Joint contractures, hyperkeratosis, and severe hypoplasia of the posterior columns: a new recessive syndrome.

We report on 2 brothers with arthrogryposis, hyperkeratosis, and severe hypoplasia of dorsal roots and posterior columns in the one sib who was examined at autopsy. This appears to represent a new arthrogryposis syndrome with poor prognosis, most likely inherited as a single gene, either autosomal or X-linked recessive trait.

Effects of drugs on beta-adrenergic receptors on human lymphocytes.

The density of beta-adrenergic receptors has been determined on membranes prepared from lymphocytes of normal human volunteers. Long-term administration of propranolol resulted in an increase in the density of receptors, whereas administration of the agonists ephedrine and terbutaline elicited a marked decrease in the density of receptors. These changes may explain the delayed side effects observed when propranolol administration is abruptly discontinued and the decreased efficacy that occurs during long-term administration of an agonist. In other experiments, pindolol, an antagonist with intrinsic sympathomimetic activity, was administered to normal subjects. A marked decrease in the density of receptors occurred within 1 day of administering pindolol. This effect persisted beyond the time at which pindolol administration was discontinued.

Changes in the density of beta adrenergic receptors in rat lymphocytes, heart and lung after chronic treatment with propranolol.

Abrupt withdrawal after the chronic administration of propranolol results in clinical syndromes that suggest adrenergic hypersensitivity. Furthermore, propranolol administration has been shown to lead to an increase in the density of beta adrenergic receptors on human lymphocytes. The present studies were designed to assess the relevance of changes measured in lymphocytes to changes that may occur in solid tissues. Direct measurement of the density and properties of beta adrenergic receptors in membrane fragments was performed in vitro using the radioligand [125I]iodohydroxybenzylpindolol. Chronic infusion of propranolol by s.c. implanted osmotic minipumps generated sustained plasma concentrations of propranolol sufficient to cause chronic blockade of beta adrenergic receptors. Infusion of propranolol for 7 days resulted in significant increases in the density of beta adrenergic receptors in rat ventricles, lungs and lymphocytes. A computer-assisted graphic analysis of results obtained in studies with drugs selective for beta-1 or beta-2 receptors revealed increases in the densities of both beta-1 an beta-2 adrenergic receptors. These results are consistent with the hypothesis that change in beta adrenergic receptors on lymphocytes are qualitatively similar to alterations in beta adrenergic receptors in solid tissues not routinely accessible in humans. Increases in the densities of beta-1 and/or beta-2 adrenergic receptors in solid tissues may be related to some of the untoward effects observed in humans after abrupt discontinuation of propranolol administration.

Elevation of beta-adrenergic receptor density in human lymphocytes after propranolol administration.

Abrupt withdrawal after the chronic administration of propranolol has resulted in clinical syndromes that suggest adrenergic hypersensitivity. The effect of propranolol administration and withdrawal on beta-adrenergic receptors was studied in human lymphocyte membranes. Receptor density was quantitated by direct binding assays with the radioligand [125I]iodohydroxybenzylpindolol. Administration of propranolol (160 mg/d) for 8 d resulted in trough plasma levels of approximately 35 ng/ml. By day 5 of propranolol administration the density of beta-adrenergic receptors had increased 43 +/- 4% (P less than 0.01) above pretreatment levels. Abrupt withdrawal of propranolol was followed by the disappearance of propranolol from the plasma within 24 h. The density of beta-adrenergic receptors did not return to pretreatment level for several days. Physiologic supersensitivity of beta-adrenergic receptor-mediated responses was suggested by the appearance of significant increases in the orthostatic change in heart rate (P less than 0.05) and the orthostatic change in the heart rate-systolic blood pressure product (P less than 0.01) during the first 48 h after propranolol withdrawal. These data show that propranolol administration leads to an increase in the density of beta-adrenergic receptors in human tissue. The results are consistent with the hypothesis that some of the untoward effects observed after abrupt discontinuation of propranolol are caused by beta-receptor-mediated adrenergic hypersensitivity.