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Biomedical subjects

Z Farfel

Publications and source records attributed to Z Farfel.

At least 91 records · Page 5Linked to original sources
PubMed1986

A variant of the "DIDMOAD" syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness).

A 29-year-old female with diabetes insipidus, deafness, a visual disorder and an abnormal glucose tolerance test, who gave birth to a healthy baby is described. Her male sibling is probably also similarly affected. These patients may represent previously unreported variants of the "DIDMOAD" (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness) syndrome. This is the first reported case of childbirth in an affected patient.

Adult↗
PubMed1986

Mental deficiency in pseudohypoparathyroidism type I is associated with Ns-protein deficiency.

Pseudohypoparathyroidism type I is a hereditary disorder characterized by resistance to parathyroid hormone and other hormones that work via cyclic adenosine 3', 5'-monophosphate (cAMP). Most patients with this disorder have generalized deficient activity of Ns-protein (type Ia), which couples stimulatory hormone receptors to catalytic adenylate cyclase. In patients with normal Ns-protein activity (type Ib), a decreased incidence of resistance to hormones other than parathyroid hormone exists. Mental deficiency of unknown cause occurs in 47% to 75% of all patients with pseudohypoparathyroidism type I. Because mutations in the adenylate cyclase-cAMP system may affect the learning ability of Drosophila flies, we assessed mental deficiency in 25 patients whose Ns-protein activity we had determined: 9 of 14 patients with type Ia disorder and 0 of 11 patients with type Ib disorder had mental deficiency. We suggest that Ns-protein deficiency, reduced cAMP levels, or both, are involved in the mental deficiency in these patients and probably in mental function in humans.

Adolescent↗
PubMed1986

Serum theophylline concentrations are not affected by coadministration of doxycycline.

Doxycycline (D) is often administered during respiratory infections to asthmatic patients, many of them treated by theophylline (T) as well. We therefore investigated a possible interaction between D and T. Steady-state basal T levels were measured on two successive days before and after three and four days of D administration in ten stable asthmatic patients. Mean T levels before D were 9.9 +/- 3.1 micrograms/mL and after D 10.1 +/- 2.9 micrograms/mL, which are not significantly different. But T levels in four patients increased and in two patients, T levels decreased. We conclude that in some patients, T concentrations may be affected by D. This may require determination of T blood levels and T dose adjustment in some patients treated by T and D.

Adolescent↗
PubMed1985

Bordetella pertussis invasive adenylate cyclase. Partial resolution and properties of its cellular penetration.

The existence of an invasive adenylate cyclase in dialyzed urea extracts of the bacterium Bordetella pertussis has been suggested recently. Gel filtration of B. pertussis dialyzed urea extract shows that the invasive enzyme constitutes only a small portion of the total adenylate cyclase activity found in the extract. Its size is different than the size of the two peaks of adenylate cyclase activity identified in the extract. Ca2+ is absolutely required for the penetration of the invasive enzyme, it also controls the rate of intracellular cAMP accumulation in human lymphocytes exposed to dialyzed extract. These characteristics may be attributed to the increase in the size of the invasive enzyme as found by gel filtration chromatography of the extract in the absence of Ca2+. Removal of nonpenetrating adenylate cyclase that adheres to lymphocytes permits a direct assay of the intracellular enzyme. The time course of intracellular accumulation of adenylate cyclase activity is similar to the time course of intracellular accumulation of cAMP, suggesting that the invasive enzyme is rapidly deactivated, but not degraded, since it can be detected upon cell disruption. No appreciable amount of the enzyme is introduced when cells are incubated with extract at 4 degrees C for 120 min, then washed and incubated further at 37 degrees C. Concanavalin A inhibits cAMP accumulation irrespective of the time of its addition, and EGTA prevents penetration of the invasive enzyme even if added 20 min after addition of extract. These findings are different from those observed in other bacterial toxins thought to be internalized by receptor-mediated endocytosis. However, the cellular penetration of B. pertussis adenylate cyclase is cell-selective. It does not occur in human erythrocytes. In addition to human lymphocytes, S49 cyc- murine lymphoma, turkey erythrocytes, and rat oocytes accumulate cAMP in response to B. pertussis extract.

Adenylyl Cyclases↗
PubMed1985

Mechanism of warfarin potentiation by amiodarone: dose--and concentration--dependent inhibition of warfarin elimination.

Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.

Adult↗
PubMed1985

Beta-adrenergic receptors on polymorphonuclear cell membranes in essential hypertension.

