Age-related involvement of the endothelium in beta-adrenoceptor-mediated relaxation of rat aorta.

The signalling pathway involved in beta-adrenoceptor relaxation was studied in aortas from rats either 8 or 54 weeks of age. The vasorelaxation produced by isoprenaline was almost completely abolished by endothelium removal in 54-week aortas, whereas in 8-week aortas, the effect was much smaller. The nitric oxide synthase inhibitor N-methyl-1-arginine acetate (L-NMMA) partially attenuated the isoprenaline induced relaxation to a similar extent in both age groups when the endothelium was intact, suggesting that although nitric oxide was involved, it could not explain the age-related difference. The K(+) channel inhibitor, tetraethylammonium inhibited isoprenaline vasorelaxation to a larger degree in 54-week compared to 8-week aortas indicating that K(+) channels were responsible for the age-related differences. We suggest that as the animals age, the smooth muscle cyclic AMP signalling system declines, and that this is compensated for by an alternate pathway involving the opening of K(+) channels.

Elevated glutamate levels in the vitreous body of an in vivo model of optic nerve ischemia.

OBJECTIVE: To explore the possibility that an elevation of glutamate levels in the vitreous might be associated with the microvascular compromise of the optic nerve. MATERIALS AND METHODS: Endothelin-1, 0.1 microg/d (5 rabbits), or balanced salt solution (4 rabbits) was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for 2 weeks. Vitreous specimens were obtained, and their amino acid contents were determined by high-performance liquid chromatography. RESULTS: There was a statistically significant elevation in the mean +/- SEM vitreous concentrations of glutamate (264% +/-41%; P = .04), aspartate (269% +/-31%; P = .04), and glycine (232% +/-26%; P = .04) in the eyes subjected to endothelin-1 when compared with the fellow control eyes. CONCLUSION: Administration of endothelin-1 to the microvasculature of the optic nerve leads to elevation of glutamate, aspartate, and glycine concentrations in the vitreous. CLINICAL RELEVANCE: The increase of excitatory amino acids in the vitreous might be associated with various ischemic processes of the optic nerve, including glaucomatous optic neuropathy, and may play a role in the neuronal damage that is seen in these diseases.

Inhibitory effect of 1alpha-hydroxyvitamin D3 on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastrointestinal carcinogenesis in Wistar rats.

The effect of 1alpha-hydroxyvitamin D3 (1alpha(OH)D3) on gastrointestinal carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in male Wistar rats. After oral treatment with 0.01% MNNG for 24 weeks, rats were given 0.04 microg of 1alpha(OH)D3 or its vehicle by gastric intubation three times a week for 24 weeks. The incidence of gastrointestinal tumors was 16/30 (53%) in rats treated with MNNG alone, 16/30 (53%) in those treated with MNNG plus vehicle and 8/30 (27%, P < 0.05) in those treated with MNNG plus 1alpha(OH)D3. The number of tumors per rat in the group treated with MNNG plus 1alpha(OH)D3 was half those in the control groups (P < 0.05). Results indicated that a non-hypercalcemic dose of 1alpha(OH)D3 had an inhibitory effect on MNNG-induced duodeno-intestinal carcinogenesis.

Importance of pretreatment viral load and monitoring of serum hepatitis C virus RNA in predicting responses to interferon-alpha2a treatment of chronic hepatitis C. Hanshin Chronic Hepatitis C Study Group.

The aim of this study was to determine what factors correlate with a favorable response to interferon-alpha2a (IFN-alpha2a) treatment in chronic hepatitis C. Fifty patients with chronic hepatitis C who received a 26-week treatment with IFN-alpha2a (474 million units in total) were assessed for pretreatment parameters and biochemical and virologic events during the treatment. According to biochemical and virologic responses to the treatment, 16 patients (32%) were categorized as sustained complete responders (SR), 13 (26%) as initial complete responders (IR), and 21 (42%) as nonresponders (NR). By multivariate analysis, a low viremia level was the only independent predictor of SR among pretreatment parameters (p = 0.0088). The percentage of patients showing hepatitis C virus RNA negativity at 2 and 12 weeks of treatment was significantly higher in SR (94% and 100%, respectively) or IR (69% and 92%, respectively) than in NR (14% and 33%, respectively) (p = 0.001). In contrast, the normalization of serum alanine aminotransferase levels at both time points failed to differentiate among SR, IR, and NR. These results indicate that monitoring of serum hepatitis C virus RNA at an appropriate time during treatment in addition to determination of pretreatment viral load is important in predicting responses to IFN-alpha2a treatment.

