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Biomedical subjects

P E Graves

Publications and source records attributed to P E Graves.

At least 19 recordsLinked to original sources
PubMed2001

Factor analysis of asthma and atopy traits shows 2 major components, one of which is linked to markers on chromosome 5q.

BACKGROUND: A variety of definitions of asthma and atopy traits have been used in genetic studies. The variables used may be correlated, increasing the likelihood of type I error. OBJECTIVE: We sought to clarify and quantify phenotypes that may be characterized by related traits. Principal components and factor analysis were applied to the correlation matrix of asthma and atopy traits before linkage analysis. METHODS: Factor analysis was performed on 468 Hispanic and non-Hispanic white children enrolled in the Tucson Children's Respiratory Study, with complete information on 24 items, including skin test response to 7 allergens, total serum IgE levels, presence or absence of asthma attacks, wheezing episodes, hay fever, and cough. Factor score coefficients were then applied to all siblings (n = 877), and quantitative factor scores were derived. Single-point and multipoint nonparametric sib-pair analyses were performed to assess linkage to markers on chromosome 5q31-33. Analyses were also performed for individual items. RESULTS: Two main factors were identified: Factor I had high loadings on atopic items, including skin test responses, IgE, and hay fever, and Factor II had high loadings that included asthma diagnosis, wheezing, cough, and Alternaria species skin test response. Factors I and II were correlated at an r value of 0.19. For the quantitative factor scores, significant single-point linkage (P < .0001) was demonstrated only for atopic Factor I, and a peak multipoint LOD score of 2.7 was seen for marker D5S479. Multipoint LOD scores for individual items were 1.1 or less. CONCLUSION: These analyses suggest evidence for a locus or loci mapping to chromosome 5q31-33 associated with this composite atopic phenotype.

Asthma↗
PubMed2001

Genetic variation in beta-adrenergic receptors and their relationship to susceptibility for asthma and therapeutic response.

Our early work focused on quantitative variation in traits related to beta-adrenergic signaling: lymphocyte levels of cAMP and the binding properties of the beta-adrenergic receptor. We confirmed the work of others that the major histocompatibility locus had an effect on cAMP levels in mice and in man. The latter result was presumably due to the influence of beta-adrenergic receptors, since it was the isoproterenol-stimulated lymphocyte cAMP level that was studied. We went on to directly study beta-adrenergic receptor levels in mouse hepatic plasma membranes using dihydroalprenolol binding. We discovered a strain variation, apparently controlled by a single locus, which determined a magnesium influence on measurable levels of dihydroalprenolol binding. More recently, our group's work has focused on the human single nucleotide polymorphisms (SNPs) in the human beta2-adrenergic receptor. We found that variation at amino acid position 16 had a very marked effect on the response of subjects to albuterol. Similar trends were observed for asthmatic and nonasthmatic children, and the results were independent of baseline lung function. Our results, and those of other groups relating SNPs in the beta-adrenergic receptor to a number of responses, mostly related to asthma, are reviewed in this article.

Animals↗
PubMed2000

A cluster of seven tightly linked polymorphisms in the IL-13 gene is associated with total serum IgE levels in three populations of white children.

BACKGROUND: Increased levels of total serum IgE are a strong risk factor for the development of asthma. IgE is also involved in host defenses against parasites and fungi. Linkage of total serum IgE with markers located close to the 3 Mb cluster of cytokine genes in chromosome 5q31 has been reported. IL-4 or IL-13 are regarded as essential for IgE synthesis. OBJECTIVE: We tested whether polymorphisms in the IL-13 gene might explain the linkage between chromosome 5q31 and total serum IgE levels. METHODS: We used denaturing HPLC to detect polymorphisms in overlapping PCR fragments of the IL-13 gene including promoter and 3' untranslated regions. After sequencing was performed to identify the locations of the polymorphisms, PCR and primer-induced restriction site assays were used to genotype subjects in 3 unselected populations. RESULTS: We report here 7 polymorphisms (6 novel) in IL-13. Four of these polymorphisms are tightly linked to a variant in the terminal portion of the coding region of the gene that results in a predicted amino acid change in residue 130 (Arg130Gln). The Gln form is strongly associated (P =.000002) with increased serum IgE levels in 3 different populations comprising a total of 1399 children. Two additional polymorphisms in the promoter region of IL-13 are more loosely linked to Arg130Gln and are also less significantly associated with total serum IgE levels. CONCLUSION: These data suggest that the Arg130Gln polymorphism in IL-13, or others in close linkage with it, is associated with the development of the elevated serum IgE phenotype.