Beta adrenergic receptor binding sites were determined and characterized by specific binding of (+/-)[125I] iodocyanopindolol to membranes obtained from circulating polymorphonuclear leukocytes. No difference was found in the number of receptor sites and in their dissociation constants (Kd) between patients with untreated essential hypertension (EH), EH treated with drugs other than beta blockers, and in normotensive controls. The group with EH receiving treatment with beta blockers had a significantly higher receptor density and Kd as compared with all the other groups (p less than 0.05). It is concluded that the beta-adrenergic system of patients with essential hypertension at the receptor level is not different from normotensive subjects and responds to beta blockers by up-regulation.

Adult↗
PubMed1984

Receptor-cyclase coupling protein in erythrocytes of patients with essential hypertension.

In order to define the alteration of the function of the adrenergic system in hypertension, we studied directly the receptor-cyclase coupling protein (N protein), which is one of the components of the enzyme adenylate cyclase. N protein was determined in erythrocyte membranes of patients with essential hypertension and normal subjects, with a complementation assay in vitro. Fifteen normal subjects and 18 patients with essential hypertension (eight untreated and ten treated with beta-adrenoreceptor blocking drugs alone or in combination with other antihypertensive drugs), and two patients with pseudohypoparathyroidism type Ia (known to have deficient N protein activity), were studied. Erythrocyte N protein activities in the various groups expressed as percentages of the means +/- SD of normals were: normal subjects 100 + 13.7, untreated hypertensive 108.9 +/- 20.4, treated hypertensive 104.3 +/- 11.3 and pseudohypoparathyroidism type Ia 43%. The difference between N protein activity in the hypertensive patients and normals was not statistically significant. We suggest that the molecular basis for the altered sympathetic responsiveness in essential hypertension may reside in other components of the cyclic AMP protein kinase effector system.

Adolescent↗
PubMed1984

Adenylate cyclase in the maturing human reticulocyte: selective loss of the catalytic unit, but not of the receptor-cyclase coupling protein.

Hormone sensitive adenylate cyclase consists of at least three components; hormone receptor, a catalytic unit, and the N-protein, which couples the receptor to the catalytic unit. Human erythrocytes have very low adenylate cyclase activity, but do have N-protein activity. We have investigated the fate of the catalytic unit and the N protein during maturation of human reticulocytes. We compared red blood cell membranes derived from nine patients with reticulocytosis averaging 12% to erythrocyte membranes from eight normal subjects. The catalytic unit was assayed by stimulation of adenylate cyclase with forskolin, and the N-protein activity by an in vitro complementation assay. Forskolin stimulated adenylate cyclase activity was ten times higher in membranes derived from patients with reticulocytosis as compared with those of normal subjects. N-protein activity was only slightly (12%) and insignificantly (P = 0.08) higher in the reticulocytosis patients membranes. We conclude that during maturation of the human erythrocyte there is a differential loss of the catalytic unit of adenylate cyclase.

Adenylyl Cyclases↗
PubMed1983

A convenient method for measuring receptor-cyclase coupling activity in whole blood: application to Duchenne muscular dystrophy.

Activity of the guanine nucleotide-binding regulatory (N protein) component of adenylate cyclase can be measured in extracts of whole blood, using a modification of an assay previously applied to erythrocyte membranes. N protein activities in the blood of three patients with Duchenne muscular dystrophy and eight heterozygous carriers of the disease did not differ significantly from activities measured in blood of seven normal subjects. In contrast, the modified assay showed a 50% deficiency of N protein activity in blood of four patients with pseudohypoparathyroidism, type I, in whom erythrocyte studies had previously demonstrated a comparable degree of N deficiency.

Adenylyl Cyclases↗
PubMed1982

Platelets of pseudohypoparathyroid patients: evidence that distinct receptor-cyclase coupling proteins mediate stimulation and inhibition of adenylate cyclase.