Does the presence of serum autoantibodies influence the responsiveness to interferon-alpha 2a treatment in chronic hepatitis C?

The serum autoantibodies, antinuclear antibody, anti-DNA antibody, anti-smooth muscle antibody, antithyroglobulin antibody, antimicrosomal antibody, antimitochondrial antibody, rheumatoid factor and antibody to deoxyribonucleoprotein were measured at the baseline and on completion of interferon-alpha 2a (IFN-alpha 2a) treatment in chronic hepatitis C (CHC) patients who did not present with any autoimmune disease prior to treatment. Of the 57 patients examined, 27 spontaneously manifested at least one autoantibody. Only the prevalence of rheumatoid factor (26%) was significantly higher in the CHC patients than in the control subjects. There were no differences in the prevalence of the 8 autoantibodies examined between hepatitis C virus (HCV) genotypes 1b and 2a/2b. Twenty-six patients responded to IFN-alpha 2a. Subclinical hypothyroidism developed in two patients with elevated antithyroid antibody titres during treatment. No relationship was observed between changes in the status of autoantibodies and either response to IFN-alpha 2a or HCV genotype. Irrespective of the HCV genotype, autoantibodies might be present in CHC patients before and during the IFN-alpha 2a treatment. The presence of such antibodies does not represent a contraindication to the use of IFN-alpha 2a in CHC patients not complicated by autoimmune diseases. Careful observations are necessary for CHC patients positive for antithyroid antibodies during the IFN-alpha 2a treatment. Preexisting or newly developed autoantibodies do not necessarily predict a poor response to IFN-alpha 2a.

A case of pseudolymphoma of the liver with chronic hepatitis C.

A case of pseudolymphoma (reactive lymphoid hyperplasia) of the liver in a 72-year-old male with chronic hepatitis C is presented. Imaging studies, comprising ultrasonography, computed tomography, incremental computed tomography, and magnetic resonance imaging, suggested hepatocellular carcinoma. A tumor-like lesion was therefore resected. Grossly, the lesion was relatively poorly defined and measured 15 x 17 mm; microscopically, it consisted of lymphocytic proliferations forming follicles comprising numerous germinal centers that were mainly composed of L-26 positive B-cell lymphocytes. The lymphocytes surrounding germinal centers were mainly UCHL-1 positive T lymphocytes. The B cells in the lymphoid follicles stained positive for both kappa and lambda light chains at sequential frequencies, indicating polyclonal and benign features. These findings suggest that the diagnosis of pseudolymphoma of the liver is tenable from imaging studies supplemented, when necessary, with biopsy. Further studies may provide insights into diagnostic strategies and the mechanism of stimulation in HCV infections.

Clinicopathological study of minimum-sized hepatocellular carcinoma: an approach to the definition of early hepatocellular carcinoma.

Clinicopathologic examination of 33 nodules from 23 cases of minimum-sized hepatocellular carcinoma (HCC), less than 15 mm in diameter, was carried out by imaging and clinical follow up. On ultrasound (US), 16 hypoechoic nodules (48%) and 15 hyperechoic nodules (45%) on angiography 7 tumour stains (21%) and on computerized tomography (CT) 3 low density nodules (9%) were detected. Of 27 nodules on lipiodol CT (LpCT), 7 lipiodol-deposited nodules (26%) were detected. Of 16 nodules on CO2US angiography (US-angiography), 7 hypervascular (44%), 5 hypovascular (31%) and 4 isovascular nodules (25%) were detected. Of 13 nodules on CT during arterial portography (CTAP), 7 perfusion defect nodules (54%) were detected. The nodules were graded according to the Edmondson & Steiner Classification. Three nodules were resected; grossly, two were not distinct and one was poorly demarcated. Histologically, they were highly differentiated with irregularly-thin trabecular-patterned HCC where portal triads were detected. Cancer cells invaded the non-cancerous liver cells by replacement, and the border between the cancerous and non-cancerous regions was unclear; the latter region manifested chronic hepatitis or liver cirrhosis without hyperplasia. Minimum-sized HCC is characteristically hypovascular in arterial and portal supply of blood, of multicentric origin and of a well-differentiated pattern. Because the three resected nodules did not damage the liver acinus structure, they were considered to be an early stage of HCC.