Biomedical subjects
J Allgrove
Publications and source records attributed to J Allgrove.
Homozygous protein C deficiency--management with protein C concentrate.
UNLABELLED: Two unrelated female infants with homozygous protein C (Pr C) deficiency are reported. Both are of U.K. Pakistani origin and in each case the parents are consanguinous. A previous sibling had died in each family. Both sets of parents were shown to be carriers. The concentration of Pr C in both infants was low at birth. Both developed necrotic skin lesions (purpura fulminans) and responded well to Pr C concentrate. Both are developing normally although one has visual impairment due to retinal artery thrombosis which occurred before treatment was commenced. Both infants are treated with intravenous Pr C concentrate administered daily by the parents at home. Studies of the half-life of exogenous Pr C in one of the patients has shown an increase from 2.7 to 10.8 h during the course of treatment thus enabling it to be administered once daily while still maintaining effective plasma concentrations. In the other patient half-life has fluctuated but Pr C is also given once daily. This is the first report of this condition being treated in this way in the United Kingdom. CONCLUSION: Infusion of Pr C is a safe and efficient way of treating infants with homozygous Pr C deficiency in the medium term.
Replacement therapy with a monoclonal antibody purified protein C concentrate in newborns with severe congenital protein C deficiency.
Protein C replacement therapy with a monoclonal antibody purified, virus inactivated protein C concentrate was carried out in nine infants (three male, six female) with severe congenital protein C deficiency and life-threatening purpura fulminans and/or thrombosis associated with disseminated intravascular coagulation (DIC). Eight infants were homozygous for protein C deficiency; one was a compound heterozygote. The treatment period varied from 22 days to three years. The half-life of protein C was found to be as short as two to three hours during activation of the coagulation system, increasing to approximately ten hours after stabilization. During the acute phase, protein C levels of 0.10 to 0.25 IU/mL were associated with elevated markers of coagulation activation indicating DIC, while protein C levels greater than 0.25 were associated with normalization of coagulation markers. No product-related side effects were reported. Episodes of bleeding or purpura recurred in all patients who were switched to oral anticoagulant therapy, necessitating reinstatement of protein C replacement therapy, either as needed to control symptoms, or on a long-term prophylactic schedule, alone or in addition to oral anticoagulation. Home treatment with protein C concentrate allowed a near-normal life-style for patients who otherwise would be hospitalized for long periods of time.
Intracranial germ cell tumours presenting with hypopituitarism. Successful treatment with chemotherapy alone.
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A homozygous deletion/insertion mutation in the protein C (PROC) gene causing neonatal Purpura fulminans: prenatal diagnosis in an at-risk pregnancy.
A novel homozygous mutation in the protein C (PROC) gene was detected in an individual with severe type I protein C deficiency who presented with neonatal Purpura fulminans. The deletion/insertion mutation found [3351del4, 3350insA] resulted in an Asn102-->Lys substitution and the removal of codon Gly103. First trimester prenatal diagnosis was performed in a subsequent pregnancy by chorionic villus sampling and PCR/direct sequencing; the foetus was shown to be heterozygous for the lesion. This diagnosis was confirmed phenotypically after the birth of a clinically healthy child.
Improved diabetic control in a district general hospital clinic.
A clinic for diabetic children was established in 1983 in a district general hospital to coordinate the changeover to a standard 100 unit insulin regimen. The children's progress was monitored for the next three years. Glycated haemoglobin A1 (HbA1c), measured at the same time each year, fell from a mean (SD) of 15.8 (4.7)% to 9.9 (2.6)% over the three years. A similar degree of improvement was seen when newly diagnosed patients were excluded from the analysis. This improvement was associated with a rise in mean (SD) insulin dosage from 0.89 (0.29) U/kg/day to 1.17 (0.35) U/kg/day. Good control was achieved more easily in children who had been diabetic for less than two years and in those who were prepubertal (particularly boys). A combination of isophane and soluble insulin appeared to be more effective than zinc and soluble insulin in maintaining good control. Ten complications of diabetes were noted in eight patients from 5.2 to 12.4 years after diagnosis. These results show that setting up a diabetic clinic for children in a district general hospital had a beneficial effect on the quality of diabetic control and such improvement may help to reduce the incidence of diabetic complications.
