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Biomedical subjects

D K Price

Publications and source records attributed to D K Price.

At least 19 recordsLinked to original sources
PubMed2001

The androgen receptor gene and its influence on the development and progression of prostate cancer.

Prostate adenocarcinoma has the highest incidence of any malignancy and is the second leading cause of cancer-related deaths in men in industrialized countries. The development and progression of prostate cancer are dependent on testosterone and dihydrotestosterone; the androgen receptor is the vehicle through which these androgens exert their regulation on prostate cellular proliferation and differentiation. As a result, much effort has been devoted to elucidating the role of the androgen receptor in prostate cancer. The CAG and GGN trinucleotide repeats in exon 1 of the androgen receptor gene have been linked to prostate cancer risk and progression in some studies. Also, androgen receptor gene amplification may be a mechanism of prostate cancer cell adaptation to hormonal therapy. In addition, androgen receptor somatic mutations can result in receptors that have altered binding specificity when compared with wild-type receptors and heightened affinity for hormones other than testosterone and dihydrotestosterone. Gene amplification and somatic mutations, coupled with the fact that various growth factors have been shown to stimulate androgen receptor activity independently of androgens, may enable prostate cancer cells to grow despite testicular-androgen ablation. Unfortunately, current medical therapy for metastatic prostate cancer is deficient, hormone-refractory prostate cancer is a major obstacle in treatment, and, as a result, prostate cancer mortality is still significant. Further study of the function of the androgen receptor will offer a better understanding of prostate cancer pathogenesis and progression, aiding the development of more effective treatments for this disease.

Adenocarcinoma↗
PubMed2001

Approaches to preclinical screening of antiangiogenic agents.

Angiogenesis, or new blood vessel growth, is essential for the growth, invasion, and metastasis of solid tumors. The inhibition of this process, or antiangiogenesis, is a promising new therapeutic anticancer strategy. Several antiangiogenic compounds are currently in preclinical or clinical development for the treatment of cancer. However, the challenge for the discovery and characterization of antiangiogenic targets remains in developing efficient in vitro or in vivo preclinical angiogenesis screening assays to assess and compare antiangiogenic activity. Several semiquantitative or quantitative angiogenesis assays exist, including in vitro endothelial cell systems and ex vivo or in vivo neovascularization models utilizing mouse, rat, or human tissues. We describe the more common and cost-effective angiogenesis assays currently in use, summarizing their unique advantages and disadvantages. Since angiogenesis inhibition is a novel therapeutic modality towards controlling solid tumors, antiangiogenic drug development underlines the importance in describing, standardizing, and developing quantitative screening assays for the next generation of antiangiogenic agents.

Angiogenesis Inhibitors↗
PubMed2000

Effect of age on the expression of Pex (Phex) in the mouse.

Pex is a newly discovered gene (also called Phex) whose mutation is the cause of X-linked hypophosphatemia. Other members of this gene family encode endopeptidases that activate or inactivate endocrine and paracrine factors. Though embryonic bone expresses mRNA for the Pex gene at relatively high levels, we have found Pex expression to be widespread in adult organs and to be poorly expressed in adult bone. This led to the hypothesis that Pex mRNA expression changes with age. To test this, genetically normal mice of the B6C3H hybrid strain were studied at 0 (newborn), 2, 3, 10, and 72 weeks of age. Organs known to express Pex were collected, and RNA was extracted from them. Following reverse transcription, cDNA was amplified by the polymerase chain reaction with primers for Pex and G3PDH, a housekeeping gene. The amplimers were separated by electrophoresis, blotted onto nylon membranes, and hybridized with radioactively labeled internal oligonucleotide probes. The radioactivity was quantified, and the data were analyzed as the Pex/G3PDH ratio. The brain samples had high levels of Pex mRNA expression that rose slightly with age. Calvaria, kidney, and lung samples had the highest Pex mRNA expression at birth. In these organs Pex mRNA expression fell with age to undetectable or barely detectable levels. Thymus, heart, and skeletal muscle samples had low Pex mRNA expression at birth that did not change with age. Some organs showed a decline in G3PDH levels with age, but Pex expression decreased more, leading to a reduced Pex/G3PDH ratio. The widespread expression of mRNA for Pex suggests a role beyond that of phosphate homeostasis. The high level of expression in newborn animals suggests a role in growth and development. This seems to occur in addition to its role for the endocrine regulation of phosphate homeostasis by as yet unknown humoral agents that must occur throughout life. In summary, Pex mRNA expression is high in brain and bone at birth. Expression remains high in brain with age but falls with age in bone, kidney, and lung.

