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Biomedical subjects

C Van Dop

Publications and source records attributed to C Van Dop.

At least 37 records · Page 2Linked to original sources
PubMed1991

Immunodetectable levels of the inhibitory guanine nucleotide-binding regulatory proteins in failing human heart: discordance with measurements of adenylate cyclase activity and levels of pertussis toxin substrate.

Human hearts with idiopathic dilated cardiomyopathy have diminished adenylate cyclase activity and increased amounts of the alpha-subunit of the inhibitory guanine nucleotide-binding regulatory protein (alpha Gi) as measured by pertussis toxin catalyzed ADP-ribosylation. We utilized specific antisera against synthetic peptides corresponding to amino sequences deduced from cDNA's encoding the three alpha Gi subspecies to compare the immunologic and bioactivity levels of Gi in failing and non-failing human hearts. The various antisera detected three peptides with Mr 42,000, 38,000, and 37,000. Only the Mr 42,000 peptide co-migrated with the pertussis toxin substrate. Although functional activity of alpha Gi was increased in the particulate fractions of the failing heart as measured by inhibition of guanine nucleotide-stimulated adenylate cyclase activity and the quantity of pertussis toxin substrate was also increased, there were not associated changes in the levels of immunodetectable Gi. Therefore, the increased functional activity of Gi in the failing human heart as assessed by adenylate cyclase measurements cannot be explained by a relative increase in the among of Gi protein.

Adenylate Cyclase Toxin↗
PubMed1991

Glucose tolerance in children with renal allografts and effect of growth hormone treatment.

We performed oral glucose tolerance tests (oGTTs) on 15 children who had functioning renal allografts received greater than or equal to 18 months previously, had adequate renal function, and had heights greater than 2.5 SD below the mean height for age. Three of the children had impaired glucose tolerance; their mean glucose levels during the last 2 hours of the oGTT were higher (p less than 0.05) than published control values. Integrated glucose concentrations correlated inversely with the prednisone dose on the first day of an alternate-day dosage schedule (R2 = 0.383) and directly with adiposity (partial R2 = 0.322). The integrated insulin concentration correlated directly with the prednisone dose on day 1 of an alternate-day regimen (R2 = 0.355) and with age (partial R2 = 0.163). In 10 children with renal transplants who had been treated with growth hormone for greater than or equal to 6 months, the mean fasting glucose concentration, integrated glucose concentration, and integrated insulin concentration during the oGTTs obtained after 6 months or 12 months of growth hormone treatment were not significantly different (p greater than 0.05) from values measured before the treatment. We conclude that increased integrated concentrations of both glucose and insulin during oGTTs in children with renal allografts correlate with the dose of prednisone administered on the first day of an alternate-day schedule, with age, and with adiposity index. Growth hormone treatment of children with renal allografts who are growing poorly does not significantly affect glucose metabolism as assessed by oGTT.

Adolescent↗
PubMed1990

Endocrinologic evaluation of children who grow poorly following renal transplantation.

Some children do not grow well following successful renal transplantation. We reviewed 25 children with renal allografts who receive regular medical care in the renal transplant program at The Children's Hospital, were less than or equal to 18 years of age, and had stable renal function. We compared children who were growing well (n = 14) with those who were growing poorly (n = 11). The children with poor growth more frequently had elevated serum creatinine concentrations (8/11 vs. 3/14). The mean age at transplantation was the same, although the duration of follow-up was shorter for the children growing well (3.3 +/- 0.5 years) than for those growing poorly (6.2 +/- 1.0 years, P less than 0.02). Eight of the children who were growing poorly underwent endocrinologic evaluation. Plasma growth hormone (GH) concentrations were measured during sleep, after arginine and L-DOPA administration, and during a 4-hr oral glucose tolerance test. In 4 patients, the maximum GH concentration was inadequate both following pharmacologic stimulation (4.0 +/- 2.6 ng/ml, n = 4) and during sleep (4.4 +/- 0.2 ng/ml, n = 3). In 2 additional patients, maximal GH concentrations were subnormal during sleep despite adequate responses during pharmacologic stimulation. In the final two patients, GH secretion was adequate both during sleep and after stimulation. All children studied had some degree of renal insufficiency with a mean creatinine clearance of 39 +/- 4 ml/min/1.73 m2. Plasma concentrations of thyroxine, thyrotropin, and IGF-I were normal for age in all eight patients. We conclude that abnormalities in GH secretion occur frequently among patients who grow poorly following successful renal transplantation. Evaluation of GH secretion may be useful in evaluating growth failure in this group of patients, and the usefulness of GH therapy should be investigated.

