Model of nonalcoholic steatohepatitis

BACKGROUND: Obesity and diabetes are frequently associated with nonalcoholic steatohepatitis (NASH), but studies have been hampered by the absence of a suitable experimental model. OBJECTIVE: Our objective was to create a rat model of NASH. DESIGN: Sprague-Dawley rats were fed a high-fat, liquid diet (71% of energy from fat, 11% from carbohydrates, 18% from protein) or the standard Lieber-DeCarli diet (35% of energy from fat, 47% from carbohydrates, 18% from protein). The diets were given ad libitum or as two-thirds of the amount consumed ad libitum. RESULTS: Rats fed the high-fat diet ad libitum for 3 wk developed panlobular steatosis, whereas those fed the standard diet had few fat droplets. Accordingly, total lipid concentrations with the high-fat and standard diets were 129.9 +/- 9.1 ( +/- SEM) and 66.7 +/- 4.6 mg/g liver, respectively (P < 0.001). The high-fat diet caused abnormal mitochondria and mononuclear inflammation, which were accompanied by increased hepatic tumor necrosis factor alpha (TNF-alpha; P < 0.001), TNF-alpha messenger RNA (mRNA) (P < 0.001), collagen type 1, and alpha1(I) procollagen mRNA (P < 0.001). In addition, these rats had increased cytochrome P4502E1 (CYP2E1) mRNA (P < 0.001), which was accompanied by CYP2E1 induction (P < 0.001) and oxidative stress with increased 4-hydroxynonenal (P < 0.001). Plasma insulin was elevated, which reflected insulin resistance, a NASH pathogenic factor. Rats fed a restricted high-fat diet developed only mild steatosis with attenuated biochemical changes, whereas those given a restricted standard diet had normal livers. CONCLUSION: This rat model reproduces the key features of human NASH and provides a realistic experimental model for elucidating its treatment.     

Fate of branch arteries after intracranial stenting

OBJECTIVE: One concern with respect to stent procedures performed to treat patients with intracranial lesions is the fate of normal major arterial branches after stents are placed across them. Because most of these lesions occur at vessel bifurcations or at branch points, a normal major branch often arises near the lesion and may be difficult to avoid during stent positioning. The aim of this article is to describe the angiographic outcome of intracranial major branch arteries crossed by a stent in the intracranial circulation. METHODS: We examined the immediate postprocedural cerebral angiograms of the 40 patients who underwent intracranial stenting at the University at Buffalo, Buffalo, NY, between June 1998 and April 2000. In each of 10 patients, the stent was placed across a normal major branch artery. Stents were used to treat aneurysms in seven patients and intracranial stenosis in three patients. The latest cerebral angiogram available was reviewed, and the patency of the major branch arteries was evaluated. RESULTS: The angiographic follow-up period ranged from 4 days to 35 months (mean follow-up, 10 mo). Each of the 10 major branch arteries was patent. No infarcts were associated with the territory of the major branch arteries crossed by the stents, and no patient experienced a related episode of clinical ischemia. Four patients died as a result of causes unrelated to the stenting procedure. The histology of a middle cerebral artery stent that was placed across a lenticulostriate perforator is presented. CONCLUSION: The flexible, low-profile stents used in this study had no angiographically or clinically apparent effect on the major intracranial branches across which they were placed.     

Quantitative assessment of myocardial scar in delayed enhancement magnetic resonance imaging

PURPOSE: To characterize the extent and distribution of left ventricular myocardial scar in delayed enhancement magnetic resonance imaging (MRI). MATERIALS AND METHODS: Delayed enhancement images from 18 patients were categorized into three groups based on myocardial scar appearance: discrete myocardial infarction (N = 10), diffuse fibrosis (N = 4), and circumferential endocardial scarring (N = 4). Images were segmented manually by two observers (twice by one observer) to identify nonviable myocardium. Scar was characterized by the following morphologic parameters: the relative area of nonviable myocardium (Percent Scar); a measure of scar cohesion (Patchiness); and the extent to which scar traversed the ventricle wall (Trans>50). RESULTS: The three scar parameters successfully discriminated between patient groups, although no one parameter was able to differentiate between all groups. The average bias between readers was approximately 3% for each parameter, and the average bias between repeated measurements was 1%. In addition, five patients exhibited regions of nonhyperenhanced nonviable myocardium that were expected to show hyperenhancement based upon their location within the infarct zone and appearance on cine images. CONCLUSION: Quantitative characterization of myocardial scar showed good interobserver and intraobserver agreement. However, the appearance of nonhyperenhanced scar in chronic ischemia is problematic for segmentation of delayed enhancement images.     

Bleeding complications in patients with atrial fibrillation undergoing cardioversion randomized to transesophageal echocardiographically guided and conventional anticoagulation therapies

In a multicenter randomized trial, we studied a transesophageal echocardiography (TEE) guided strategy with short-term anticoagulation compared with a conventional strategy for patients with atrial fibrillation >2 days' duration and undergoing cardioversion. Composite major and minor bleeding was a predetermined secondary end point of the study. The objective of the study was to assess the incidence, location, and predictors of bleeding in the 2 treatment groups. A total of 1,222 patients were assigned to a TEE guided or conventional strategy and followed over 8 weeks. We present data on major and minor adjudicated bleeding complications for the 2 study groups during the 8-week study period. Composite major and minor bleeding complications occurred in 51 of 1,222 patients (4.2%) and were significantly lower in the TEE guided group compared with the conventional group (2.9 vs 5.5%, p = 0.025). The TEE group had fewer cancellations of cardioversion as a result of bleeding (0% vs 0.7%, p = 0.003). Major (n = 14) and minor (n = 38) bleeding complications were predominantly gastrointestinal (71.4% and 31.6%, respectively) and were associated with warfarin use. Predictors of bleeding included patient age, conventional group assignment, inpatient status, and functional status. Thus, composite major and minor bleeding complications occurred in 4.2% of the 1,222 patients and were significantly lower in the TEE guided group compared with the conventional group. Treatment variables affecting length of anticoagulant therapy in the conventional arm combined with advancing age and functional status are important concerns in patients who undergo cardioversion of atrial fibrillation.     

