Case Report: Interferon induced coma in Sheehan's syndrome

A 54-year-old woman who was being treated with 10 million units (mu) of natural interferon (IFN)-α per day for chronic active hepatitis C at a local clinic, developed coma on the fourth day of treatment. On admission to Yamagata University Hospital, she was still in a state of semicoma with severe hyponatraemia (122 mEq/L) and hypochloraemia (89 mEq/L). After the administration of electrolytes, her condition improved remarkably. Endocrinological loading tests showed a hypofunction of the anterior pituitary gland. In consideration of these results, and her past experiences of haemorrhage during childbirth and subsequent amenorrhoea, we diagnosed her illness as a coma as a result of Sheehan's syndrome which had become overt during IFN therapy. She recovered completely after treatment with hydrocortisone and 1-thyroxine.     

Hepatotoxicity of Agents That Enhance Formation of Focal Hepatocellular Proliferative Lesions (Putative Preneoplastic Foci) in a Rapid Rat Liver Bioassay

Hepatotoxicity of Agents That Enhance Formation of Focal HepatocellularProliferative Lesions (Putative Preneoplastic Foci) in a RapidRat Liver Bioassay. WARD, J. M., TSUDA, H., TATEMATSU, M., HAGIWARA,A., AND ITO, N. (1989). Fundam Appl Toxicol. 12., 163–171.The histopathology of hepatic toxicity for 58 chemicals previouslytested in a rapid rat liver bioassay for demonstrating potentialhepatocellular carcinogens and/or tumor promoters was reviewed.Rats received the test diet for 1 week prior to partial hepatectomyand for an additional 5 weeks thereafter at doses near the estimatedmaximally tolerated dose. These rats served as controls forothers receiving initiation by N-nitrosodiethylamine (DEN) andthe test diets. Twenty-two of these chemicals were previouslyfound to enhance the formation of glutathione S-transferase,placental form (GST-P)-positive putative preneoplastic hepatocellularfoci (promoters) following DEN initiation in this rapid bioassay,whereas 36 chemicals did not. Of the agents that promoted GST-P-positivefoci, 14/22 (63.6%) produced toxic hepatocyte lesions whileonly 4/36(11.1%) of the nonpromoters did so at the doses used.Biliary toxicity was found for 7/22 (31.8%) of the promotersand 6/36 (16.7%) of the nonpromoters. Only 2/13 (15%) chemicalsthat inhibited GST-P-positive foci produced hepatic toxicity.Thus, agents that were presumed hepatic tumor promoters characteristicallywere hepatotoxins while nonpromoters of carcinogenesis werenot hepatotoxins in this rapid rat liver bioassay.     

Moment analysis of hepatic local disposition of allopurinol and oxipurinol: metabolism kinetics from allopurinol to oxipurinol in the rat isolated perfused liver

Abstract— Drug metabolism in the liver was examined by the rat isolated perfused liver using the single-pass bolus-input technique. The test compounds, allopurinol and its metabolite oxipurinol, were independently introduced into the liver from the portal vein, and the concentration profiles in the venous outflow were monitored and kinetically analysed by moment theory. The recovery ratios of allopurinol and oxipurinol after the individual administration of each drug were estimated to be 0·17 (±0·08 s.d.) and 1·03 (± 0·02 s.d.), respectively. The outflow recovery ratio of oxipurinol as the metabolite after allopurinol administration was estimated to be 0·80 (±0·07 s.d.). These results indicate that the combined outflow recovery of the precursor and the metabolite after allopurinol administration is almost 100% in the rat liver.     

Defective response to thrombopoietin and impaired expression of c-mpl mRNA of bone marrow cells in congenital amegakaryocytic thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is an uncommon disorder in newborns and infants, characterized by isolated thrombocytopenia and megakaryocytopenia in the first year without physical anomalies. The defect of thrombopoiesis is not well understood. Recently, thrombopoietin (TPO), the ligand for the c-mpl receptor, was cloned. Accumulating evidence from in vitro and in vivo studies indicate that TPO plays a key role in the regulation of megakaryocytopoiesis. In this study we examined the effect of TPO on megakaryocyte colony formation from a patient with CAMT using a plasma-containing methylcellulose clonal culture. The in vitro results demonstrated a defective response to TPO in megakaryocyte colony formation from bone marrow mononuclear cells (MNC) of the patient, although interleukin-3 (IL-3) but not stem cell factor (SCF) induced only a small number of megakaryocyte colonies. These findings indicated that thrombocytopenia in CAMT could not be corrected by administration of TPO in vitro. Additionally, clonal cultures containing SCF, IL-3, IL-6 and erythropoietin showed decreased numbers of erythroid and myelocytic progenitors in the bone marrow of the patient. The serum TPO level measured by enzyme-linked immunosorbent assay was significantly higher than that in healthy controls. By PCR, marrow MNC from healthy children and from a patient with essential thrombocytosis expressed c-mpl mRNA, whereas no c-mpl mRNA was detected in marrow MNC from the patient with CAMT. There was no difference in the CD34 expression and c-kit mRNA between the CAMT patient and healthy children. The results of this study suggest that the pathophysiology in CAMT may be a defective response to TPO in haemopoietic cells through impaired expression of c-mpl mRNA.     

Electrophysiological Characteristics of Localized Reentrant Atrial Tachycardia Occurring After Catheter Ablation of Long-Lasting Persistent Atrial Fibrillation

Background: Mapping of recurrent atrial tachycardia (AT) after extensive ablation for long-lasting persistent atrial fibrillation (AF) is complex. We sought to describe the electrophysiological characteristics of localized reentry occurring after ablation of long-lasting persistent AF.
Methods: Out of 70 patients undergoing catheter ablation of long-lasting persistent AF, 9 patients (13%, 55 ± 8 years, 8 males) in whom localized reentry was demonstrated in a repeat ablation were studied. Localized reentry was defined as reentry in which the circuit was localized to a small area and did not have a central obstacle. The mechanism of AT was determined by electroanatomical and entrainment mapping.
Results: Nine localized reentries with cycle length of 243 ± 41 ms were mapped in 9 patients. The location of AT was the left atrial appendage in 4 patients, anterior left atrium in 2, left septum in 2, and mitral isthmus in 1. In all ATs, a critical isthmus of <10 mm in width was identified in the vicinity of the prior linear lesions or ostia of isolated pulmonary veins. Ablation of the critical isthmus, which was characterized by continuous low-voltage activity (median voltage: 0.15 mV, mean duration: 117 ± 31 ms), terminated AT and rendered it noninducible. Additionally, ablation was performed for all of inducible ATs. At 11 ± 7 months after the procedure, 8 of 9 patients (89%) were free from any arrhythmias.
Conclusions: After ablation of long-lasting persistent AF, localized reentry may arise from a site in the vicinity of the prior ablation lesions. Ablation of the critical isthmus eliminates the arrhythmia.