Biomedical subjects
Publications and source records attributed to J E Carroll.
A child with the Dyggve-Melchior-Clausen syndrome associated with elevated pipecolic acid levels in plasma and urine is described. Other studies of peroxisomal function, including phytanic acid, very long-chain fatty acids, and plasmalogen synthesis, were normal. This disorder may represent an incompletely characterized defect in peroxisomal metabolism.
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In the developing nation of Kuwait, we undertook a case-control study of 43 consecutively born, asphyxiated, term infants. The asphyxia incidence of 9.4/1000 was only slightly higher than that in more developed countries. Severe morbidity occurred in 1.1/1000, and mortality in 1.1/1000. We found significant associations between asphyxia and primiparity, maternal hypertension, consanguinity, increased length of labour, and instrumental deliveries. Maternal age, socio-economic class, maternal illnesses other than diabetes, and breech delivery did not seem to play a role. The fact that the chosen method of delivery failed for a number of the asphyxiated patients, necessitating emergency Caesarian section, suggests that obstetric factors may need closer analysis.
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Fatty acid oxidation rates tend to increase with age in most developing tissues. In skeletal muscle, heart, and liver of developing rats, we measured activities of three acyl-CoA dehydrogenase enzymes, which constitute the first step in the mitochondrial beta-oxidation sequence. In skeletal muscle, activities of all three enzymes increased with age. In heart muscle, palmityl-CoA dehydrogenase increased, while the other two enzymes changed only minimally. In liver, palmityl-CoA dehydrogenase activity steadily increased with age. Decanoyl- and butyryl-CoA dehydrogenase also increased with age, but much more irregularly. We also examined the electrophoretic characteristics of these enzyme proteins in the three tissues. There were no changes in their electrophoretic patterns during development.
Defective activity of carnitine palmitoyltransferase I was demonstrated in fibroblasts derived from a patient with hypoketotic hypoglycemia. The level of activity observed was approximately 10% of the control mean. Oxidation of palmitate by intact fibroblasts was reduced to 5% of control values. The patient presented at age 14 months with seizures and was found to have marked hypoglycemia and no ketones in the urine. In response to fasting, she developed hypoglycemia, but the curves for acetoacetate and 3-hydroxybutyrate were flat. Administration of medium-chain triglycerides relieved the hypoglycemia and generated a brisk ketogenesis.
A child is reported with adrenocortical unresponsiveness to ACTH and autonomic dysfunction. The latter consisted of cold extremities, progressive loss of tear production, the development of achalasia of the esophagus, pupillary dysfunction, and an abnormal histamine skin test. These findings suggest progressive parasympathetic denervation as a cause for the adrenocortical abnormality.
Patients with disorders of propionate metabolism have low plasma levels of free carnitine and excrete higher than normal quantities of esterified carnitine. The response to a 19 h fast was assessed as a physiological index of carnitine deficiency. In patients with propionic acidaemia and methylmalonic acidaemia a substantial ketogenesis developed in response to fasting. Supplementation with L-carnitine significantly reduced this ketogenic response.
Ambient hydrogen ion concentration modulates the effects of angiotensin II (AII) on adrenal aldosterone secretion, but the mechanism of this modulation is unknown. We examined the influence of pH on AII receptors and responses in bovine adrenal glomerulosa cells. Lowering pH from 7.4 to 6.8 increased AII binding 20.5% and increased maximal All-stimulated aldosterone secretion 43%. By contrast, at pH 8.0, All binding and stimulation of aldosteronogenesis fell by 56.6% and 39%, respectively. Effects on All binding intermediate to these changes were observed at pH 7.1 and 7.7. Similar effects of altered pH were observed on All binding to a crude membrane fraction of bovine glomerulosa cells. Analysis indicated that pH primarily affected receptor number rather than affinity. In studies of proposed postreceptor mediators of All actions, pH had no effect on All stimulation of phosphatidylinositol turnover or All inhibition of calcium influx. The results show that pH affects All interaction with its receptors. The larger magnitude of the change in aldosterone compared with receptor binding suggests that a postreceptor step is also altered by pH; however, this postreceptor step is not reflected in calcium influx or phospholipid turnover.
Using bicycle ergometry with computerized respiratory gas exchange measurements, we compared exercise capacities in patients with various neuromuscular diseases to those in normal controls. As expected, male and female patients had significantly reduced maximum work capacities (kilopond-meters per minute per kilogram of body weight) and maximal oxygen consumptions. The oxygen cost of exercise was normal in the majority of patients, although some appeared to have abnormally high oxygen consumptions during exercise. Breathing patterns during exercise, particularly in regard to onset of hyperventilation, were similar in patients and controls.
A 38-hr fast was used as a provocative test in patients suspected of having defects in muscle substrate utilization. In five controls and nine patients, exercise capacity and respiratory exchange ratio were determined before and at the end of the fast. Blood was collected at intervals during the fast from ten controls and nine patients for creatine kinase (CK), free fatty acids, (FFA) beta-hydroxybutyrate, acetoacetate, free and total carnitine, glucose, and alanine. Two patients with myophosphorylase deficiency had increased exercise capacity, and a marked fall in CK, and one had a lesser fall in blood glucose than normal at the end of the fast. Two patients with known lipid myopathies (carnitine deficiency and carnitine palmityl transferase deficiency) had decreased exercise capacity and apparent increased dependence on carbohydrate metabolism during the fast. Carnitine concentrations became even more abnormal in the patient with carnitine deficiency during fasting. Several patients with less well-defined defects were also significantly different from the controls in several respects, indicating that the fast might be useful for finding new defects.
The response to a standardized exercise test was investigated in 12 volunteers and 13 patients with aches, cramps, and pains. In men, creatine kinase (CK) levels peaked (up to 1600 mU per milliliter) between 10 and 20 hours after exercise. High levels of blood lactate during exercise were related to the intensity of work and to high levels of CK after exercise. The patients could be divided into several groups: (1) those with no change in blood metabolites (psychogenic); (2) those with a disproportionate rise in CK (metabolic myopathies); (3) those with a disproportionate rise of lactate (mitochondrial abnormalities); and (4) in one patient with exercise-related pains, subnormal elevation of fatty acid levels. The correlation of changes in blood lactate, CK, and fatty acids may be useful, whereas an isolated measurement, even if outside the normal range, is often meaningless.
The effect of 2 hours of exercise on the serum creatine kinase (CK) level was investigated in 11 men and 9 women. The mean increase of CK 24 hours after exercise was significantly greater in men. The relative lack of CK elevation in women may: (1) indicate that female muscle is less susceptible to damage by adverse factors; and (2) explain discrepancies in previous reports.
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An infant was born with marked rigidity, a paucity of spontaneous movements, and increased serum creatine phosphokinase activity. Electromyogram was normal. A muscle biopsy, taken at the age of 7 weeks, contained numerous fibers composed of three concentric zones, warranting the designation "trilaminar fibers." Electronmicroscopy showed the innermost zone contained a densely packed collection of mitochondria, glycogen, electron opaque material, and single filaments. The middle zone consisted of myofibrils with Z-band smearing. The outer zone resembled a sarcoplasmic mass. Extrajunctional acetylcholine receptor (AChR) was present in the trilaminar fibers between the middle and outer zones. The increased muscle tone and extrajunctional AChR suggest and altered neural influence, but the markedly increased creatine phosphokinase activity is more characteristic of muscle damage. Precise definition of the nature of the defect awaits further study.
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