We studied platelets of patients with the genetic disorder pseudohypoparathyroidism (PHP) to test whether the nucleotide-binding proteins mediating stimulation of adenylate cyclase (termed N(s)) are identical to those mediating inhibition of cyclase (termed N(i)). Functional responses to hormones that work through stimulation of adenylate cyclase are blunted in PHP patients. The erythrocytes of many of these patients (PHP-Ia) have previously been shown to have decreased N(s) activity whereas those of other PHP patients (PHP-Ib) have normal N(s) activity. We find that this decreased N(s) activity (measured by the ability to restore adenylate cyclase activity to membranes prepared from S49 cyc(-) cells) also occurs in the platelets of PHP-Ia but not of PHP-Ib patients. Platelets from both groups of patients accumulate less cAMP in response to prostacyclin than do platelets from control subjects. In contrast to the decreased N(s) function in patients with PHP-Ia, we find that N(i) function in platelets is similar in these patients and control subjects in several types of experiments: (i) epinephrine-mediated inhibition of prostacyclin-stimulated cAMP production in intact platelets; (ii) the affinity of platelet alpha(2)-adrenergic receptors for epinephrine, as determined by competition for [(3)H]yohimbine binding; (iii) the decrease in receptor affinity for epinephrine produced by Na(+) and GTP; and (iv) the concentration dependence of GTP for decreasing the affinity of these receptors for epinephrine. Because N(i) is expressed normally in platelets from patients that are genetically deficient in N(s), we conclude that N(s) and N(i) are likely to be distinct gene products.

Adenylyl Cyclases↗
PubMed1982

Deficient activity of receptor-cyclase coupling protein is transformed lymphoblasts of patients with pseudohypoparathyroidism, type I.

Erythrocytes of many patients with pseudohypoparathyroidism, type 1 (PHP-I) exhibit quantitatively reduced activity of the N protein, the guanine nucleotide-binding regulatory component of adenylate cyclase. We have designated this group of patients PHP-Ia to distinguish them from PHP-Ib patients, in whom erythrocyte N activity is quantitatively normal. In virus-transformed lymphoblasts of three normal, three PHP-Ia, and two PHP-Ib subjects, we compared N and adenylate cyclase activities, as well as cAMP accumulation and susceptibility to radiolabeling in the presence of [32P]NAD and cholera toxin. In comparison to normal lymphoblasts, N activities were reduced by approximately 50% in lymphoblasts of the PHP-Ia patients, but were not reduced in lymphoblasts from the PHP-Ib patients. Toxin-catalyzed radiolabeling of the 42,000 molecular weight subunit of the N protein was also reduced in lymphoblasts of the PHP-Ia patients. These results are consistent with the hypothesis that N deficiency is generalized in tissues of PHP-Ia patients. Deficient lymphoblast N activity in PHP-Ia was not associated with decreases in adenylate cyclase activity or cAMP accumulation, probably because these activities involve many potential regulable cellular components in addition to the N protein.

Adenylyl Cyclases↗
PubMed1981

Pseudohypoparathyroidism: inheritance of deficient receptor-cyclase coupling activity.

Pseudohypoparathyroidism, type I (PHP-I) is an inherited disorder of primary resistance to multiple hormones that work by stimulating adenylate cyclase. In an attempt to clarify the mode of inheritance of PHP-I, we measured the activity of the N protein, a receptor-cyclase coupling component, in erythrocyte membranes. Erythrocyte N-protein activity was reduced by approximately 50% in erythrocytes of 15 PHP-I patients and was normal in 19 of their clinically normal first degree relatives. Reduced N-protein activity and the PHP-I phenotype in these families exhibited both dominant and recessive patterns of inheritance. This suggests that at least two distinct genetic loci are involved in inheritance of N-protein deficiency. In two additional families, dominant inheritance of the PHP-I phenotype was associated with normal activities of erythrocyte N protein. Thus, it appears that mutation of at least one additional genetic locus, not involving the N protein, can produce PHP-I.

Adenylyl Cyclases↗
PubMed1981

Fibroblast defect in pseudohypoparathyroidism, type I: reduced activity of receptor-cyclase coupling protein.

Erythrocytes of many patients with pseudohypoparathyroidism, type I (PHP-I), exhibit reduced activity of the N protein, a guanine nucleotide-binding regulatory component of hormone-sensitive adenylate cyclase. We compared N and adenylate cyclase activities and the accumulation of cAMP in fibroblasts propagated from skin biopsies of six normal subjects and seven PHP-I patients. N activities were reduced by approximately 40% in fibroblasts as well as erythrocytes of five PHP-I patients. N activities in fibroblasts from two PHP-I patients with normal erythrocyte N activities were within the normal range. These results are consistent with the hypothesis that N deficiency is generalized in tissues of most PHP-I patients and is the primary defect responsible for their resistance to metabolic effects of hormones that work by stimulating adenylate cyclase. Fibroblast N deficiency was not associated with decreases in hormone-stimulated adenylate cyclase or cAMP accumulation in fibroblasts, probably because these activities involve many potentially regulable cellular components in addition to the N protein.

Adenylyl Cyclases↗