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Familial dysautonomia is a hereditary disorder that affects autonomic and sensory neurons. Nerve growth factor (NGF) is required for the normal development of sympathetic and sensory neurons and it has been postulated that an abnormality involving NGF may be responsible for familial dysautonomia. Previous studies have shown that the beta-NGF gene is not linked to the disease. However, NGF appears to be abnormal by immunochemical assays; the putative altered form of NGF could result from a disturbance in the processing pathway. To study the processing of the 35-kD glycosylated NGF precursor and the secretion of NGF in familial dysautonomia, we have employed a recombinant vaccinia virus vector to express high levels of NGF mRNA in primary fibroblast cultures from patients with the disorder; the processing pathway was then studied directly. Cells from several unrelated patients all produce the same 35-kD NGF precursor, process this normally to NGF within the cell, and release NGF into the medium. There are no differences in the ability of cells from patients and from unaffected relatives to process and secrete NGF. The use of similar recombinant vaccinia virus vectors to express proteins at high level in primary cell lines should facilitate the detection of posttranslational processing defects in a variety of human disorders.

The circulatory, respiratory, and metabolic responses to steady state submaximal exercise have been studied in four women and two men with hypertrophic obstructive cardiomyopathy, before treatment, after intravenous, and after three months of oral propranolol. The physical working capacity was significantly lower than in normal subjects, and the response to exercise was characterized by a tachycardia, low cardiac output and stroke volume, and high ventilation and blood lactate concentration. After propranolol there was a significant reduction in heart rate, but changes in most other measurements were slight and there was no improvement in effort tolerance though angina was relieved in the two patients in whom it was present. The possible causes of breathlessness and effort intolerance in hypertrophic obstructive cardiomyopathy are discussed in relation to known effects of propranolol. It is concluded that further trial of propranolol and other beta-adrenergic blocking agents is warranted.

1. Cardiorespiratory and metabolic responses to paired patterns of continuous and intermittent exercise with the same average power output were studied in eight men. Heart rate, ventilation and pulmonary gas exchange were measured during the different patterns of exercise performed on a cycle ergometer. The recovery oxygen volume was measured over 30 min of loadless pedalling. Needle biopsy samples of the vastus lateralis muscle were taken before, during and after completion of the exercise for measurement of muscle metabolites.2. Heart rate, ventilation, oxygen intake, respiratory exchange ratio, and blood lactate concentration were generally higher with intermittent compared with continuous exercise as were the accumulated totals for heart beats, ventilation and oxygen intake. Muscle biopsy samples tended to have higher lactate and lower phosphocreatine contents in intermittent exercise. The lactate concentration in muscle and blood water was the same during loadless pedalling before exercise but was significantly higher in muscle than blood during exercise. This concentration gradient was larger in intermittent than in continuous exercise.3. Work efficiency, calculated from the total oxygen cost of work in excess of a loadless pedalling control, was significantly lower in intermittent exercise. The explanation is thought to be connected with the observation that when the work was performed at a high rate in short bursts a large part of the oxidative recovery took place after the contraction during the rest periods, whereas in the low intensity continuous exercise the oxygen was mainly utilized while the work was being performed. This indicates that for part of the time in the intermittent exercise the muscle was working under anaerobic conditions. Although the possibility exists that the efficiency of resynthesis of phosphagen may be reduced in this form of activity, it is more likely that the result described is due to the greater amount of lactate formed in the intermittent exercise.

Seven patients in acute exacerbation of chronic respiratory failure were given 24.5% and later 28% oxygen through Ventimasks. The mean increases in arterial PO(2) were 11 and 21 mm. Hg while breathing 24.5% and 28% oxygen respectively compared with control values while breathing air. Associated increases in arterial PCO(2) were 4 and 8 mm. Hg, respectively. In five of the patients these increases in inspired oxygen concentration resulted in useful increases in tissue oxygen supply without significant deterioration in ventilation, but in two patients arterial PCO(2) rose excessively and artificial ventilation was required.