Search PubMed⌕ Search

Biomedical subjects

B Cooper

Publications and source records attributed to B Cooper.

At least 163 records · Page 9Linked to original sources
PubMed1981

Clinical consequences of acquired transfusional iron overload in adults.

We assessed the clinical sequelae of transfusional iron overload in 15 nonthalassemic adults (40 to 71 years of age) with anemias requiring transfusions. Iron loading had been present for less than four years in 14 patients. The number of units of blood transfused ranged from 60 to 210 (mean, 120). Liver-biopsy specimens in 10 patients contained seven to 26 times the normal amount of iron and typically showed focal portal fibrosis. Left ventricular cardiac function was impaired in only the most heavily transfused patients or in those with coexisting coronary-artery disease, All patients had glucose intolerance associated with significantly reduced insulin output, compared with controls (P < 0.01). Pituitary reserve of ACTH was limited in 10 of 12 patients, and that of gonadotropin in five of 13. We conclude that widespread subclinical organ dysfunction can result from transfusional iron overload developing in adulthood. The pattern of organ involvement resembles that encountered in idiopathic hemochromatosis.

Adult↗
PubMed1979

Desensitization of prostaglandin-activated platelet adenylate cyclase.

Prostaglandin D2 (PGD2) is one of several prostaglandins that can inhibit platelet aggregation and activate adenylate cyclase. Platelets were exposed to varying concentrations of PGD2 washed, and the adenylate cyclase response to prostaglandins, epinephrine, and sodium fluoride determined. Incubating platelets with 5 x 10(-5) M PGD2 for 2 hr resulted in a 45% decrease in PGD2 activation of adenylate cyclase and a 25% decrease in stimulation by PGE1. Fluoride activation (7-fold) epinephrine inhibition (30%) and basal enzyme activity were unchanged by exposure of the platelets to PGD2. Desensitization was concentration dependent, with loss of enzyme activity first noted when platelets were incubated with 10(-7) M PGD2. Enzyme sensitivity could be partially restored when desensitized platelets were washed free of PGD2 and incubated in buffer for 2 hr; complete resensitization required incubation for 24 hr in plasma. Regulation of prostaglandin sensitive platelet adenylate cyclase could be of importance in mediating the response of platelets to aggregating agents.

Adenylyl Cyclases↗
PubMed1979

Characterization of the platelet prostaglandin D2 receptor. Loss of prostaglandin D2 receptors in platelets of patients with myeloproliferative disorders.

Prostaglandin (PG) D(2) is synthesized in platelets at concentrations which could inhibit aggregation via activation of adenylate cyclase. To more directly define platelet-PG interactions, a binding assay has been developed for platelet PG receptors with [(3)H]PGD(2) as ligand. [(3)H]PGD(2) binding to intact platelets was saturable and rapid with the ligand bound by 3 min at 20 degrees C. PG competed with the [(3)H]PGD(2) binding site with a potency series: PGD(2) (IC(50) = 0.08 muM) >> PGI(2) (IC(50) = 2 muM) > PGE(1) (IC(50) = 6 muM) > PGF(2alpha) (IC(50) = 8 muM). Scatchard analysis of binding data from six normal subjects showed a single class of binding sites with a dissociation constant (K(d)) of 53 nM and 210 binding sites per platelet. This PGD(2) receptor assay was then used to study platelets from five patients with myeloproliferative disorders (polycythemia vera, essential thrombocythemia, and chronic myelogenous leukemia), as over 90% of these patients have platelets resistant to the effects of PGD(2) on aggregation and adenylate cyclase activity (1978. Blood.52: 618-626.). In the presence of 50 nM [(3)H]PGD(2), the patients' platelets bound 7.1+/-2.9 fmol ligand/10(8) platelets compared with 15.1+/-1 fmol/10(8) platelets in normals, a decrease of 53% (P < 0.01). Scatchard analysis showed that the K(d) of [(3)H]PGD(2) binding (33 nM) was comparable to normal platelets, which indicates that the decreased PGD(2) binding in these platelets represented fewer receptors rather than altered affinity of the ligand for the binding site. The 53% decrease in [(3)H]PGD(2) binding correlated with a 48% decrease in PGD(2)-activated platelet adenylate cyclase. The characterization of the platelet PGD(2) binding site provides further direct evidence that there are at least two PG receptors on platelets, one for PGE(1) and PGI(2), and a separate receptor for PGD(2). Direct binding analysis will be a useful tool for studying the role of PG in regulating platelet function, as demonstrated by the selective loss of PGD(2) binding sites in patients with myeloproliferative disorders.

Adenylyl Cyclases↗
PubMed1979

Loss of Rh antigen associated with acquired Rh antibodies and a chromosome translocation in a patient with myeloid metaplasia.