Update on oncocytoma

Oncocytoma is the most common benign solid renal tumor, comprising roughly 5% of resected renal masses. Typically discovered incidentally, oncocytoma is generally asymptomatic and very rarely metastasizes; however, multifocal disease and coexistence with renal cell carcinoma can occur. No currently used imaging techniques can reliably distinguish between oncocytoma and malignant lesions; therefore, patients must undergo resection, or in certain circumstances, biopsy, to definitively establish diagnosis. Careful attention to pathologic features and the adjunctive use of immunostains can aid in discriminating oncocytoma from other renal tumors characterized by granular, eosinophilic cytoplasm, especially chromophobe renal cell carcinoma. Nephron-sparing and laparoscopic surgical approaches can be used to treat appropriately selected patients.     

Alcohol and health: a drink a day won't keep the doctor away

We should not advise patients to start drinking alcohol for its alleged cardiovascular benefits. The negative effects of alcohol are well established, and the evidence of alcohol's benefits comes mainly from epidemiologic studies that were not well controlled for other influences, such as lifestyle factors. Moreover, we have other means of lowering cardiovascular risk that are safe and proven. Those who are healthy and whose drinking history shows little risk of developing alcohol dependency may continue to drink moderate amounts. Heavy drinkers should be advised to quit.     

Europium fluorescence to visualize N-butyl 2-cyanoacrylate in embolized vessels of an arteriovenous malformation swine model

BACKGROUND AND PURPOSE: Standard tissue staining using the lipid dye Oil-Red-O has been previously applied to stain vessel specimens, which were embolized with a mixture of n-butyl 2-cyanoacrylate (NBCA) and oil (Lipiodol). That technique, however, results in nonspecific and nonquantitative staining that does not provide the necessary differentiation between NBCA and Lipiodol. We present an innovative staining procedure that quantifies NBCA within treated tissues. METHODS: An arteriovenous malformation (AVM) model in swine was used to evaluate the polymerization characteristics of various ratios of Lipiodol/NBCA/glacial acetic acid (GAA) mixtures. To determine the depth of NBCA penetration within the AVM model and to characterize the polymerization patterns of various mixtures within the vessel, histologic cross- and longitudinal sections were prepared for microscopy. These paraffin-embedded tissue sections were stained with a europium aryl-beta-diketone complex (TEC) to improve differentiation between NBCA and Lipiodol. Quantification of NBCA and Lipiodol within the lumen of rete cross-sections was accomplished using image analysis software to determine percent luminal area occluded by embolization. RESULTS: Upon application of TEC, intense europium fluorescence was seen when the tissue samples were excited by low-power UV light (excitation at 365 nm; emission at 614 nm). The area of europium intensity within the lumen corresponded to NBCA concentration, and addition of GAA aided the NBCA distribution throughout the lumen without affecting fluorescence intensity. It was seen that NBCA could be easily differentiated from Lipiodol and that quantification could be readily performed on these sections because of the improved differentiation. For the case of a 50:50 (vol. %) mixture with an added 20 microL of GAA, luminal area distribution of Lipiodol, NBCA, and blood products was 42.6 +/- 3.5%, 33.8 +/- 5.7%, and 23.7 +/-2.7%, respectively. CONCLUSION: The rare earth metal europium, when added as a fluorescent chelate compound to histologic tissue sections, allowed for differentiation between NBCA and Lipiodol with good detail. These results have facilitated further characterization of NBCA polymerization for the use of AVM embolization.     

Hepatic, metabolic, and nutritional disorders of alcoholism: from pathogenesis to therapy

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in an improvement in treatment. Nutritional deficiencies should be corrected when present but, because of the alcohol-induced disease process, some of the nutritional requirements change. For instance, methionine, one of the essential amino acids for humans, must be activated to S-adenosylmethionine (SAMe), but, in severe liver disease, the activity of the corresponding enzyme is depressed. Therefore, the resulting deficiencies and associated pathology can be attenuated by the administration of SAMe, but not by methionine. Similarly, phosphatidylethanolamine methyltransferase (PEMT) activity, which is important for hepatic phosphatidylcholine (PC) synthesis, is also depressed in alcoholic liver disease, therefore calling for the administration of the products of the reaction. Inasmuch as free radical generation by the ethanol-induced CYP2E1 plays a key role in the oxidative stress, inhibitors of this enzyme have great promise and PPC, which is presently being evaluated clinically, is particularly interesting because of its innocuity. In view of the striking negative interaction between alcoholic liver injury and hepatitis C, an antiviral agent is eagerly awaited that, unlike Interferon, is not contraindicated in the alcoholic. Antiinflamatory agents may also be useful. In addition to steroids, down-regulators of cytokines and endotoxin are being considered. Finally, anticraving agents such as naltrexone or acamprosate should be incorporated into any contemplated therapeutic cocktail.