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Biomedical subjects

B A Cooper

Publications and source records attributed to B A Cooper.

At least 19 recordsLinked to original sources
PubMed1995

Inhibition of the oncogene product p185erbB-2 in vitro and in vivo by geldanamycin and dihydrogeldanamycin derivatives.

The erbB-2 oncogene encodes a transmembrane protein tyrosine kinase which plays a pivotal role in signal transduction and has been implicated when overexpressed in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the quinoid moiety of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2 (FRE/erbB-2). Specifically, dosed intraperitoneally at 100 mg/kg, 17-(allylamino)-17-demethoxygeldanamycin and other 17-amino analogs were effective at reducing p185 phosphotyrosine in subcutaneous flank FRE/erbB-2 tumors. Modifications to the 17-19-positions of the quinone ring revealed a broad structure-activity relationship in vitro.

Animals↗
PubMed1995

erbB-2 oncogene inhibition by geldanamycin derivatives: synthesis, mechanism of action, and structure-activity relationships.

Overexpression of the erbB-2 oncogene has been linked to poor prognosis in breast, ovarian, and gastric cancers. Naturally occurring benzoquinoid ansamycin antibiotics herbimycin A, geldanamycin (GDM), and dihydrogeldanamycin were found to potently deplete p185, the erbB-2 oncoprotein, in human breast cancer SKBR-3 cells in culture. Chemistry efforts to modify selectively the ansa ring of GDM afforded derivatives with greater potency in vitro and in vivo. Analogs demonstrated inhibition of p185 phosphotyrosine in cell culture and in vivo after systemic drug administration to nu/nu nude mice bearing Fisher rat embryo cells transfected with human erbB-2. Functional group modification in the ansa ring was performed stereoselectively and regiospecifically without the need for protection strategies. Essential functional groups that were required for anti-erbB-2 activity were the 7-carbamate and the 2,3-double bond. Modification of the functional groups at the other positions was permitted. Structure-activity relationships are described for 1-5-, 7-9-, 11-, 15-, and 22-substituted geldanamycins.

Animals↗
PubMed1994

Outcome of very low birth weight infants: multiple gestation versus singletons.

OBJECTIVE: Multiple gestation infants are overrepresented in intensive care nurseries, and have been reported to have greater morbidity than singletons. A cohort of very low birth weight infants was examined to determine outcome of premature infants based on gestation type (multiple or single) and hypothesized that at this low birth weight, the outcome of the groups would be similar. METHOD: The sample was composed of all infants with birth weights < or = 1250 g born in a 10-year period (September 1977 through September 1987). Ninety-two percent (n = 364) of the infants discharged were seen at 1 year of age, and 73% (n = 249) were observed to school age. Morbidity was assessed by neurodevelopmental examinations and standard developmental tests. RESULTS: At 1 year of age and at school age, there were no differences in neurologic or neurosensory outcome between multiple gestation and single gestation infants. Logistic regression analyses were performed on the school age data, using cognitive outcome as the dependent variable and gestation type, birth weight, gestational age, intracranial hemorrhage, chronic lung disease, and a social risk factor as predictor variables. Gestation type was not associated with cognitive outcome at school age. Social risk factors and chronic lung disease showed an association with cognitive outcome at school age. CONCLUSIONS: Multiple gestation was not related to increased morbidity in this very low birth weight group. The developmental outcome of all infants with birth weights < or = 1250 g in this study was related to medical and social risk factors. These findings were consistent for a large group of infants over a 10-year period.

Developmental Disabilities↗
PubMed1994

Homocysteine: relationship to serum cobalamin, serum folate, erythrocyte folate, and lobation of neutrophils.

Serum levels of total homocysteine were studied in the following: 26 healthy adults; 79 hospitalised patients in whom serum cobalamin, serum folate, and erythrocyte folate were greater than 230 pmol/L, 12 nmol/L, and 600 nmol/L, respectively; 32 hospitalised patients whose serum cobalamin was less than 147 pmol/L, compared to 25 patients whose serum cobalamin was greater than 147 pmol/L but unmatched in any other parameter; and 194 patients in whom samples were sent for determination of cobalamin and folate from a neurological service. None of this last group had megaloblastic anaemia. There was a relationship between the elevated concentrations of total homocysteine in serum and low concentrations of serum cobalamin and of erythrocyte folate. This relationship was most evident in samples with serum cobalamin < 86 pmol/L and erythrocyte folate < 335 nmol/L, although elevated homocysteine levels were found in some samples where serum cobalamin and erythrocyte folate levels were greater than these. Serum folate correlated poorly with serum total homocysteine. There was only a poor-to-fair correlation of neutrophil lobe counts to total serum homocysteine.

Adult↗
PubMed1991

Lysosomal cobalamin accumulation in fibroblasts from a patient with an inborn error of cobalamin metabolism (cblF complementation group): visualization by electron microscope radioautography.