Asthma↗
PubMed1998

Linkage of circulating eosinophils to markers on chromosome 5q.

Although peripheral blood eosinophilia is strongly associated with the risk of developing asthma, genetic determinants of eosinophilia have not been extensively studied. We used sib-pair analysis to assess linkage of circulating eosinophils (as a percent of total white blood cells [WBC]) to nine markers located in chromosome 5q31-33. The study was divided into two phases. Of 246 sib pairs available for the first phase, 35 were classified as low concordant (LC) (both sibs had <= 2% circulating eosinophils), 18 were defined as high concordant (HC) (both sibs had 5% or more circulating eosinophils), and 26 were defined as discordant (one sib had <= 2% and the other sib had 5% or more circulating eosinophils). Significant evidence for linkage among low concordant sib pairs was found for several markers in the region under study, with a peak for marker D5S500 (proportion of alleles shared identical by descent [ibd] = 0.68 +/- 0.05 [mean +/- SE], p = 0.0004). A cross-validating study was done in which an additional 19 sib pairs that were low concordant for circulating eosinophils were studied. Evidence for linkage was also observed in this subset. Results were independent of current wheezing, total serum IgE levels, and other potential confounders. A multipoint analysis done for all low-concordant sib pairs available showed that the maximal logarithm of the odds favoring genetic linkage (LOD) score (2.4, p = 0.0004) was observed in correspondence with marker D5S658. We conclude that a locus or loci may be present in chromosome 5q31-33 that controls for circulating eosinophils as a proportion of total WBC.

Alleles↗
PubMed1997

Association between genetic polymorphisms of the beta2-adrenoceptor and response to albuterol in children with and without a history of wheezing.

The beta2-adrenergic receptor (beta2AR) agonists are the most widely used agents in the treatment of asthma, but the genetic determinants of responsiveness to these agents are unknown. Two polymorphic loci within the coding region of the beta2AR have been recently described at amino acids 16 and 27. It has been reported that glycine at codon 16 (Gly-16) is associated with increased agonist-promoted downregulation of the beta2AR as compared with arginine-16 (Arg-16). The form of the receptor with glutamic acid at codon 27 (Glu-27), on the other hand, has been shown to be resistant to downregulation when compared with glutamine-27 (Gln-27), but only when coexpressed with Arg-16. To assess if different genotypes of these two polymorphisms would show differential responses to inhaled beta2AR agonists, we genotyped 269 children who were participants in a longitudinal study of asthma. Spirometry was performed before and after administration of 180 microg of albuterol, and a positive response was considered an increase of >15.3% predicted FEV1. There was marked linkage disequilibrium between the two polymorphisms, with 97.8% of all chromosomes that carried Arg-16 also carrying Gln-27. When compared to homozygotes for Gly-16, homozygotes for Arg-16 were 5.3 times (95% confidence interval 1.6-17.7) and heterozygotes for beta2AR-16 were 2.3 times (1.3-4.2) more likely to respond to albuterol, respectively. Similar trends were observed for asthmatic and nonasthmatic children, and results were independent of baseline lung function, ethnic origin, and previous use of antiasthma medication. No association was found between the beta2AR-27 polymorphism and response to albuterol. These results may explain some of the variability in response to therapeutic doses of albuterol in children.

