Endosomal proteolysis regulates calcitonin gene-related peptide responses in mesenteric arteries.

BACKGROUND AND PURPOSE: Calcitonin gene-related peptide (CGRP) is a potent vasodilator, implicated in the pathogenesis of migraine. CGRP activates a receptor complex comprising, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1). In vitro studies indicate recycling of CLR●RAMP1 is regulated by degradation of CGRP in early endosomes by endothelin-converting enzyme-1 (ECE-1). However, it is not known if ECE-1 regulates the resensitization of CGRP-induced responses in functional arterial tissue. EXPERIMENTAL APPROACH: CLR, ECE-1a-d and RAMP1 expression in rat mesenteric artery smooth muscle cells (RMA-SMCs) and mesenteric arteries was analysed by RT-PCR and by immunofluorescence and confocal microscopy. CGRP-induced signalling in cells was examined by measuring cAMP production and ERK activation. CGRP-induced relaxation of arteries was measured by isometric wire myography. ECE-1 was inhibited using the specific inhibitor, SM-19712. KEY RESULTS: RMA-SMCs and arteries contained mRNA for CLR, ECE-1a-d and RAMP1. ECE-1 was present in early endosomes of RMA-SMCs and in the smooth muscle layer of arteries. CGRP induced endothelium-independent relaxation of arteries. ECE-1 inhibition had no effect on initial CGRP-induced responses but reduced cAMP generation in RMA-SMCs and vasodilation in mesenteric arteries responses to subsequent CGRP challenges. CONCLUSIONS AND IMPLICATIONS: ECE-1 regulated the resensitization of responses to CGRP in RMA-SMCs and mesenteric arteries. CGRP-induced relaxation did not involve endothelium-derived pathways. This is the first report of ECE-1 regulating CGRP responses in SMCs and arteries. ECE-1 inhibitors may attenuate an important vasodilatory pathway, implicated in primary headaches and may represent a new therapeutic approach for the treatment of migraine.

Balloon valvuloplasty versus closed commissurotomy for pliable mitral stenosis: a prospective hemodynamic study.

Closed surgical mitral valvotomy is the procedure of choice in most patients with symptomatic pliable mitral stenosis in developing countries. The procedure is efficacious and safe. Mitral valvotomy performed with a balloon has shown similar good results, with infrequent complications in selected subjects. Because there is a paucity of studies comparing the two techniques, this study was undertaken to compare the results of percutaneous balloon mitral valvuloplasty with those of closed commissurotomy as determined by catheterization studies. Forty-five patients with tight pliable mitral stenosis were randomly assigned to one of two groups: 23 patients had balloon valvuloplasty by the single catheter technique (group I) and 22 underwent closed surgical valvotomy (group II). The two groups were similar with regard to clinical and hemodynamic findings before intervention. Mitral valve area increased from 0.8 +/- 0.3 to 2.1 +/- 0.7 cm2 in group I (p less than 0.001) and from 0.7 +/- 0.2 to 1.3 +/- 0.3 cm2 in group II (p less than 0.001). Pulmonary artery pressure and pulmonary vascular resistance decreased in both groups, but these changes did not reach statistical significance in group II. Treadmill exercise time increased from 3.8 +/- 2.3 to 7.3 +/- 2.6 min in group I (p less than 0.001) and from 4 +/- 2.6 to 5.6 +/- 2.6 min in group II (p less than 0.001). There were no deaths. One patient in each group developed moderate (3+) mitral regurgitation. A small interatrial shunt (less than 1.5:1) was detected in three patients in group I immediately after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphomatoid granulomatosis. A report of 4 cases.

Only 1 case of lymphomatoid granulomatosis has previously been reported from South Africa. Experience with 4 such adult patients (2 blacks and 2 whites) is described. These patients were followed up for 15-48 months and none developed evidence of a lymphoma during this period. Fever, weight loss, cough and breathlessness were prominent symptoms in all patients. One patient, a black woman, with a diffuse interstitial pattern of lung involvement, had digital clubbing--a rare accompaniment that resolved after therapy. Dilated congestive cardiomyopathy was found in association with pulmonary nodules in a black male patient. All 4 patients were treated with cytotoxic regimens. The 2 patients treated with oral cyclophosphamide and prednisolone responded favourably. The possible explanation for paucity of reports of lymphomatoid granulomatosis from South Africa could be under-reporting, underdiagnosis or a true geographic/ethnic variation in the incidence of this condition.

Recurrent desmoid tumour of the abdomen and thorax. A case report.

The life of a young woman was threatened by a large, recurrent, invasive desmoid tumour which penetrated the sternum. The combined thoracic and plastic surgical management is described.

Obstructed tilting disc mitral valve prosthesis associated with placenta praevia.

The occurrence of a bleeding placenta praevia in a young woman, with a viable fetus and an acutely obstructed Lillehei-Kaster valve, provided serious difficulties in priorities and decision making. This has prompted an analysis of the problems which others may encounter.

Pulsion intubation for palliation of carcinoma of the oesophagus.

One hundred and eighty-one patients with carcinoma of the upper thoracic oesophagus were intubated perorally using a Procter-Livingstone tube. The mortality was 16-6 per cent but, in the patients who survived, the palliation achieved, as judged by improved swallowing, was considered satisfactory. Factors influencing the success of intubation are also considered.

Palliation of malignant esophago-respiratory fistulae by permanent indwelling prosthetic tube.

Malignant esophago-respiratory fistula is an incurable condition calsing severe distress to those patients suffering from it. Sixty two successive patients with esophago-respiratory fistulae, secondary to squamous cell carcinomas of the esophagus, were intubated for palliation. The first 14 were intubated by a traction technique using the Celestin tube, and the remaining 48 were intubated by the Procter-Livingstone tube inserted by a pulsion method. Celestin intubation had a mortality of 64.3% but 75% of those intubated by the Procter-Livingstone tube were discharged from hospital, swallowing satisfactorily and relieved of their respiratory distress. In our experience the insertion of the Proctor-Livingstone tube by a pulsion technique, can be performed in a few minutes, with little morbidity and allows the patient to be discharged from hospital within 3-4 days of the procedure. It is a successful and acceptable method of treating malignant esophago-respiratory fistulae.

Clinical experience with the Lillehei-Kaster cardiac valve prosthesis.

This paper reviews our experience with the Lillehei-Kaster pivoting disc prosthesis in 155 patients with aortic and mitral valve disease. We employed 189 valves during the period 1971 to 1974. The early surgical mortality rates for isolated mitral, isolated aortic, and combined mitral and aortic valve replacements were 9 per cent, 14 per cent, and 3 per cent, respectively. Postoperatively, there was no evidence of significant hemolysis, and the gradients across the prostheses were satisfactory. Clinical evaluation of prosthetic function was made difficult by the infrequency of an opening click and the common occurrence of mid-diastolic murmurs even with minimal gradients. The most disturbing complication, which has led to our abandoning use of this valve, was thrombosis, which occurred in at least 10 per cent of the mitral and 5 per cent of the aortic valves. The cause is thought to be late prosthetic disproportion as the heart shrinks in size.