Cyclosporine A in a case of refractory severe aplastic anaemia.

A boy, born in 1975, developed severe aplastic anaemia in 1982. Treatment with oxymetholone plus corticosteroids and later bolus methylprednisolone was ineffective. Following a 5-d course with antithymocyte globulin, a partial remission was achieved, but thrombocytopenia necessitating platelet transfusions every 10-14 d persisted. Under treatment with cyclosporine A the thrombocytopenia improved markedly, and there is no need for further transfusions. These observations combined with those reported in another case of aplastic anaemia by Stryckmans et al (1) indicate that cyclosporine A may be of value in some cases of aplastic anaemia.

Long-term effect of pancreas transplantation on diabetic hyperglucagonemia.

Pancreas isotransplantation was performed on streptozotocin-diabetic Wistar rats. To study the influence of the graft on diabetic hyperglucagonemia, immunoreactive glucagon (IRG) and its response to alanine (peak IRG) were determined in peripheral blood at intervals for up to 8 months after the transplantation. Concentrations of IRG and immunoreactive insulin (IRI) in effluent blood from host pancreas (portal vein) and graft (caval vein) were measured 4 months after the transplantation to estimate the hormone release from both organs. Following transplantation, caval IRI increased sixfold. Portal IRI increased 180% and reached 65% of the concentration observed in control rats. Peripheral basal and peak IRG were initially restored to normal, but were later increased to levels equal to those of diabetic rats. Also portal and caval IRG concentrations were similar in recipients and diabetic rats. The results show that relatively small amounts of glucagon are released from the graft, and that the exaggerated glucagon release from the host pancreas is only transiently normalized following pancreas transplantation.

Immunohistochemical, morphometric, and clinical studies of the pancreatic islets in infants with persistent neonatal hypoglycemia of familial type with hyperinsulinism and nesidioblastosis.

A new era has been started in the morphological research of the human pancreatic islet parenchyma by the introduction of immunohistochemical (IHC) and modern morphometric techniques. This statement is illustrated by a report of two infants from two families with persistent neonatal hypoglycemia with hyperinsulinism, where specimens of pancreas, obtained at subtotal pancreatectomy, were analyzed together with autopsy specimens from age-matched "controls" (cardiac malformations). It was found that a nesidioblastosis-like picture occurred in the pancreas of the "controls", at least up to 6-7 months of age, and that in IHC stained sections this was indistinguishable from that observed in the endocrine pancreas of the hypoglycemic infants. Moreover, there was no difference in the total volume density of the islet parenchyma in pancreas of controls and hypoglycemic children when analyzed by morphometry. However, an increase in the relative incidence of insulin cells was found in the hypoglycemic infants as well as a moderate reduction of glucagon cells and a marked decrease of somatostatin cells. Clinically, some alleviation of the symptoms could be obtained by administration of glucagon and somatostatin, indicating that the hypothesis is correct that a defect in the maturation of the islet parenchyma during infancy may be a main pathogenetic factor in the syndrome. The familial occurrence of the disease may be more common than previously realized.

Immunoreactive insulin in amniotic fluid from Rh-immunized women.

Immunoreactive insulin was measured in amniotic fluid from Rh-immunized women (anti-D antibody). The degree of immunization was expressed by the spectrophotometric index of the amniotic fluid and by the capillary hemoglobin concentration of the newborn. Higher levels of insulin were found in amniotic fluid from severely Rh-immunized mothers than from non-immunized, and a correlation between the degree of immunization and insulin concentration was indicated. To our knowledge this has not previously been demonstrated, and may justify some new hypotheses concerning the pathogenesis of the observed higher frequency of hyperinsulinism in babies of Rh-immunized mothers.

Gluconeogenesis in infancy and childhood. I. A method for the study of the in vivo gluconeogenesis from alanine and glycerol.