Adrenergic beta-Agonists↗
PubMed1995

Sequence variation in the 5', putative promoter of Sry and its possible relevance to the C57BL/6J-YDOM sex reversal.

Sry is the testes determining factor gene located on the Y chromosome. We sought sequence variation in potential promoter regions that might explain the gradiation in sex reversal seen when different domesticus strains are bred to C57BL/6J females since sequence variation previously found in the coding region is not sufficient to explain it. Dideoxy sequencing identified a 10 bp deletion in the 5' flanking region limited to YDOM chromosomes of weak effect. A PCR strategy to search for deletions in this region disclosed another deletion which was shown to be different by sequencing.

Animals↗
PubMed1995

Cloning of a receptor for prostaglandin F2 alpha from the ovine corpus luteum.

A complementary DNA clone encoding a functional receptor for prostaglandin F2 alpha (PGF2 alpha) has been isolated from an ovine large luteal cell complementary DNA library (prepared from day 10 mid-luteal phase RNA). This receptor, which has been designated FP, consists of 362 amino acids (M(r) = 40,982) and is a member of the family of G protein-coupled receptors. Radioligand binding studies with membranes prepared from transfected COS cells demonstrated specific 17-[3H]phenyl-trinor-PGF2 alpha binding that was displaced by prostanoids in the order of 17-phenyl-trinor-PGF2 alpha > PGF2 alpha > fluprostenol > PGD2 > PGE2 >> 8-epi PGF2 alpha. Xenopus laevis oocytes injected with RNA encoding the ovine FP receptor responded to 17-phenyl-trinor-PGF2 alpha with increased membrane chloride conductance in calcium-free medium. Northern blot analysis with RNA from day 10 corpus luteum showed a major band of approximately 6.1 kilobases. On day 14, when luteolysis usually starts, the abundance of this 6.1-kilobase band was variable between individual ewes, and on day 16, when luteolysis is underway, the message was uniformly less abundant. This variability appeared to correlate with circulating progesterone. Thus, when the progesterone level was high (days 10 and 14 depending on whether luteolysis had started), the amount of FP receptor message was high, whereas when the progesterone level was low or falling (day 16), the amount of FP receptor message decreased. We have cloned an ovine FP receptor whose expression confers appropriate functional activity in COS cells and Xenopus oocytes. Furthermore, the level of messenger RNA encoding the FP receptor is high in the midluteal phase ovine corpus luteum and decreases during luteolysis.

Amino Acid Sequence↗
PubMed1994

Phosphorus-31 metabolism of post-menopausal breast cancer studied in vivo by magnetic resonance spectroscopy.

We have studied the metabolism of 31P-containing metabolites of post-menopausal breast cancers in vivo using magnetic resonance spectroscopy (MRS) and a 5.5 cm surface coil. Spectra were acquired from 23 diameter. The spectra of the 19 previously untreated tumours had significantly higher phosphomonoester (PME) 31P relative peak areas than the normal breasts of eight post-menopausal women (11.7% and 7.7% respectively, P = 0.002). Although an increased PME relative peak area was characteristic of malignancy, PME relative peak area is similarly raised in lactating breast and, therefore, not a specific feature of cancer. An apparently lower nucleotide triphosphate (NTP) relative peak area in tumours than healthy postmenopausal breast was secondary to the differences in PME relative peak area; contamination by signal from chest wall muscle probably accounts for the ostensibly higher phosphocreatine (PCr) relative peak area of the tumours. Spectroscopy was repeated following chemotherapy in six women. An increase in PCr relative peak area was seen in all five patients who responded, but again this may represent increased contamination secondary to changes in tumour size. A fall in PME relative peak area was noted in four responders, but also one non-responder, so this finding may not be sufficiently specific to be of use clinically. Further studies are need to elucidate fully the role of MRS in breast cancer.

Adult↗
PubMed1994

Phosphorus-31 metabolism of human breast--an in vivo magnetic resonance spectroscopic study at 1.5 Tesla.

