The receptor-type protein tyrosine kinases in murine pancreatic islets were screened to identify possible growth/differentiation factors in pancreatic beta-cells. The analysis revealed that insulin receptor-related receptor (IRR) is highly expressed in the islets as well as in several highly differentiated beta-cell lines derived from transgenic mice. Islets predominantly contain IRR as uncleaved proreceptors compared with IRR as processed forms in the beta-cell lines, suggesting that the activity of IRR is regulated on the level of processing proteases in vivo. To examine the IRR signaling pathway, a chimeric receptor consisting of the extracellular domain of insulin receptor and the intracellular domain of IRR was expressed in Chinese hamster ovary cells. The hybrid receptor is functional because insulin is capable of tyrosine-phosphorylating the catalytic domain in these cells. It also stimulates the tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and IRS-2, indicating that both proteins serve as substrates of IRR-protein tyrosine kinase in intact cells. The phenotype of the IRS-2 knockout mouse recently reported suggests that an IRS-2-mediated signaling pathway controls the compensatory increase in pancreatic beta-cell mass in insulin-resistant states. From our findings of the specific expression of IRR and its ability of signaling to IRS-2, we speculate that this receptor might play a role in the regulation of beta-cell mass.

SummaryA 35-year-old Japanese woman was admitted with coma following flu-like symptoms. She was diagnosed with diabetic ketoacidosis and fulminant type 1 diabetes (FT1D) and received intravenous infusion of insulin and saline. The next day, the ketoacidosis disappeared, and she recovered consciousness. However, extensive ST-segment elevations in the electrocardiogram appeared with a positive troponin test, and the patient developed pulmonary edema on day 3. An echocardiogram showed globally reduced wall motion of the left ventricle and mild pericardial effusion. Despite medical therapy with intravenous furosemide, carperitide, and catecholamines, her cardiac function deteriorated rapidly, with the left ventricular ejection fraction decreasing to 26% within 7 hours, and progressed to cardiogenic shock that afternoon. The patient received mechanical circulatory support for 4 days with intra-aortic balloon pumping and percutaneous cardiopulmonary support, and recovered fully from circulatory failure. A paired serum antibody test showed a significantly elevated titer against parainfluenza-3 virus, indicating a diagnosis of fulminant viral myocarditis. She was discharged on multiple daily insulin injection therapy, and her subsequent clinical course has been uneventful. In summary, we present a case of concurrent FT1D and fulminant viral myocarditis. Parainfluenza-3 viral infection was confirmed serologically and was considered to be a cause of both the FT1D and fulminant myocarditis. (Int Heart J 2015; 56: 239-244)

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BackgroundPheochromocytomas are rare catecholamine-producing neuroendocrine tumors. Hypertension secondary to pheochromocytoma is often paroxysmal, and patients occasionally present with sudden attacks of alternating hypertension and hypotension. Spontaneous, extensive necrosis within the tumor that is associated with catecholamine crisis is an infrequent complication of adrenal pheochromocytoma, but its pathogenesis remains unclear.Case presentationA 69-year-old Japanese man developed acute-onset episodic headaches, palpitations, and chest pains. During the episodes, both marked fluctuations in blood pressure (ranging from 40/25 to 300/160 mmHg) and high plasma levels of catecholamines were found simultaneously. Radiological findings indicated a 4-cm left adrenal pheochromocytoma. These episodic symptoms disappeared within 2 weeks with normalization of plasma catecholamine levels. Two months later, the patient underwent adrenalectomy. Microscopic examinations revealed pheocromocytoma with a large central area of coagulative necrosis. The necrotic material was immunohistochemically positive for chromogranin A. Granulation tissue was adjacent to the necrotic area, accompanied by numerous hemosiderin-laden macrophages and histiocytes with vascular proliferation. Viable tumor cells, detected along the periphery of the tumor, demonstrated pyknosis, and the Ki-67 labeling index was 2 % in the hot spot. No embolus or thrombus formation was found in the resected specimen harboring the whole tumor. The Pheochromocytoma of the Adrenal gland Scaled Score was 2 out of 20. The patient’s postoperative course was unremarkable for > 7 years.ConclusionsPresumed causal factors for the extensive necrosis of adrenal pheochromocytoma in previously reported cases include hemorrhage into the tumor, hypotension induced by a phentolamine administration, embolic infarction, high intracapsular pressure due to malignant growth of the tumor, and catecholamine-induced vasoconstriction. In the present case, histopathological and clinical findings suggest that under conditions of chronic ischemia due to catecholamine-induced vasoconstriction, an acute infarction occurred after sudden attacks of alternating hypertension and hypotension. Over the subsequent 2 weeks, repetitive massive release of catecholamines from the infarcts into circulation likely accelerated infarction progression by causing repeated attacks of alternating hypertension and hypotension and resulted in the large necrosis. This case highlights the need for physicians to consider acute spontaneous tumor infarction accompanying episodic catecholamine crisis as a rare but severe complication of pheochromocytoma.

SUMMARYAcute hemodynamics of pimobendan were compared to captopril in a crossover trial in patients with chronic heart failure (NYHA II-III). Heart failure had been stabilized by conventional therapy with diuretics and digitalis for more than 2 weeks. Patients receiving vasodilators were excluded.The hemodynamics were analyzed using a Swan-Ganz catheter at the bedside during drug administration.Following an intravenous injection of 2.5mg of pimobendan, there was a significant increase in heart rate and decrease in mean pulmonary artery pressure, total pulmonary resistance, mean arterial pressure, systemic vascular resistance and mean right atrial pressure 2 hours after the injection.Captopril (12.5mg, orally) significantly decreased mean arterial pressure, systemic vascular resistance and double product 2 hours after administration.In this study, the inotropic effect was evaluated through the relation between the stroke volume index and diastolic pulmonary artery pressure, and also between the stroke volume index and mean arterial pressure.Although decreases of diastolic pulmonary artery pressure and mean arterial pressure were seen with both drugs, the differences in stroke volume index were not significant. In comparison with captopril, the acute hemodynamics of pimobendan are characterized as follows: 1) the systemic arteriovasodilating effects of the two drugs were equal, 2) the pulmonary arteriovasodilating effect of pimobendan was marked, 3) a venodilating effect, documented through a decrease of mean right atrial pressure, was seen only with pimobendan.This study concluded that pimobendan is a stronger arterio-venodilator than captopril.

We performed radiofrequency current catheter ablation in two patients with nonischemic sustained ventricular tachycardia (VT). In one patient, two morphologically distinct VTs were induced by electrical stimulation. One showed right bundle branch block pattern and the other left bundle branch block pattern. The earliest site of activation during each VT was determined at the septum of the right ventricle. However, these two sites were close to the His-bundle electrogram recording area. In the other patient, a VT with a left bundle branch block pattern occurred spontaneously after the administration of isoproterenol. The earliest site of activation during VT was determined at the outflow tract of the right ventricle. During tachycardia, radiofrequency current ablation (40 W x 30 sec) was delivered to the earliest site of activation. A few seconds after fulguration, each VT was terminated and additional radiofrequency currents were given near these sites. After the ablation, VT could not be induced by the electrical stimulations, nor did it recur. No side effects were observed and the atrioventricular conduction remained intact. We feel that nonischemic VTs could possibly be treated by using radiofrequency current catheter ablation.

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