The collecting duct,dopamine and vasopressin‐dependent hypertension

AVP not only increases osmotic water permeability (P_f) in the rat cortical collecting duct (CCD), but also acts synergistically with aldosterone to augment sodium reabsorption (J_Na). These effects are inhibited by catecholamines via α₂ adrenergic receptors, and by dopamine. We review here studies designed to determine the mechanism and receptor involved in dopamine action. The inhibitory effect of dopamine on Na⁺ and water transport was found to be reversible, and was not produced by agonists specific to D_1A and D_1B receptors. D₂‐type (D₂, D₃ or D₄) receptors and activation of the GTP‐binding protein G_i were implicated by the observation that dopamine had no inhibitory effect when J_Na and P_f were stimulated by a cyclic AMP analogue plus isobutylmethylxanthine. The only dopaminergic antagonist that reversed the inhibitory effect of dopamine was clozapine, which is relatively D₄‐specific. We also found that dopamine or D₁‐specific agonists by themselves had no effect on cAMP production. However, dopamine inhibited the high rate of AVP‐dependent cAMP production, and this effect of dopamine was reversed by clozapine but not other antagonists or by inhibitors of protein kinase C. The D₄ receptor was observed in western blots of renal cortical proteins, and it was localized to the collecting duct by RT‐PCR and immuno‐histochemistry using a D₄‐specific antibody. These results show that at least a portion of the natriuretic effect of dopamine can be attributed to inhibition of AVP‐dependent Na⁺ reabsorption by the CCD, and they introduce another signalling system as a candidate in the aetiology of low‐renin, salt‐dependent hypertension.     

Malignant uveal melanoma and simulating lesions: MR imaging evaluation

Twenty-one patients with intraocular disease were studied by magnetic resonance (MR) imaging and computed tomography (CT). In 13 cases, malignant uveal melanoma was considered the likely diagnosis. Both imaging methods were accurate in determining the location and size of uveal melanomas. MR imaging was superior for the assessment of possible associated retinal detachment, for assessment of vitreous change, and for differentiating uveal melanoma from choroidal hemangioma and choroidal detachment. A case of retinal gliosis could not be differentiated from uveal melanoma by either technique. Uveal melanomas appeared as hyperintense lesions on T1-weighted images and as hypointense lesions on T2-weighted images. High signal intensity of the vitreous was observed in patients with vitritis and in those who were thought to have protein leaking into the vitreous as a result of impairment of the retinal-blood barrier.     

Perturbations in the erythroid marrow progenitor cell pools may play a role in the augmentation of HbF by 5-azacytidine

In vivo observations on the kinetics of F cells and of fetal hemoglobin (HbF) synthesis and in vitro studies of erythroid progenitors, their number, and the gamma-gene expression in their progeny were carried out in baboons (Papio cynocephalus) treated with 5-azacytidine. Maximum effect on the increase of HbF production in vivo was observed only when an expanded erythroid marrow population was present. In these animals, as well as in normal animals, treatment resulted in a significant reduction of the late erythroid progenitor cell pools (erythroid clusters and erythroid colony-forming units, CFU-E) in the marrow. This reduction was more pronounced among those progenitors grown in the absence of added erythropoietin, and it was followed by a rebound a few days after treatment cessation, reflecting the accumulation of regenerating progenitors. An early increase in the in vitro synthesis of HbF in erythroid clusters and CFU-E colonies was observed. This increase was further documented at the cellular level, with immunofluorescent labeling of colonies with monoclonal anti-gamma- globin chain antibodies. In contrast to the findings in late progenitors, the number of erythroid burst-forming unit (BFU-E) colonies and the synthesis of HbF in these colonies was not influenced significantly by 5-azacytidine treatment. It is proposed that the toxic effects of 5-azacytidine on late progenitors, leading to faster mobilization of earlier progenitors to the next more mature compartment, play a role in the in vivo augmentation of HbF synthesis by this drug. This perturbation in the progenitor cell population kinetics and the presumed hypomethylation of the surviving differentiating cells may act synergistically to produce a maximum HbF response after 5-azacytidine treatment.     