Fructosamine or glycated haemoglobin as a measure of diabetic control?
Glycated haemoglobin A1 (HbA1c), fructosamine, and total serum proteins were measured in 30 normal and 61 diabetic children. The normal range for HbA1c was 4.7-8.8% and for fructosamine was 0.98-1.88 mmol/l. These were similar to adult normal ranges and there were no significant age differences during childhood. There was a highly significant correlation between HbA1c and fructosamine in the diabetic children but this was lost when only concentrations within the established normal ranges were considered. Adjustment of concentrations of fructosamine for total serum proteins made no difference to the results. Changes in HbA1c and fructosamine were followed in three newly diagnosed patients and in one whose diabetes was getting worse. HbA1c decayed with a half life of 28.7 days and fructosamine decayed with a half life of 16.5 days. Fructosamine concentrations were lower than expected in the patients who were improving and higher than expected in the patient who was deteriorating. It is suggested that while fructosamine is not a direct substitute for HbA1c it may be a useful adjunct in determining whether a patient is worsening or improving in the short term. A change from HbA1c to fructosamine for routine assessment of diabetes while retaining HbA1c on selected occasions would result in some cost savings while retaining the advantages of having both assays available.
Cytochemical bioassay of parathyroid hormone in maternal and cord blood.
Parathyroid hormone and calcium were measured in plasma taken from pregnant women at term and from the umbilical veins of their infants at birth. Three assays were used to measure parathyroid hormone, a cytochemical bioassay of bioactivity and two immunoradiometric assays, one specific for the amino terminus, the other specific for the carboxy terminus of the parathyroid hormone molecule. Plasma calcium was significantly higher in the infants than in the mothers. Maternal parathyroid hormone bioactivity and the amino terminus were both slightly raised, but the carboxy terminus value was normal; these findings supported the view that late pregnancy is a time of mild physiological hyperparathyroidism. In the infants, the amino terminus was undetectable and the carboxy terminus was either undetectable or towards the lower end of the normal range: bioactivity of parathyroid hormone was considerably raised and was related to the gradient of calcium across the placenta. This suggests that the parathyroid glands are not suppressed during fetal life and that they may play an important part in the maintenance of high fetal plasma calcium concentrations.
An investigation of the biological activity of parathyroid hormone in pseudohypoparathyroidism: comparison with vitamin D deficiency.
Circulating parathyroid hormone was studied in patients with pseudohypoparathyroidism and compared with that in normal subjects and patients with hypocalcaemia due to postsurgical or idiopathic hypoparathyroidism or vitamin D deficiency. The cytochemical bioassay was used to measure bioactivity and an amino-terminal specific immunoradiometric assay was used to measure immunoreactivity. In normal subjects (n = 12) the concentration of bioactive parathyroid hormone was 1.1-5.9 pg/ml. It was higher in patients with newly diagnosed, untreated pseudohypoparathyroidism (n = 4, range 20-53 pg/ml) and similarly raised in patients with untreated vitamin D deficiency (n = 9, range 23-74 pg/ml). The degree of hypocalcaemia was similar in these two groups of patients. By contrast, the concentration of bioactive parathyroid hormone was low (less than 0.6 pg/ml) in four patients with untreated postsurgical or idiopathic hypoparathyroidism. Restoration of normocalcaemia reduced the concentrations of bioactive PTH in both pseudohypoparathyroidism and vitamin D deficiency. Thus, in this respect the parathyroid glands in both conditions appeared to respond to the circulating calcium concentration. Immunoreactive PTH was also raised in patients with untreated pseudo-hypoparathyroidism and vitamin D deficiency, but restoration of normocalcaemia did not always reduce immunoreactive PTH to normal in these patients. Thus, there can be dissociation between bioactivity and immunoreactivity even when the PTH is measured in an amino-terminal specific assay.
Hypomagnesaemia: studies of parathyroid hormone secretion and function.