Aging↗
PubMed2000

Detection of Neisseria gonorrhoeae and Chlamydia trachomatis colonization of the gravid cervix.

OBJECTIVES: The aims of the study were to determine whether a Gram stain of cervical mucus can accurately rule out infection with Neisseria gonorrhoeae or Chlamydia trachomatis and to compare a diagnostic test that is based on the polymerase chain reaction with a deoxyribonucleic acid probe in the detection of these organisms. STUDY DESIGN: Gravid patients were screened for N gonorrhoeae and C trachomatis with a deoxyribonucleic acid probe, Gram stain, and analysis with the polymerase chain reaction. A normal, noninfected sample was defined by <10 polymorphonuclear leukocytes per high-power field on the Gram stain. Standard statistical methods were used to compare results of the Gram stain and the deoxyribonucleic acid probe, as well as to compare results of deoxyribonucleic acid probe hybridization and polymerase chain reaction analysis. A P value of <.05 was considered statistically significant. RESULTS: Patient enrollment totaled 519. The prevalence of infection as determined by deoxyribonucleic acid probe hybridization was 1.4% for N gonorrhoeae (7/518) and 6.8% for C trachomatis (35/518). The cervical Gram stain predicted the absence of infection in 17% (90/518) of patients, with a negative predictive value of 99% for N gonorrhoeae and 97% for C trachomatis. African American race, age <20 years, and unmarried status were all predictors of the presence of C trachomatis or N gonorrhoeae cervicitis. For the patients who lacked these risk factors (n = 74), the Gram stain had 100% negative predictive value. Analysis with the polymerase chain reaction detected 8 additional patients with C trachomatis and 105 additional patients with N gonorrhoeae, in comparison with deoxyribonucleic acid probe hybridization. CONCLUSION: The cervical Gram stain can accurately predict the absence of N gonorrhoeae and C trachomatis in gravid women. Analysis with the polymerase chain reaction indicates that N gonorrhoeae and C trachomatis are significantly more prevalent in this population than previously reported.

Cervix Uteri↗
PubMed2000

The phosphoprotein Op18/stathmin is differentially expressed in ovarian cancer.

To identify potential prognostic indicators of ovarian cancer and identify targets for therapeutic strategies, mRNA differential display was used to analyze gene expression differences in normal, benign, and cancerous ovarian tissue. One cDNA isolated by this technique, Op18/stathmin, is a highly conserved gene that is reported to have many different functions within a cell, including signal transduction, control of the cell cycle, and the regulation of microtubules. Quantitative Northern blot analysis of 12 malignant ovarian samples, 8 benign ovarian tumors, and 10 normal ovarian tissue samples demonstrated overexpression of Op18/stathmin mRNA in the malignant cancers. Immunohistochemistry showed an apparent overexpression of Op18/stathmin protein level and an association with proliferating cells.

Blotting, Northern↗
PubMed1999

Age- and sex-distribution of the mutation load.

We investigate the age and sex distribution of genetic fitness under mutation-selection balance by means of simple one-locus two-allele models. We find that the extent of age and sex variation in the mutation load is very dependent on the average effect of new mutations. If the average heterozygote selective effect of new mutations is large, then age and sex differences may constitute a significant fraction of the total load, and be significant as compared to standing genetic variation. Whether the mutation load will increase or decrease with age depends on the age- and sex-specific effects of the new mutations, and on the rate of accumulation of mutations in the germ line as individuals age. We argue that the load will most likely increase with age in animals with continuous germ-cell division throughout life, and that this will occur even when mutations have unconditionally deleterious effects. We show that a male-biased mutation rate is likely to result in both a male-biased mutation load and a load that increases with male age.

Age Distribution↗
PubMed1998

Partial deletion of both the spermine synthase gene and the Pex gene in the X-linked hypophosphatemic, gyro (Gy) mouse.