The in vivo gluconeogenesis from alanine and glycerol in infants and children was studied by an isotope method, using 14C-labeled substates with subsequent separation of the radioactive compounds by thin-layer chromatography. Seven patients, aged 2 months to 2 years 11 months, with normal carbohydrate metabolism were studied. Trace amounts of [14C]alanine were injected intravenously in four fasting patients. The 14C moved quickly from alanine to lactate, with a peak activity in lactate obtained before 5 min. From 10 min on, the label disappeared rapidly from both. An equilibrium was established between alanine and lactate, displaced towards lactate. The peak activity in glucose was reached in 10-20 min, amounting to 10% of total injected activity. In one patient, who was also studied after a meal, the disappearance rate of alanine was reduced by 50%. Despite this reduction the appearance of label in lactate was increased, whereas the amount of label in glucose was much reduced. [14C]glycerol was injected intravenously in three fasting patients. In one patient, who received only a tracer dose of glycerol, 5 times more 14C appeared in glucose than in the patients studied with [14C]alanine. In two patients receiving a glycerol load together with the [14C]glycerol, the disappearance rate of glycerol was markedly reduced, as was the conversion of carbon to glucose and lactate.

Gluconeogenesis in infancy and childhood. III. Deficiency of the extramitochondrial form of hepatic phosphoenolpyruvate carboxykinase in a case of persistent neonatal hypoglycaemia.

A deficiency of extramitochondrial form of hepatic phosphoenolpyruvate carboxykinase has been demonstrated in a boy with severe, persistent neonatal hypoglycaemia. Hepatic glucose-6-phosphatase, fructose-1.6-diphosphatase and pyruvate carboxylase were normal. The total activity of phosphoenolpyruvate carboxykinase was also normal, but the enzyme showed an abnormal subcellular distribution, virtually no activity being detected in the extramitochondrial fraction of a liver homogenate. The boy died at the age of 2 years 10 months. Autopsy revealed severe cerebral atrophy, atrophy of the optic nerve, and fatty infiltration of liver and kidney.

Gluconeogenesis in infancy and childhood. II. Studies on the glucose production from alanine in three cases of persistent neonatal hypoglycaemia.

Gluconeogenesis was studied in 3 cases of persistent neonatal hypoglycaemia. In 2 of the cases the labelling of blood glucose after i.v. injection of 1415C-alanine was reduced. In these 2 patients only 1.3-5% of the injected radioactivity was recovered in blood glucose, compared with 10% in normoglycaemic patients. The labelling of glucose from 14C-glycerol, as studied in one case, was not reduced. In this patient the labelling of blood glucose from C-alanine was improved after subtotal resection of the pancreas, and with increasing age. By the time of the isotope studies the plasma insulin was normal in all patients, and no deficiency of glucagon secretion could be detected after stimulation with an alanine load. A quantitative amino acid analysis of plasma revealed a moderate increase of some of the glucogenic amino acids. The results were interpreted as a deficiency of gluconeogenesis, probably at the phosphoenolpyruvate carboxykinase or pyruvate carboxylase step.

Persistent neonatal hypoglycaemia. A clinical and histopathological study of three cases treated with diazoxide and subtotal pancreatectomy.

Two boys and one girl developed persisting hypoglycaemia 12, 24, and 48 hours after birth. Although there was no known history of hereditary diabetes mellitus, the birth weight was high in two cases, and some additional traits of foetopathia diabetica could not be excluded clinically. All had high serum insulin levels with frank hyperinsulinaemia in one case. Glucose tolerance tests also indicated hyperinsulinism. Diazoxide (8 to 27 mg/kg) elevated the blood glucose levels, but did not prevent severe hypoglycaemic episodes. The effects of subtotal pancreatectomy were only transient. The patients have now been kept on permanent diazoxide therapy for 2-4 years at dosages slightly lower than those used before operation. No islet-cell tumour was found at the subtotal pancreatectomy. In all 3 cases, the pancreatic islets were markedly hyperplastic and of irregular shape with the occurrence of large B-cells with giant hyperchromatic nuclei and chromophobe "agranular" or sparsely granulated cells. The predominating kind of islet cells showed tinctorial features of A2-cells but--in the absence of available material set aside for ultrastructural analysis--it could not be settled whether this was a result of a proliferation of A2-cells only or of "type IV cells" as well. Against the background of previously published reports, the present cases serve to illustrate that additional accuracy of diagnosis and classification of neonatal persistent hypoglycaemia requires quantitative information about the structural changes in the pancreatic islet cells, and that this can be obtained from conventional biopsy specimens.