Adolescent↗
PubMed1990

Diminished beta-adrenergic receptor responsiveness and cardiac dilation in hearts of myopathic Syrian hamsters (BIO 53.58) are associated with a functional abnormality of the G stimulatory protein.

Previous studies have demonstrated a diminution in the bioactivity of the guanine nucleotide-binding regulatory protein that stimulates adenylyl cyclase (Gs) in hearts of the hypertrophic BIO 14.6 Syrian hamster. In this study, we measured functional activity and immunodetectable levels of Gs in a mutant strain of hamsters (BIO 53.58) that develop a dilated cardiomyopathy. Pathological studies demonstrated that 100-day-old BIO 53.58 hamsters had substantial ventricular dilation when compared with age-matched F1B controls. Additionally, these 100-day-old hamsters demonstrated diminished contractile response to beta-adrenergic receptor stimulation. The pathological and hemodynamic changes were associated with defective coupling of Gs to adenylyl cyclase as adenylyl cyclase activation was distinctly decreased in the presence of isoproterenol, fluoride ion, guanine nucleotides, and forskolin. Additionally, the ability of the alpha-subunit of Gs to reconstitute isoproterenol-stimulated adenylyl cyclase activity in S49 cyc- membranes was reduced approximately 65%. By contrast, cyc- complementation assays did not reveal a difference between the functional activity of Gs in hearts from 30-day-old BIO 53.58 hamsters and F1B controls. Furthermore, beta-adrenergic receptor stimulation of adenylyl cyclase in the membranes of the young BIO 53.58 hamsters was not significantly different from controls. The substantial alterations in Gs bioactivity in hearts of the 100-day-old BIO 53.58 hamsters was not associated with alterations in the immunodetectable levels of either alpha Gs or alpha Gi on Western Blots. These results suggest that G protein changes are associated with ventricular dilation in BIO 53.58 hamsters and that G protein levels are not always reflective of G protein bioactivity.

Adenylyl Cyclases↗
PubMed1989

Altered expression of alpha-subunits of G proteins in failing human hearts.

We have recently demonstrated that the activity of the inhibitory guanine nucleotide-binding regulatory protein Gi is increased in the hearts of patients with idiopathic dilated cardiomyopathy. We determined whether altered Gi protein levels in the failing human heart correlate with changes in steady state levels of the mRNA encoding one of the alpha Gi peptides. cDNAs encoding alpha Gs, alpha Go, and three subspecies of alpha Gi were used as hybridization probes to quantify steady state levels of mRNA encoding these alpha G peptides in failing and non-failing human heart. The lengths of the mRNAs that encode each alpha G peptide were the same in non-failing and failing hearts. Steady state levels of mRNA encoding both alpha Gi-3 and alpha Gs were significantly increased in the failing hearts when compared to non-failing hearts. By contrast, there was no significant change in the levels of mRNA encoding alpha Go or of rRNA. The relative abundance of the mRNA encoding each of the subspecies of alpha Gi was different in the human heart; alpha Gi-3 mRNA was abundant, alpha Gi-2 was barely detectable, and we were not able to detect alpha Gi-1 utilizing our hybridization conditions. These results suggest that alterations at the level of transcription as well as post-translational modifications can affect the activities of transmembrane signaling proteins in chronic congestive heart failure.

Adult↗
PubMed1989

Two distinct areas of unequal crossingover within the steroid 21-hydroxylase genes produce absence of CYP21B.

We mapped crossover sites in chimeric, recombinant CYP21 genes from six patients with salt-losing congenital adrenal hyperplasia (CAH). Nucleotide sequences unique to the CYP21A pseudogene or to the active CYP21B gene were mapped using gene-specific restriction sites and oligonucleotide hybridizations. Each chimeric CYP21 gene in the CYP21-deletion linked haplotypes contained sequences near the 5' end that were characteristic of CYP21A and only a single transition from sequences of CYP21A to those of CYP21B at the 3' end. The transitions all occurred within either of two discrete regions (+470 to +999 and +1375 to +1993). All eight chimeric CYP21 genes coupled with HLA-Bw47 in five unrelated patients had the CYP21A-CYP21B sequence transition within the same gene region (+1375 to +1993). One of the three other "CYP21B deletion" haplotypes (HLA-B7) had a sequence transition within this same region, while in the other two haplotypes (HLA-B61 and HLA-B18) the transition occurred between base pairs +470 and +999. By contrast, both CYP21 genes in a haplotype containing a gene conversion of CYP21B to CYP21A contained apparent transitions between sequences of CYP21A and CYP21B. We conclude that a single, unequal crossingover between the CYP21A and the CYP21B genes yields deletion of the active CYP21 gene and salt-losing CAH and that these crossingovers do not occur randomly within the CYP21 genes of our patients.