Gy, along with Hyp, is a dominant mutation of the normal gene Pex causing X-linked hypophosphatemia in the mouse. Hemizygous Gy male mice, however, have greater defects in survival, bodily growth, skeletal mineralization, and neurological function than those found in heterozygous Gy females or in Hyp mice. Since the gene for spermine synthase is immediately upstream of the homologous human gene PEX, we compared the effects of the Gy and Hyp mutations on both the spermine synthase gene and the Pex gene. Barely detectable levels of spermine (< 5% of normal) with elevated levels of its precursor, spermidine, were found in organs of Gy male mice compared to normal male littermates. Neither Gy females nor Hyp male mice were significantly affected. Four missing introns of the spermine synthase gene were identified in Gy male mice, suggesting extensive gene disruption. A pseudogene for spermine synthase was also identified in the mouse genome. Pex mRNA was found in several but not all tissues studied in adult normal mice. Pex mRNA was altered in both Gy and Hyp mice. All male Hyp mice were lacking the 3' end of the Pex message, whereas all male Gy mice were deficient at the 5' end. In summary, the Gy mutation is associated with a recessively expressed mutation of the spermine synthase gene, leading to spermine deficiency, and a dominantly expressed mutation of the Pex gene, leading to hypophosphatemia. Alterations in two contiguous genes in Gy may explain the additional phenotypic abnormalities present in the Gy male mouse.

Animals↗
PubMed1998

Detection and clearance of prostate cells subsequent to ultrasound-guided needle biopsy as determined by multiplex nested reverse transcription polymerase chain reaction assay.

OBJECTIVES: To determine if circulating prostate cells are detectable subsequent to transrectal ultrasound (TRUS)-guided biopsy, and if so, whether cells remain in circulation for up to 4 weeks. METHODS: Blood samples were drawn from 90 patients with elevated serum prostate-specific antigen (PSA) levels and/or abnormal digital rectal examination. Two samples were drawn from all patients immediately prior to TRUS and 30 minutes postbiopsy. Blood samples were also obtained 1 week postbiopsy from 83 patients, and 1 month postbiopsy from 61 patients. Multiplex nested reverse transcription polymerase chain reaction assay (RT-PCR) for PSA and prostate-specific membrane antigen (PSM) was performed on total ribonucleic acid (RNA) from each sample. Results were reported as positive if at least one of the targets was detected. RESULTS: Of 45 patients with biopsy-proven adenocarcinoma, 22 were RT-PCR positive prebiopsy and all remained positive 30 minutes postbiopsy. Of 23 patients with adenocarcinoma who were RT-PCR negative prebiopsy, 5 (22%) converted to positive 30 minutes postbiopsy (P < 0.001). Four of these 5 patients returned to negative after 1 week or 1 month. Of 45 patients without cancer at biopsy, 32 were RT-PCR negative prebiopsy and 6 (19%) converted to positive 30 minutes postbiopsy (P < 0.001). Although four of six available samples were still positive at 1 week, all four samples available 1 month postbiopsy were negative. CONCLUSIONS: Detection of circulating prostate cells subsequent to biopsy occurred in 11 of 55 (20%) previously RT-PCR negative patients, a proportion twice that reported in the literature. We attribute this higher proportion to the simultaneous detection of PSA and PSM mRNA in our multiplex assay. Conversion rates were similar in patients regardless of biopsy result. Testing of serial postbiopsy blood demonstrates clearing of these cells by 4 weeks in most patients.

Aged↗
PubMed1998

How does offspring quality change with age in male Drosophila melanogaster?

We examined the relationship of genetic quality to age in male Drosophila melanogaster to test two contrasting hypotheses. The traditional hypothesis is that older males have proven their viability and therefore produce offspring of superior genetic quality. This hypothesis is often evoked as an explanation for female preference for older mates. In contrast, we have recently argued that older fathers may produce offspring of inferior genetic quality. Here, we present results from an experiment designed to measure the genetic quality of offspring produced by 2 day old, 2 week old and 5 week old male D. melanogaster. We found a statistically significant small reduction in larval viability and a similar but statistically non-significant reduction in son mating ability among the offspring of the 5 week old males. Daughter fecundity showed no apparent trend for a reduction nor an increase in performance with increasing age of the fathers. There was no evidence of a difference between the 2 day old and the 2 week old males for any of these three fitness components. These results are in somewhat better accordance with our alternative hypothesis, but the relatively weak and late occurring effects indicate that mate choice based on age may not be a viable strategy in this population.