Cobalamin (Cbl, vitamin B12) bound to transcobalamin II (TCII) enters cultured fibroblasts by receptor-mediated endocytosis. Following degradation of the TCII, Cbl is subsequently found in either the cytoplasm bound to methionine synthase or in the mitochondria bound to methylmalonyl CoA mutase. In fibroblasts from patients belonging to the cblF complementation group, Cbl is found free in the cell and is not transferred to the above two target enzymes. Quantitative EM radioautography was utilized to visualize intracellular Cbl in fibroblasts from cblF patients and from normal subjects. In cblF cells, 60% of all silver grains were assigned to lysosomes, with only 12.6% over cytoplasm and 1.2% over mitochondria. In contrast, in control cells, only 4.7% were assigned to lysosomes, with 47% to cytoplasm and 23.4% to mitochondria. Subcellular fractionation showed that in cblF cells, the majority of label was associated with clearly recognizable lysosomes. These studies conclusively demonstrate that secondary lysosomes accumulate Cbl in cblF disease.

Autoradiography↗
PubMed1991

The use of the Lanthony New Color Test in determining the effects of aging on color vision.

The primary purpose of this study was to collect data on the loss of color vision as a function of age. The Lanthony New Color Test (NCT), which measures acquired losses of color vision in the dimensions of hue, saturation, and brightness, was used to compile data on 68 subjects. The minimum number of subjects were 10 per decade from age 30 to 90 years. An age gradient of selective loss of discrimination of saturation beginning at age 50 was demonstrated, with rapid change noted after age 60. Similar findings were seen for hue but were not evident for brightness. By age 70, a neutral zone emerged at blue/purple, Munsell chroma level 2. The instrument was shown to be reliable and valid in comparison to the Farnsworth Dichotomous Panel D.15. It is seen that this information will provide a basis for planning safer, more functional environments for elderly people.

Adult↗
PubMed1991

Barrier-free design: a review and critique of the occupational therapy perspective.

This review of the occupational therapy literature on barrier-free design identifies both a paucity of related occupational therapy research on the topic and a lack of a common conceptual base with which to guide the development and use of environmental assessments. Nonetheless, two fledgling themes can be extrapolated: the consistent reference to the concepts of accessibility, mobility, function, and safety and an increased awareness among occupational therapists regarding the accessibility standards developed by the American National Standards Institute (ANSI) (ANSI, 1971, 1980). A problem-solving model suggested by designers for the 1979 revision of ANSI standards that incorporates these conceptual themes is described and discussed.

Activities of Daily Living↗
PubMed1990

Methylmalonic aciduria due to a new defect in adenosylcobalamin accumulation by cells.

A child with methylmalonic aciduria due to failure to accumulate adocbl in mitochondria has a phenotype similar to cblA disease. Deficient utilization of labeled propionate by his fibroblasts is corrected by their fusion with those from cblA patients, indicating that he belongs to a different complementation class and probably is deficient in a different gene product. The defect appears not to be due to reduced affinity of enzymes for adocbl, or for ATP, and the minimal thiol required for adocbl synthesis is not different from that of extracts of normal cells.

Amino Acid Metabolism, Inborn Errors↗
PubMed1990

Inherited disorders of vitamin B12 utilization.

Inborn errors of vitamin B12 (cobalamin) metabolism are associated with homocystinuria and methylmalonic aciduria, either alone or in combination. A number of these disorders have provided the first evidence for the existence of important steps in the transport or metabolism of cobalamin in eukaryotic cells. Eight complementation classes have been defined on the basis of somatic cell hybridization studies. Although the majority of patients present in infancy or early childhood, some are not diagnosed until adolescence or later. For some of these disorders, prenatal diagnosis and therapy with cobalamin during pregnancy has been attempted. Although only males have been described with cblE disease, all of these disorders are presumed to be autosomal recessive in inheritance. The clinical and laboratory aspects of the different complementation classes (cblA-cblG) are reviewed here.

Cells, Cultured↗
PubMed1990

Stable perfluorocarbon emulsions using XMO-10 as surfactant: potential oxygen-carrying plasma expanders.

XMO-10, a perfluorocarbon surfactant produced emulsions of a perfluorocarbon (Perfluorotripropylamine, FTPA) in vitro which were stable at a range of temperatures for at least 5 days. Most of the emulsion particles were smaller than 1 micron, and all emulsion particles were of these dimensions when the emulsification mixture included 2% lecithin. XMO-10 produced more stable emulsions with smaller particles than did PF68, a widely-used emulsifying agent. XMO-10 was toxic to cells in culture but this toxicity was reduced or abolished when the XMO-10 was emulsified with perfluorocarbon. XMO-10 and lecithin produced relatively stable emulsions of perflurodecalin. Such emulsions, if non-toxic in vivo, might permit excretion of perfluorocarbon through the lungs and thus would permit infusion of sufficient quantities of the preparations to function in oxygen transport in severely anemic animals and man.

Emulsions↗
PubMed1990

cblC disease: case report and monitoring of a pregnancy at risk by chorionic villus sampling.