Adrenal Hyperplasia, Congenital↗
PubMed1989

Decreased bioactivity of the guanine nucleotide-binding protein that stimulates adenylate cyclase in hearts from cardiomyopathic Syrian hamsters.

We investigated regulation of cardiac adenylate cyclase in 29-d-old BIO 14.6 Syrian hamsters, which inherit cardiomyopathy as an autosomal recessive trait. Pharmacologic stimulation of adenylate cyclase in cardiac membranes with isoproterenol, fluoride ion, guanine nucleotide, forskolin, and manganous ion indicated that there was defective coupling of the guanine nucleotide-binding protein that stimulates adenylate cyclase (Gs) to adenylate cyclase. Cyc complementation assays revealed congruent to 50% less Gs activity in cardiac and skeletal muscle from cardiomyopathic hamsters. Despite this decrease in functional Gs, there were no changes in immunologic levels of the alpha-subunit of Gs (alpha Gs) or in levels of mRNA encoding alpha Gs. The defect in Gs bioactivity was limited to cardiac and skeletal muscle, occurred only in animals homozygous for the dystrophic trait, and was demonstrable before any cardiac abnormalities were evident on light microscopy. By contrast, cardiac levels of beta-adrenergic receptors were not different in cardiac membranes from BIO 14.6 hamsters. We conclude that a functional defect in alpha Gs may contribute to a contractile abnormalities in the cardiomyopathic BIO 14.6 hamster. However, the etiology of the alpha Gs defect remains obscure.

Adenylate Cyclase Toxin↗
PubMed1989

Multiple effects of ethanol on cardiac adenylate cyclase.

We characterized the effects of ethanol on the activators of adenylate cyclase complex that act through the receptor site, the stimulatory guanine nucleotide-binding regulatory protein (Gs), or the catalytic unit. Ethanol had no effect on adenylate cyclase activity stimulated by Mn2+, a selective activator of the catalytic unit, whereas high concentrations of ethanol inhibited both basal and isoproterenol-stimulated adenylate cyclase. In contrast, in the presence of nonhydrolyzable GTP analogs, ethanol potentiated substantial increases in adenylate cyclase activity. In the presence of these GTP analogs, ethanol increased the Vmax without altering the affinity of adenylate cyclase for ATP. Ethanol also increased adenylate cyclase activity in membranes in which Gs had been preactivated with isoproterenol plus a nonhydrolyzable GTP analog, suggesting that ethanol enhanced the interaction between activated Gs and the catalytic unit. Paradoxically, the ability of cholera toxin and NAD+ to augment adenylate cyclase activity through an effect on Gs was attenuated by increasing concentrations of ethanol. These results suggest that acute exposure to ethanol has multiple effects on cardiac membrane adenylate cyclase.

Adenosine Diphosphate↗
PubMed1988

Pseudopseudohypoparathyroidism with spinal cord compression.

We describe a patient with pseudopseudohypoparathyroidism who had an osseous tubercle on the anterolateral margin of the foramen magnum causing compression of the spinal cord. This patient had no evidence for any endocrinopathies and had no other spinal canal anomalies. We suggest that the morphologic phenotype found in patients with pseudopseudohypoparathyroidism, also known as Albright's hereditary osteodystrophy, has an associated risk for spinal cord compression due to congenital vertebral anomalies. The poor recovery of neurologic function following spinal decompression mandates prompt recognition and therapy of this condition in patients with Albright's hereditary osteodystrophy.

Adolescent↗
PubMed1988

Restriction fragment analysis of duplication of the fourth component of complement (C4A).