Bleeding and thrombosis in the myeloproliferative disorders

Bleeding and thrombosis are major causes of morbidity and mortality in patients with myeloproliferative disorders. The significance of uncontrolled polycythemia as a risk factor for thrombosis in these patients has been established. However, the role of thrombocytosis in the pathogenesis of hemostatic complications remains controversial. Abnormalities of platelet function and prolongation of the bleeding time occur in a highly variable number of cases. Specific platelet defects that have been identified in the myeloproliferative defects include abnormal platelet morphology, acquired storage pool disease, platelet membrane abnormalities, and abnormal arachidonic acid metabolism. Causal relationships between any of these specific abnormalities and either bleeding or thrombosis have not been clearly established. The therapeutic efficacy of myelosuppression to reduce the platelet count in patients with thrombocytosis and the role of antiplatelet drugs in the myeloproliferative disorders are controversial issues.     

Visual evoked potentials in a rabbit model of hepatic encephalopathy. I. Sequential changes and comparisons with drug-induced comas

The recording of visual evoked potentials in rabbits has been shown to be an objective, reproducible, noninvasive technique for quantitating changes in the pattern of cerebral neuronal activity. The development of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure was consistently associated with a series of distinctive changes in the visual evoked potential waveform. The pattern of the visual evoked potential in hepatic coma (due to galactosamine-induced fulminant hepatic failure) differed fundamentally from that in ether-induced coma, but was identical to that in comas induced by three drugs which activate gamma-aminobutyric acid-ergic neural mechanisms: pentobarbital, diazepam, and muscimol. These findings are compatible with activation of the gamma-aminobutyric acid inhibitory neurotransmitter system contributing to cerebral neuronal inhibition in hepatic coma due to galactosamine-induced fulminant hepatic failure.     

Visual evoked potentials in a rabbit model of hepatic encephalopathy. II. Comparison of hyperammonemic encephalopathy, postictal coma, and coma induced by synergistic neurotoxins

To assess neuronal mechanisms of potential importance in the pathogenesis of hepatic encephalopathy, visual evoked potentials were recorded in rabbits with acute hyperammonemic encephalopathy, postictal coma, and toxin-induced coma resulting from the administration of a combination of subcoma doses of three neurotoxins: ammonia, dimethyldisulfide, and octanoic acid. The patterns of visual evoked potentials in these three syndromes were compared with those of rabbits with hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. In the absence of seizures, the patterns of visual evoked potentials associated with hyperammonemic encephalopathy and toxin-induced coma were fundamentally different from those associated with any stage of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. In contrast, the pattern of visual evoked potentials in early postictal coma induced by four different precipitating factors (including toxin-induced seizures) resembled that of late-stage hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. These findings suggest that the recording of visual evoked potentials may be of value in experimentally testing hypotheses of the pathogenesis of hepatic encephalopathy due to fulminant hepatic failure. They indicate that acute hyperammonemia is not a satisfactory model of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure, that the occurrence of seizures may lead to incorrect interpretation of experimental data from models of hepatic encephalopathy, and that the syndromes of hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure and postictal coma may share similar neural mechanisms. Finally, the results of this study do not support the hypothesis that hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure is mediated by the synergistic interaction of ammonia, mercaptans, and fatty acids on the brain.     

Hepatosplenic T-cell lymphoma: sinusal/sinusoidal localization of malignant cells expressing the T-cell receptor gamma delta

Peripheral T-cell lymphomas consist of a clinically heterogeneous group of malignant disorders whose immunophenotype usually corresponds to that of normal mature T cells. We describe and correlate the clinical, histopathologic, phenotypic, and genotypic findings in two patients with malignant lymphoma presenting with hepatosplenic disease. The morphologic pattern of lymphoma was that of a sinusal/sinusoidal infiltration in spleen, marrow, and liver. This morphologic characteristic was associated with the presence of a productive clonal rearrangement of the T-cell receptor (TCR) delta gene. Lymphoma cells expressed a CD3-TCR-gamma delta- phenotype. They were also double negative (ie, CD4-CD8-) and lacked the CD5 and CD7 antigens. In one patient, tumor progression was associated with phenotypic changes that resulted in a CD3-TCR-gamma delta- phenotype with the same delta-gene rearrangement as initially. These observations suggest the existence of a new type of peripheral T-cell lymphoma characterized by its hepatosplenic presentation, and by the sinusal/sinusoidal tropism and the TCR-gamma delta phenotype of the malignant cells.