Aging↗
PubMed1998

Inheritance of behavioural differences between two interfertile, sympatric species, Drosophila silvestris and D. heteroneura.

The Hawaiian fly species, Drosophila silvestris and D. heteroneura, are sympatric and interfertile but show strong behavioural isolation and major differences in male aggressive behaviour and the associated morphology. As a first step in elucidating the genetic control of the differences between these species, we examined the mating and aggressive behaviour of their reciprocal F1 hybrids. The latency to the first wing vibration and the latency to copulate did not differ significantly between the parental species. However, D. heteroneura females had a very low tendency to copulate with D. silvestris males, rarely mating during the observation period. The duration of copulation also differed significantly; same-species pairs of D. silvestris had copulations that lasted about 50% longer than those of same-species pairs of D. heteroneura. The hybrids were intermediate between the parental species for both the tendency to copulate with D. silvestris males and the duration of copulation, suggesting codominance or polygenic inheritance for those traits. The aggression traits that we scored were the leg posture and wing extension during early aggression, and the leg posture and head position during escalated aggression. The parental species showed clear differences for each of these traits. The F1 hybrids resembled one parent or the other, without showing intermediate values, suggesting single-gene dominance or threshold expression of many genes for those traits. None of the courtship or aggressive traits showed X-chromosomal effects, although the head shape of hybrids is influenced by genes on the X chromosome. It is difficult to reconcile the patterns of inheritance of aggressive behaviour and the lack of an X-chromosomal effect with the hypothesis that these traits are influenced by a coadapted gene complex.

Aggression↗
PubMed1996

The chicken FMR1 gene is highly conserved with a CCT 5'-untranslated repeat and encodes an RNA-binding protein.

The transcriptional silencing of the human gene, fragile X mental retardation 1 (FMR1), is due to abnormal methylation in response to an expanded 5'-untranslated CGG trinucleotide repeat and accounts for most cases of fragile X syndrome, a frequent inherited form of mental retardation. Although the encoded fragile X mental retardation protein (FMRP) is known to have properties of a RNA-binding protein, the precise function of FMRP remains to be elucidated. We report the cloning of the chicken homolog of FMR1 and show strong evolutionary conservation, with nucleotide and amino acid identities of 85 and 92%, respectively, between chicken and human. In place of the mammalian CGG trinucleotide repeat, a 99-nt tripartite repetitive element containing a CCT trinucleotide repeat flanked on both sides by dinucleotide repeats was identified. Blocks of highly conserved 3'-untranslated sequence were also found. Within the coding region, two copies each of the highly conserved K homology motif and the Arg-Gly-Gly (RGG) box motif, both ribonucleotide particle family domains implicated in RNA binding, were identified. Chicken FMRP was found to bind RNA in vitro, and this activity correlated with the presence of the carboxy-terminal portion of the protein that includes the RGG motifs.

Animals↗
PubMed1995

Hemobilia presenting as intermittent gastrointestinal hemorrhage with sincalide confirmation. A case report.

An 82-year-old man had his third episode of melanotic stool. Two previous workups had failed to localize the source of bleeding. A Tc-99m labeled RBC scan visualized the gallbladder early in the study. Administration of sincalide visually decreased the activity, confirming gallbladder activity. Three months later, at his second surgery, hepatic metastases were finally identified as the source of bleeding. In retrospect, the hepatic activity is inhomogeneous with at least two cold defects that could have represented hepatic metastases.

Adenocarcinoma↗
PubMed1993

Constraints on the evolution of attractive traits: genetic (co)variance of zebra finch bill colour.