The two genes encoding the fourth component of complement (C4A and C4B) reside between HLA-B and HLA-DR on human chromosome 6. Two kilobases downstream from each C4 gene lies a 21-hydroxylase gene (CA21HA and CA21HB, respectively). Utilizing the method of Southern blotting and a 5'-end 2.4-kb BamHI/KpnI fragment of the C4 cDNA, we have analyzed TaqI-digested DNA from four pedigrees with one or more extended haplotypes containing a C4A duplication, as demonstrated by protein electrophoresis and segregation analysis. Two C4A protein duplications (C4A*2,A*3,C4B*QO and C4A*3,A*5,C4B*QO) segregated with two large TaqI DNA restriction fragments (7.0 and 6.0). In pedigree Fi, one individual homozygous for HLA-A3,B35,C4,DR1,DQ1,BFF,C2C,-C4A2,3,C4BQO had TaqI 7.0- and 6.0-kb restriction fragments with equal hybridization intensities as measured by two-dimensional densitometry (7.0/6.0 kb = 0.83, SD = 0.12, N = 7). A hybridization probe for the 21-hydroxylase gene also demonstrated equal gene dosage (CA21HA/CA21HB = 1.01). DNA from another individual (Ma I-2) with a different C4A gene duplication (C4A*3,A*5,C4B*QO) also had equal densitometry measurements (7.0/6.0 kb = 1.07). We conclude that two extended haplotypes from unrelated pedigrees have two C4 genes and both C4 genes encode separate C4A alleles. These findings are compatible with a gene conversion event of C4B to C4A.

Adrenal Hyperplasia, Congenital↗
PubMed1988

Genetic deficiency of the alpha subunit of the guanine nucleotide-binding protein Gs as the molecular basis for Albright hereditary osteodystrophy.

Patients who have pseudohypoparathyroidism type I associated with Albright hereditary osteodystrophy commonly have a genetic deficiency of the alpha subunit of the G protein that stimulates adenylyl cyclase (alpha Gs) (ATP pyrophosphate-lyase, EC 4.6.1.1). To discover the molecular mechanism that causes alpha Gs deficiency in these patients, we examined eight kindreds with one or more members affected with Albright hereditary osteodystrophy or pseudohypoparathyroidism and alpha Gs deficiency. In these families, alpha Gs deficiency and the Albright hereditary osteodystrophy phenotype were transmitted together in a dominant inheritance pattern. Using a cDNA hybridization probe for alpha Gs, restriction analysis with several endonucleases showed no abnormalities of restriction fragments or gene dosage. RNA blot and dot blot analysis of total RNA from cultured fibroblasts obtained from the patients revealed approximately equal to 50% reduced mRNA levels for alpha Gs in affected members of six of the pedigrees but normal levels in affected members of the two other pedigrees, compared to mRNA levels in fibroblasts from unaffected individuals. By contrast, mRNA levels encoding the alpha subunit of the G protein that inhibits adenylyl cyclase were not altered. Our findings suggest that several molecular mechanisms produce alpha Gs deficiency in patients with pseudohypoparathyroidism type Ia and that major gene rearrangements or deletions are not a common cause for alpha Gs deficiency in pseudohypoparathyroidism type I.

Cell Membrane↗
PubMed1988

Increase of the 40,000-mol wt pertussis toxin substrate (G protein) in the failing human heart.

Human heart failure is associated with a diminished contractile response to beta-adrenergic agonists. We hypothesized that alterations in the activity of a guanine nucleotide-binding regulatory protein (G protein) might be partially responsible for this abnormality. We therefore measured the activity of G proteins in failing human myocardium utilizing bacterial toxin-catalyzed ADP ribosylation. The activity of a 40,000-mol wt pertussis toxin substrate (alpha G40) was increased by 36% in failing human hearts when compared with nonfailing controls. In contrast, there was no change in the level of the stimulatory regulatory subunit (Gs). The increased activity in alpha G40 was associated with a 30% decrease in basal as well as 5'-guanylyl imidodiphosphate-stimulated adenylate cyclase activity. These data suggest that increased alpha G40 activity is a new marker for failing myocardium and may account at least in part for the diminished responsiveness to beta 1-adrenergic agonists in the failing human heart.

Adenosine Diphosphate Ribose↗
PubMed1987

NAD+-mediated stimulation of adenylate cyclase in cardiac membranes.

NAD+ significantly enhances adenylate cyclase activity in crude cardiac membrane preparations. This increase is dose-dependent, does not occur in the presence of nicotinamide, ADP-ribose or NADP+, and can be effected by a 30 min pre-incubation period with NAD+. Time course studies are consistent with an enzymatically mediated modification that used NAD+ as substrate. Furthermore, inhibition of NAD+-mediated activation by arginine suggests that this modulation of cardiac adenylate cyclase is analogous to that catalyzed by endogenous ADP-ribosyl transferases.

Adenosine Diphosphate Ribose↗