolytic Therapy Within One Hour of the Onset of Acute Myocardial Infarction

Between 1986 and 1988, 239 consecutive patients with acute myocardialinfarction received thrombolytic therapy up to 285 minutes afteronset of symptoms; in 39 (17 with anterior infarction, 21 inferior,one lateral infarction) recombinant tissue plasminogen activatoror anistreplase was administered a mean of 51 minutes (range20–60 minutes) after the onset of symptoms. The patencyrates (26 of 30; 87 per cent), rapid ST segment resolution (36of 38; 95 per cent) and QRS score of 3 (28 of 38; 74 per cent)were statistically significantly higher for those seen and treatedin the first hour in comparison with those seen and treatedlater. For those treated within the first hour mean peak creatine kinasewas 1264 U/I for those with TIMI grade 2 or 3 (partial or completeperfusion) compared with 3005 U/I for those with TIMI grade0 or 1 (no perfusion or penetration without perfusion) (p=0.02):mean peak creatine kinase-MB for those with TIMI grade 2 or3 perfusion was 115 U/I compared with 312 U/I for those withTIMI grade 0 or 1 (p=0.01). Four of the 39 patients developedventricular fibrillation following thrombolytic therapy, threewithin 24 hours of infarction and one following reinfarctionon day 15. There were no significant bleeding complications.One patient died. Thrombolytic therapy within 1 hour of the onset of symptomsled to a very high angiographic patency rate, rapid ST segmentresolution with preservation of left ventricular function. Thistherapy is without significant complications.     

Gastroprotective effect of the aqueous leaf extract of Guiera senegalensis in Albino rats

ObjectiveTo evaluate the effect of aqueous leaf extract of Guiera senegalensis (G. senegalensis) on gastric mucosal damage using different ulcer models.MethodsConsidering the above claims, the present study was undertaken to validate the gastroprotective potential of the aqueous leaf extract of this plant against ethanol, water immersion and Aspirin induced ulcer models.ResultsThe leaf extract (50, 100 and 200 mg/kg, p.o.) significantly (P<0.05) decreased the ulcer index in all assays used.ConclusionsThe results obtained, provide strong evidence of antiulcer activity of the leaf extract of G. senegalensis and support the traditional uses of the plant for the treatment of ulcer.     

Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience

Objective

Orthotopic-liver-transplantation (OLT) in patients with Human-Immunodeficiency-Virus infection (HIV) and end-stage-liver-disease (ESDL) is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients.

Material and methods

This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post-OLT.

Results

Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61 years) were included. OLT indications were HCV (n = 5), HBV (n = 2), HCV/HBV/HDV-related cirrhosis (n = 1) and acute liver-failure (n = 1). At OLT, CD4 cell-counts ranged from 113-621 cells/μl, and HIV viral-loads from < 50-175,000 copies/ml. Seven of eight patients were exposed to HAART before OLT. Patients were followed-up between 1-145 months. Five died 1, 3, 10, 31 and 34 months after OLT due to sepsis and graftfailure respectively. Graft-failure causes were recurrent hepatic-artery thrombosis, HCV-associated hepatitis, and chemotherapy-induced liver damage due to Hodgkin-disease. One survivor is relisted for OLT due to recurrent chronic HCV-disease but non-progredient HIV-infection 145 months post-OLT. Two other survivors show stable liver function and non-progredient HIV-disease under HAART 21 and 58 months post-OLT.

Conclusions

OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease-progression under antiretroviral therapy and management of the viral hepatitis co-infection.     

Community Health Workers Can Identify and Manage Possible Infections in Neonates and Young Infants: MINI��A Model from Nepal

The mortality rates of infants and children aged less than five years are declining globally and in Nepal but less among neonates. Most deliveries occur at home without skilled attendants, and most neonates may not receive appropriate care through the existing medical systems. So, a community-based pilot programme—Morang Innovative Neonatal Intervention (MINI) programme—was implemented in Morang district of Nepal to see the feasibility of bringing the management of sick neonates closer to home. The objective of this model was to answer the question: “Can a team of female community health volunteers and paid facility-based community health workers (collectively called CHWs) within the existing heath system correctly follow a set of guidelines to identify possible severe bacterial infection in neonates and young infants and successfully deliver their treatment?” In the MINI model, the CHWs followed an algorithm to classify sick young infants with possible severe bacterial infection (PSBI). Female Community Health Volunteers (FCHVS) were trained to visit homes soon after delivery, record the birth, counsel mothers onessential newborn care, and assess the newborns for danger-signs. Infants classified as having PSBI, during this or subsequent contacts, were treated with co-trimoxazole and referred to facility-based CHWs for seven-day treatment with injection gentamicin. Additional supervisory support was provided for quality of care and intensified monitoring. Of 11,457 livebirths recorded during May 2005–April 2007, 1,526 (13.3%) episodes of PSBI were identified in young infants. Assessment of signs by the FCHVs matched that of more highly-trained facility-based CHWs in over 90% of episodes. Treatment was initiated in 90% of the PSBI episodes; 93% completed a full course of gentamicin. Case fatality in those who received treatment with gentamicin was 1.5% [95% confidence interval (CI) 1.0-2.3] compared to 5.3% (95% CI 2.6-9.7) in episodes that did not receive any treatment. Within the existing government health infrastructure, the CHWs can assess and identify possible infections in neonates and young infants and deliver appropriate treatment with antibiotics. This will result in improvement in the likelihood of survival and address one of the main causes of neonatal mortality.Key words: Antibiotic use, Bacterial infections, Drug therapy, Health workers, Infant, Newborn, Neonatal mortality, Sepsis, Nepal