Myeloid metaplasia is a clonal disease of the marrow pluripotent stem cell in which a constant cytogenetic abnormality could result in an altered antigenic characteristic of hematopoietic cells. A 57-yr-old man who had acquired myeloid metaplasia at age 37 was noted to be Rh negative, although blood typing at age 33 was Rh positive. His erythrocytes reacted with anti-c and anti-e, typical for an Rh negative individual. Analysis of 11 metaphase bone marrow cells by G-banding revealed 46 chromosomes with a consistent anomaly in 100% of cells involving chromosomes 1 and 13. The changes were consistent with a reciprocal translocation, with break points at approximately 1p32 and 13q22, although break points at 1p13 and 13q14 were also possible. Since previous cytogenetic data have localized the Rh gene to the short arm of chromosome 1, our data indicate the Rh gene lies within the segment u13 leads to 1p32. Serum of this patient had circulating anti-D and anti-C antibodies. Consequently, this patient lost immunologic tolerance to a "self antigen" after losing the ability to express this antigen.

Chromosome Mapping↗
PubMed1979

Diminished platelet adenylate cyclase activation by prostaglandin D2 in acute thrombosis.

Prostaglandin D2 (PGD2) produced by platelets can inhibit aggregation via activation of platelet adenylate cyclase. PGD2 activation of platelet cyclase in platelet membrane fractions was studied in 20 consecutive patients hospitalized with acute deep-vein thrombosis and/or pulmonary embolism. In nine patients, PGD2-stimulated enzyme activity was decreased at all concentrations of PGD2 studied. This altered enzyme sensitivity was specific for PGD2 as basal enzyme activity, and prostaglandin E1, prostaglandin I2, and sodium fluoride stimulated adenylate cyclase was normal. The effect of PGD2 on platelet aggregation and 14C-serotonin release was also studied in one patient where a four-fold higher concentration of PGD2 was required to inhibit collagen-induced 14C-serotonin release. Binding studies using [3H]PGD2 as a radioligand indicated that this patient's platelets bound 10 fmole PGD2/10(8) platelets compared to 30 fmole/10(8) platelets in a normal control. Five patients had follow-up studies between 2 and 7 mo after their acute thrombotic event, and PGD2-stimulated adenylate cyclase activity returned towards normal in four. Since PGD2 is synthesized in platelets at concentrations sufficient to inhibit aggregation and activate adenylate cyclase, diminished platelet sensitivity to this prostaglandin could result in "hyperactivity" and contribute to the thrombosis observed in these patients.

Adenylyl Cyclases↗
PubMed1978

Characterization of the human platelet alpha-adrenergic receptor. Correlation of [3H]dihydroergocryptine binding with aggregation and adenylate cyclase inhibition.

Human platelets aggregate and undergo a release reaction when incubated with catecholamines. Indirect evidence indicates that these events are mediated through alpha-adrenergic receptors. We used [(3)H]dihydroergocryptine, an alpha-adrenergic antagonist, to identify binding sites on platelets that have the characteristics of alpha-adrenergic receptors. Catecholamines compete for the binding sites in a stereo-specific manner with the potency series of (-) epinephrine > (-) norepinephrine > (+/-) phenylephrine > (-) isoproterenol. The dissociation constant (K(d)) of (-) epinephrine is 0.34 muM. Binding is saturable using a platelet particulate fraction but not with intact platelets. There are 0.130 pmol binding sites per milligram protein in fresh platelet membranes. This number represents approximately 100 binding sites per platelet. The K(d) for [(3)H]-dihydroergocryptine was 0.003-0.01 muM. The alpha-adrenergic antagonist phentolamine (K(d) = 0.0069 muM) was much more potent than the beta-adrenergic antagonist (+/-) propranolol (K(d) = 27 muM) in competing for the binding sites. The binding data were correlated with catecholamine-induced platelet aggregation and inhibition of basal and prostaglandin E(1)-stimulated adenylate cyclase. (-) Epinephrine was more potent than (-) norepinephrine in producing aggregation whereas (-) isoproterenol was ineffective. The threshold dose for inducing aggregation by (-) epinephrine was 0.46 muM. Phentolamine and dihydroergocyrptine blocked this response, whereas (+/-) propranolol had no effect. (-) Epinephrine and (-) norepinephrine inhibited basal and prostaglandin E(1)-stimulated adenylate cyclase in a dose-related manner. The concentration of (-) epinephrine inhibiting adenylate cyclase 50% was 0.7 muM. This inhibition was also blocked by phentolamine and dihydroergocryptine but not by (+/-) propranolol. The specificity of binding and the close correlation with alpha-adrenergic receptor-mediated biochemical and physiological responses suggest that the [(3)H]dihydroergocryptine binding site represents, or is closely related to, the human platelet alpha-adrenergic receptor. The ability to assay this receptor directly and to correlate these data with independently measured sequelae of receptor activation should facilitate increased understanding of the physiology and pathophysiology of the human platelet alpha-adrenergic receptor.

Adenylyl Cyclase Inhibitors↗