We have studied the metabolism of compounds containing 31P in normal breast using magnetic resonance spectroscopy (MRS). Spectra were acquired from non-lactating pre-menopausal breast (n = 14 women), lactating breast (n = 8) and post-menopausal breast (n = 8). The standard acquisition protocol used a 5.5 cm surface coil with the volunteer prone to minimize chest wall signal contamination. In pre-menopausal non-lactating women the phosphocreatine (PCr) peak area, expressed relative to the sum of all 31P peak areas, was negatively correlated with breast size (r = -0.56, p = 0.02) suggesting that much of the PCr signal originated from the chest wall. The phosphodiester (PDE) relative peak area was positively correlated with breast size (r = 0.71; p = 0.002). Spectra could be acquired at all phases of the menstrual cycle. In sequential examinations of five women not taking the oral contraceptive pill (OCP), phosphomonoester (PME) relative peak area was significantly lower on Week 2 than other weeks of the cycle (p = 0.03). Among pre-menopausal women no clear difference was apparent between the spectra from women taking the OCP and those not taking the OCP. Lactating breast had significantly higher PME relative peak area than non-lactating pre-menopausal breast (p = 0.02), probably reflecting the higher proportion of epithelial tissue in lactation; the lower PCr relative peak area in lactating breast (p = 0.05) is probably due to the greater size of the breast during lactation. Spectra were acquired from post-menopausal women but with a relatively low signal-to-noise ratio. The only significant difference between 31P relative peak areas of breast spectra acquired from pre- and post-menopausal women was that less PCr was detected in the post-menopausal volunteers (p = 0.03), probably as a result of differences in breast size.

Breast↗
PubMed1993

The role of equilibrium and disequilibrium in modeling regional growth and decline: a critical reassessment.

The authors critically examine a 1990 study by Alan W. Evans concerning the assumption of interregional equilibrium in recent migration research. "We here argue that Evans is unconvincing in his primary substantive argument; we provide an alternative reading of the literature that supports this assertion....[We then illustrate] the substantive issues in terms of a simple formal model that allows for both equilibrium and disequilibrium migration." The geographical focus is on the United States. A reply by Evans is included (pp. 89-97).

Americas↗
PubMed1992

An amino acid change in the DNA-binding region of Sry, found in Mus musculus domesticus and other species, does not explain C57BL/6J-YDOM sex-reversal.

Sry is the testes determining factor gene located on the Y chromosome. We have performed dideoxy sequencing or restriction enzyme digestion of Sry sequences amplified by PCR from a variety of inbred strains and species of mice. A nonconservative replacement of Thr for Isoleu at position 61 was found in Sry from the Y chromosome of Mus musculus domesticus, Mus spretus, and Mus caroli. We demonstrate that this variation is not sufficient to explain the gradiation in the sex-reversal seen when different domesticus strains are bred to C57BL/6J females.

Animals↗
PubMed1991

cDNA and deduced amino acid sequences of a dog liver cytochrome P-450 of the IIIA gene subfamily.

A 1.96 kbp cDNA encoding a male Beagle dog liver cytochrome P-450 of 503 amino acid residues (Mr 57,636) has been isolated and sequenced. The deduced amino acid sequence is 79.8%, 69.3% and 74.1% identical to the P450IIIA forms human NF25, rat PCN1 and rabbit LM3c, respectively. The amino terminal sequence is identical to the first 28 residues of the dog P450IIIA form PBD-1. Southern blot analysis yields restriction patterns consistent with IIIA gene subfamily multiplicity.

Amino Acid Sequence↗
PubMed1990

cDNA and deduced amino acid sequences of a dog hepatic cytochrome P450IIB responsible for the metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl.