We have studied the uptake of both propionate and leucine in a chorionic villus sample from a fetus at risk for cblC disease. The ratio of propionate to leucine incorporation (x 10(-3] was 3.85 +/- 0.27 (n = 8) in the at risk sample, and 2.8 +/- 0.14, and 3.1 +/- 0.15 (n = 4) in two control samples. The finding of an unaffected fetus was confirmed by the absence of methylmalonic acid in amniotic fluid or maternal urine in the second trimester, and after birth by study of cultured fibroblasts from the baby. Because of the reported variability in propionate incorporation in chorionic villus biopsies, however, we recommend that chorionic villus sampling be confirmed by amniocentesis.

Adult↗
PubMed1990

Desmopressin acetate in uncomplicated coronary artery bypass surgery: a prospective randomized clinical trial.

Bleeding in coronary artery bypass procedures increases morbidity and exposes patients to the risks associated with blood transfusion. Desmopressin acetate (DDAVP), a synthetic vasopressin analogue, may limit bleeding during cardiac surgery. In a prospective randomized trial, the authors evaluated the ability of DDAVP to reduce perioperative bleeding during uncomplicated coronary bypass operations. Sixty-two patients who underwent coronary artery bypass grafting were randomized to receive intraoperatively either a placebo or DDAVP. Both groups were similar with respect to operative characteristics and preoperative hematologic profiles, von Willebrand factor levels increased postoperatively in both placebo (2.77 +/- 1.06 versus 2.17 +/- 1.51 U) and DDAVP groups (2.75 +/- 0.94 versus 1.80 +/- 0.88 U). Only the increase in the DDAVP groups was significant (p less than 0.001). There was no difference in total blood loss between the placebo (1826 +/- 849 ml) and DDAVP groups (1716 +/- 688 ml). Total red cell transfusions were similar in placebo (3.4 +/- 1.3 units of blood) and DDAVP groups (3.6 +/- 0.8 units). These results do not support the intraoperative use of DDAVP to reduce perioperative bleeding in routine coronary artery bypass surgery.

Blood Transfusion↗
PubMed1989

Defective lysosomal release of vitamin B12 (cb1F): a hereditary cobalamin metabolic disorder associated with sudden death.

Here we report on a girl who presented with failure to thrive, developmental delay, minor facial anomalies, stomatitis, skin rashes, macrocytosis, mild homocystinemia(uria), and methylmalonic acidemia(uria). Fibroblast studies showed abnormal intracellular cobalamin (vitamin B12) metabolism. Reduced incorporation of 14C from [14C] propionate and [14C] methyltetrahydrofolate into TCA-precipitable macromolecules reflected decreased synthesis of adenosylcobalamin and methylcobalamin respectively. The diagnosis of cb1F mutation was established by demonstrating the accumulation of unmetabolized free cyanocobalamin in fibroblasts and by lack of genetic complementation with fibroblasts from the only other known cb1F patient. The defect is in the lysosomal release of endocytosed cobalamin. Administration of hydroxocobalamin resulted in clinical and biochemical improvement but sudden death occurred at age 5 months. The absence of brain pathological changes suggests that early treatment may prevent the neurological complications in cobalamin cofactor deficiency.

Female↗
PubMed1988

Identification of a unique type of thrombopathy of human platelets: defect in the exposure of active fibrinogen receptors in a patient with Friedreich's ataxia.

Platelets of a patient with Friedreich's ataxia have been investigated because of a codiagnosis of thrombasthenia. No aggregation occurred in response to adenosine diphosphate, platelet activating factor-acether, a stimulatory antiplatelet monoclonal antibody, or phorbol myristate acetate, although platelet aggregation could be induced with thrombin, the calcium ionophore A23187, or high concentrations of collagen. Shape change, adenosine triphosphate secretion, and the responses of the platelets' protein phosphorylation systems to all agonists were normal. Immunologic analysis of the patient's radiolabeled platelet surface proteins revealed normal levels of glycoproteins IIB and IIIa. However, no iodine 125-fibrinogen binding occurred after stimulation of the patient's platelets with adenosine diphosphate. In contrast, pretreatment of the patient's platelets with the proteolytic enzyme alpha-chymotrypsin resulted in the exposure of active 125I-fibrinogen binding sites. The patient's platelets exhibited normal aggregation to fibrinogen after their pretreatment with chymotrypsin and with elastases derived either from porcine pancreas or from human granulocytes. A murine monoclonal antibody directed against the human platelet membrane glycoproteins IIb and IIIa calcium-dependent epitope and rabbit polyclonal anti-human platelet membrane and human anti-P1A1 antibodies immunoprecipitated glycoproteins IIb and IIIa and a 66 kd cleavage product of glycoprotein IIIa from sodium dodecyl sulfate-Triton X-100 extracts of the patient's proteolytically treated platelets. The patient appears to exhibit a unique type of thrombopathy involving a defect in the exposure of fibrinogen receptors. The association between the neurologic disorder and the platelet defect is still unclear.

Adult↗