We estimated the heritability and genetic correlation between male and female bill colour in a laboratory population of zebra finches (Taeniopygia guttata) in order to examine the potential genetic constraints on the evolution of a sexually dimorphic trait. The heritability estimates of bill colour from regressions of offspring on single parents ranged from h2 = 0.34 to 0.73 and all but one of these estimates were significantly greater than zero. The restricted maximum likelihood heritability estimates for full- and half-siblings were significant for females (h2 = 0.48) but not significant for males (h2 = 0.45). The maximum likelihood estimates indicate that there is little dominance genetic variance for bill colour. The large genetic correlation between male and female bill colour (rg = 0.91) combined with opposing selection on male and female bill colour indicates that the evolution to sex-specific optima may proceed very slowly.

Animals↗
PubMed1993

Measurement of oxygen consumption and arterial-venous oxygen saturation following total artificial heart implantation.

Current algorithms for control of the total artificial heart are directed at maintaining hemodynamic homeostasis. Future control systems will also need to modify cardiac output in response to metabolic needs. This study was undertaken to evaluate oxygen metabolism monitoring as an indicator of the adequacy of organ and tissue perfusion. Following recovery from implantation of the Utah-100 pneumatic total artificial hearts, five calves (85 to 95 kg) underwent placement of fiberoptic oximetry catheters to determine mixed venous and arterial oxygen saturations. By continuously measuring oxygen consumption with a gas analyzer, oxygen utilization and delivery were determined. In the awake calves, at-rest cardiac output was varied to produce hyperperfused and hypoperfused conditions while the adequacy of tissue perfusion was assessed with continuous mixed venous oximetry and confirmed with serum lactate (Lact) levels. Inadequate tissue perfusion (Lact > 1.0 mmol/L) was evidenced by a mixed venous oxygen saturation < 40%, oxygen delivery of < 200.0 milliliters/minute/m2), and oxygen delivery to utilization ratio of < 1.8 during the hypoperfusion conditions of the experiment. By accounting for oxygen consumption, the ratio of oxygen delivery to oxygen utilization was predictive of the adequacy of tissue perfusion. These results suggest that continuous oxygen metabolism monitoring may be useful as a physiologic control modifier to maintain total artificial heart output sufficient to meet physiologic needs, while avoiding hyperperfusion, unnecessary wear and deterioration of the implanted device due to excessive heart rates.

Animals↗
PubMed1992

The 5' ends of LINE1 repeats in rabbit DNA define subfamilies and reveal a short sequence conserved between rabbits and humans.

The 5' ends of five full-length LINE1 (L1) repeats from the rabbit genome (L1Oc) were mapped and their nucleotide sequences determined. Computer-generated alignments showed that these five L1Oc repeats can be divided into subfamilies, each of which has a characteristic sequence upstream of the first open reading frame (ORF1). These five L1Ocs range in size from 6.5 to 7.3 kb, with 5' ends located 76 to 1125 bp upstream of ORF1. Two of these subfamilies appear to have diverged from a common ancestor at least 66 million years ago. Comparisons of the 5' ends of L1s from rabbit, human, mouse, and rat show no common sequence 5' to ORF1, except for a 22-bp sequence that is found near the beginning of all characterized full-length L1s from rabbit and human. A statistical analysis indicates that this 22-bp aligned block is highly significant. Part of this 22-bp sequence matches the microE1 binding site in immunoglobulin gene enhancers. This strong conservation suggests that the microE1 binding site may be part of a transcriptional regulatory element at the 5' ends of rabbit and human L1 repeats.

Animals↗
PubMed1991

Problem drinking and family history.

Data on SADQ, GHQ, disciplinary, financial and relationship problems were collected from 103 problem drinkers and 96 controls. Problem drinkers were significantly more severely affected than controls on all measures except financial problems. Of the problem drinkers, 55% had a positive family history, and this group were more severely affected on SADQ, GHQ and financial problem measures than family history negative subjects. The most severely affected group were those with a positive family history who also reported significant childhood problems, and the least affected were those without a family history who did not report significant childhood problems.

Alcoholism↗
PubMed1989

Neuroleptic malignant syndrome in a case of post-partum psychosis.

A 27-year-old woman with a post-partum psychosis developed NMS which proved difficult to diagnose because of the organic features of the presenting illness. Possible contributory factors to the development of NMS included exhaustion, a non-specific viral illness, and rapid loading with haloperidol.

Adult↗