The nucleotide sequence of a cDNA that codes for the major phenobarbital (PB)-inducible male beagle dog hepatic cytochrome P450 has been determined. Using a rabbit P450IIB cDNA probe (R. Gasser, M. Negishi, and R. M. Philpot, 1988, Mol. Pharmacol, 32, 22-30), a cDNA clone with a 2.6-kilobase pair insert was isolated from a lambda gt11 library prepared from hepatic mRNA from a PB-treated dog. The cloned insert was sequenced and found to contain an open reading frame coding for a polypeptide of 494 amino acids (Mr 56,183). The encoded protein can be assigned to the P450IIB subfamily on the basis of homology to cytochromes P450 from other species. The deduced amino acid sequence is 79% identical to that reported for rabbit P450 BO (P450IIB4) and 75% identical to that for rat P450b (P450IIB1). The sequence identity decreases to less than 52% when the dog sequence is compared with other P450II subfamilies. The deduced NH2-terminal 30 amino acids encoded by the dog cDNA are identical to those determined by sequence analysis of purified dog cytochrome P450 PBD-2, and the amino acid composition concurs with that determined for the PBD-2 protein (D. B. Duignan, I. G. Sipes, T. B. Leonard, and J. R. Halpert, 1987, Arch. Biochem. Biophys. 255, 290-303). Northern blots revealed two mRNA species of approximately 1.9 and 2.9 kilobases in length, which hybridized to the coding region of the dog P450IIB cDNA. The level of total hybridizable mRNA was increased approximately sixfold in livers from PB-treated dogs compared with that in untreated animals. This increase correlates well with the reported nearly sixfold increase in the level of PBD-2 protein and the fivefold increase in the rate of hepatic metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl following PB treatment. The two mRNA species may result from the use of different polyadenylation signals located in the 3'-noncoding region or from transcription of more than one gene for PBD-2. Southern blot analysis indicated that the dog P450IIB subfamily contains at least two closely related genes.

Amino Acid Sequence↗
PubMed1989

On the role of amenities in models of migration and regional development.

"The role of location-specific amenities in human migration decisions, and subsequently regional development, is explored. A framework is developed which motivates a new assessment of existing alternative models of regional development, indicating the need for additional modeling efforts which focus upon amenities as critical elements in such analyses. The approach hinges upon the notion that amenity values are capitalized into wages, rents, or other local prices. This process of capitalization enables researchers to explore the implicit value that society places upon amenities, which can then be used in assessing future regional-development trends in a more comprehensive manner."

Behavior↗
PubMed1987

Evidence for functional and structural multiplicity of pregnenolone-16 alpha-carbonitrile-inducible cytochrome P-450 isozymes in rat liver microsomes.

Administration of pregnenolone-16 alpha-carbonitrile (PCN) to adult female rats caused a 2-fold increase in total liver microsomal cytochrome P-450 along with 5-7-fold increases in four in vitro monooxygenase activities considered diagnostic for the major PCN-inducible cytochrome P-450 isozyme. However, upon administration of chloramphenicol to PCN-treated rats, these monooxygenase activities could be resolved into three groups. Thus, the ability of the microsomes to convert triacetyloleandomycin to a metabolite that forms a spectral complex with the reduced heme iron was decreased by 80% by chloramphenicol, whereas only a 50% decrease was observed in the rate of conversion of (R)-warfarin to its 9,10-dehydro metabolite and in the rate of 6 beta-hydroxylation of androstenedione. More strikingly, the 10-hydroxylation of (R)-warfarin was actually enhanced 2-fold by the chloramphenicol treatment. Fractionation studies were carried out on liver microsomes from PCN-treated adult male rats, and two highly purified cytochromes P-450, referred to as PCNa and PCNb, were recovered. PCNb was found to be identical in the sequence of the first 15 amino acid residues with a PCN-inducible isozyme, the complete amino acid sequence of which has recently been deduced in another laboratory [Gonzalez, F. J., Nebert, D. W., Hardwick, J. P., & Kasper, C. B. (1985) J. Biol. Chem. 260, 7435-7441]. The other isozyme, PCNa, differed in amino acid sequence in three of the first 15 positions from PCNb. Upon immunoblot analysis, polyclonal antibodies raised to PCNb also recognized PCNa. Thus, the PCN-inducible family of rat liver cytochrome P-450 comprises at least two separate proteins.