Nine patients with hypomagnesaemia have been studied. Six had magnesium deficiency secondary to malabsorption or diarrhoea and three had excessive urinary losses of magnesium. Hypocalcaemia was also present in eight. Parathyroid hormone (PTH) was measured using amino-terminal and carboxy-terminal specific immunoradiometric assays and also, in one patient, using a cytochemical bioassay. Amino-terminal PTH (N-PTH) varied directly with the concentration of magnesium; carboxy-terminal PTH (C-PTH) was raised in all patients. When magnesium was injected, both N-PTH and C-PTH rose regardless of the initial concentration, indicating that hypomagnesaemia was limiting PTH secretion. The clearance of endogenous PTH was measured in one patient, after injection of magnesium. Seven minutes after reaching its peak, C-PTH had fallen to 69% and N-PTH fell to 22% of its maximum values; the initial half life of N-PTH was less than 2 min. In the same study biologically active PTH (bio-PTH) disappeared rapidly with a half-time of disappearance of 1.2 min. Responsiveness to PTH was measured by the rise in plasma cyclic 3'5'-adenosine monophosphate (cAMP) following PTH injection. The rise in plasma cAMP was inversely related to the concentrations of magnesium and PTH at the time. It is suggested that the concentration of PTH rather than the degree of hypomagnesaemia is the most important factor determining the responsiveness of target tissues to PTH in magnesium deficiency.
Biologically active parathyroid hormone in familial hypocalciuric hypercalcaemia.
Biologically active PTH (bio-PTH) has been assayed by the cytochemical bioassay in five members (three affected) of a family with typical features of familial hypocalciuric hypercalcaemia (FHH). Carboxy-terminal immunoreactive PTH was undetectable and bio-PTH was within the normal range in all the subjects regardless of whether or not they were hypercalcaemic. These results suggest that increased biological activity of circulating PTH cannot account for the hypercalcaemia of FHH.
The cytochemical bioassay of parathyroid hormone: further experience.
The procedure for the cytochemical bioassay of parathyroid hormone has been examined to improve the reliability and robustness of the assay. It has been shown that the control of the pH, at all stages of the assay, is essential. The use of the assay confirmed that the circulating level of the biologically active form of this hormone is less than one tenth of the values found by the more recent immunoassays, and is in good agreement with previously calculated values. The assay clearly distinguished between normal, hypoparathyroid and hyperparathyroid levels and allowed relative potencies to be ascribed to preparations of the hormone obtained from human, bovine and porcine sources.
Calcium homeostasis in the fetal pig.
Acute studies have been carried out with pregnant sows and their fetuses during the last 2 weeks of gestation. In blood samples obtained simultaneously it was shown that the concentrations of ionized calcium, calcitonin and parathyroid hormone (PTH) in fetal plasma were all greater than the corresponding values in maternal plasma. In contrast, the fetal concentrations of 24,25-dihydroxy vitamin D3 were lower than maternal and those of 1,25-dihydroxy vitamin D3 were not significantly different. In one experiment the circulatory level of fetal PTH was shown to be higher than in the sow by both an immunoradiometric assay and a very sensitive cytochemical assay. The latter showed the fetal: maternal ratio to be approximately three. This inappropriately high level of fetal PTH was unaffected by short term hypocalcaemic and hypercalcaemic changes in the fetal circulation. Although part of this fetal PTH may have been secreted in response to the action of beta-catecholamines released as a result of the experimental conditions, the transplacental gradient of PTH was also demonstrated in the chronically catheterized fetus. A short term period of either hypercalcaemia or hypocalcaemia induced in the mother was without consistent effect upon plasma calcium concentration in the fetus. However, an increase in ionized calcium concentration in the fetal plasma was found to follow the cessation of a period of maternal hypocalcaemia. It can be seen that the porcine fetus possesses the important elements of a calcium homeostatic mechanism, namely parathyroid hormone, calcitonin and the biologically active metabolites of vitamin D. Although the degree of independence from the mother is somewhat less than in the sheep, it is concluded that the porcine fetus is largely autonomous with respect to calcium homeostasis.
Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production.
Isolated glucocorticoid failure associated with achalasia of the cardia is described in two pairs of siblings in separate families. Defective tear production is also present in three of the patients, and one shows other signs of autonomic dysfunction. Two other families with adrenal insufficiency and achalasia are known. This unusual association probably represents a familial disorder of as yet unknown aetiology.
Cushing's disease: failure of treatment with cyproheptadine.
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Cautionary tale of a wandering tube.
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