Animals↗
PubMed1986

Characterization of corpora lutea in monkeys after superovulation with human menopausal gonadotropin or follicle-stimulating hormone.

The objective of this study was to characterize the corpora lutea (CL) of superovulatory follicles, which form in nonhuman primates after treatment with exogenous gonadotropins. Adult female rhesus monkeys (n = 15) with amenorrhea or irregular menstrual cycles received im injections of either human menopausal gonadotropin [hMG; equivalent amounts (37.5 IU) of hFSH and hLH] or human FSH (37.5 IU) twice daily for 6 or 9 days. One day later, hCG (1000 IU) was administered to induce ovulation. Serum estradiol levels rose rapidly in hMG-treated monkeys. In contrast, estradiol levels did not rise in FSH-treated animals for 3-4 days, but ultimately reached concentrations comparable to or greater than those in hMG-treated monkeys. Serum progesterone levels were low in all groups before hCG injection, but rose thereafter. Peak progesterone levels were greater (P less than 0.05) in 9- vs. 6-day treatment groups. Serum concentrations of hCG peaked within 24 h of injection and declined to undetectable levels 6-7 days later. The mass of luteinized tissue removed 7 days after hCG injection was markedly (P less than 0.01) increased in hMG- and FSH-treated monkeys compared to that of the active CL of the natural menstrual cycle (n = 6). However, the protein content of luteal tissue from FSH-treated monkeys was less (P less than 0.05) than that in hMG-treated groups or in the CL of the natural cycle. Luteal particulate fractions from all treatment groups had [125I]human LH binding sites, with the Kd for LH interaction comparable to that in the CL of the natural cycle. However, the LH-binding capacity in hMG-treated groups was less (P less than 0.05) than that in the CL of the cycle, when normalized per mg tissue wt or protein. Notably, the binding capacity in FSH-treated groups was comparable to that in the CL cycle when expressed per mg protein. Nevertheless, only after 6 days (not 9 days) of FSH treatment or 9 days (not 6 days) of hMG treatment did tissues have a LH-sensitive (activation constant) or LH-responsive adenylate cyclase comparable to that in the CL of the cycle. Thus, properties of the primate CL after superovulation varied markedly with the type and length of gonadotropin treatment employed for follicular stimulation. The findings support the concept that gonadotropin-regulated events in the developing follicle(s) are important determinants of the subsequent character of the primate CL.

Adenylyl Cyclases↗
PubMed1985

Adenylate cyclase in human ovarian cancers: sensitivity to gonadotropins and nonhormonal activators.

Adenylate cyclase activity in particulate preparations of ovarian tumors from 47 women was determined by measuring the conversion of phosphorus 32-labeled adenosine triphosphate to phosphorus 32-labeled cyclic adenosine monophosphate. Ovarian cancers typically exhibited an active adenylate cyclase which was stimulated by 50 mumol/L 5'-guanylylimidodiphosphate and 10 mmol/L of sodium fluoride. This activity was comparable to that in particulates of normal postmenopausal ovaries and was independent of the class of tumor. There was no significant increase in adenylate cyclase activity in any epithelial or germinal tumor in the presence of either 250 nmol/L of human chorionic gonadotropin or 333 nmol/L human follicle-stimulating hormone. However, cyclic adenosine monophosphate production by two sex cord stromal tumors was stimulated by follicle-stimulating hormone, but not by human chorionic gonadotropin. Follicle-stimulating hormone stimulated a threefold increase in activity in the granulosa-theca cell tumor, with an activation constant (57 nmol/L) similar to that in follicle-stimulating hormone-responsive rat ovaries. Prostaglandin E1 (50 mumol/L) increased cyclic adenosine monophosphate production by epithelial tumors more than twofold. These data suggest that sex cord stromal tumors, unlike the more common epithelial tumors, can be modulated directly by gonadotropin.

Adenylyl Cyclases↗