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Biomedical subjects

A M Duncan

Publications and source records attributed to A M Duncan.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cytogenetic and radiation hybrid mapping of human arachidonate 5-lipoxygenase-activating protein (ALOX5AP) to chromosome 13q12.

Arachidonate 5-lipoxygenase-activating protein (ALOX5AP) is an arachidonic acid binding protein that has been shown to be critical in the biosynthesis of leukotrienes. We mapped the ALOX5AP gene to the chromosome 13q12 region by cytogenetic mapping, yeast artificial chromosome (YAC) pool screening, and radiation hybrid mapping. It was mapped to YAC contig WC13.2 by YAC pool screening with an unambiguous hit to WI-4874, which is at 78 cR on the radiation hybrid map, 3.36 cR, by radiation hybrid mapping, from WI-4874.

5-Lipoxygenase-Activating Proteins↗
PubMed1999

Angiotensin-converting enzyme inhibition modifies angiotensin but not kinin peptide levels in human atrial tissue.

Angiotensin-converting enzyme (ACE) converts angiotensin I (Ang I) to angiotensin II (Ang II) and metabolizes bradykinin and kallidin peptides. Decreased Ang II levels and increased kinin peptide levels are implicated in the mediation of the therapeutic effects of ACE inhibition. However, alternative non-ACE pathways of Ang II formation have been proposed to predominate in human heart. We investigated the effects of ACE inhibition on cardiac tissue levels of angiotensin and kinin peptides. High-performance liquid chromatography-based radioimmunoassays were used to measure angiotensin peptides and hydroxylated and nonhydroxylated bradykinin and kallidin peptides in right atrial appendages of subjects who had been prepared for cardiopulmonary bypass. Peptide levels in subjects who received ACE inhibitor therapy were compared with those who did not receive ACE inhibitor therapy. ACE inhibition reduced Ang II levels, which was associated with an 80% reduction in the Ang II/Ang I ratio. ACE inhibition did not modify either bradykinin or kallidin peptide levels or the bradykinin-(1-7)/bradykinin-(1-9) ratio. The 80% reduction in the Ang II/Ang I ratio by ACE inhibition indicated a primary role for ACE in the conversion of Ang I to Ang II in atrial tissue. These data support a role for reduced Ang II levels but do not support a role for increased kinin peptide levels in mediating the direct cardiac effects of ACE inhibition.

Adult↗
PubMed1999

Soy isoflavones exert modest hormonal effects in premenopausal women.

Soy isoflavones are hypothesized to be responsible for changes in hormone action associated with reduced breast cancer risk. To test this hypothesis, we studied the effects of isoflavone consumption in 14 premenopausal women. Isoflavones were consumed in soy protein powders and provided relative to body weight (control diet, 10 +/- 1.1; low isoflavone diet, 64 +/- 9.2; high isoflavone diet, 128 +/- 16 mg/day) for three menstrual cycles plus 9 days in a randomized cross-over design. During the last 6 weeks of each diet period, plasma was collected every other day for analysis of estrogens, progesterone, LH, and FSH. Diet effects were assessed during each of four distinctly defined menstrual cycle phases. Plasma from the early follicular phase was analyzed for androgens, cortisol, thyroid hormones, insulin, PRL, and sex hormone-binding globulin. The low isoflavone diet decreased LH (P = 0.009) and FSH (P = 0.04) levels during the periovulatory phase. The high isoflavone diet decreased free T3 (P = 0.02) and dehydroepiandrosterone sulfate (P = 0.02) levels during the early follicular phase and estrone levels during the midfollicular phase (P = 0.02). No other significant changes were observed in hormone concentrations or in the length of the menstrual cycle, follicular phase, or luteal phase. Endometrial biopsies performed in the luteal phase of cycle 3 of each diet period revealed no effect of isoflavone consumption on histological dating. These data suggest that effects on plasma hormones and the menstrual cycle are not likely to be the primary mechanisms by which isoflavones may prevent cancer in premenopausal women.

Adult↗
PubMed1999

Modest hormonal effects of soy isoflavones in postmenopausal women.

Soy isoflavones have been hypothesized to exert hormonal effects in postmenopausal women. To test this hypothesis, we studied the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women. Isoflavones were consumed relative to bodyweight [control: 0.11 +/- 0.01; low isoflavone (low-iso): 1.00 +/- 0.01; high isoflavone (high-iso): 2.00 +/- 0.02 mg/kg/day] for 93 days each in a randomized crossover design. Blood was collected on day 1 of the study (baseline) and days 36-38, 64-66, and 92-94 of each diet period, for analysis of estrogens, androgens, gonadotropins, sex hormone binding globulin (SHBG), prolactin, insulin, cortisol, and thyroid hormones. Vaginal cytology specimens were obtained at baseline and at the end of each diet period, and endometrial biopsies were performed at baseline and at the end of the high-iso diet period, to provide additional measures of estrogen action. Overall, compared with the control diet, the effects of the low-iso and high-iso diets were modest in degree. The high-iso diet resulted in a small but significant decrease in estrone-sulfate (E1-S), a trend toward lower estradiol (E2) and estrone (E1), and a small but significant increase in SHBG. For the other hormones, the few significant changes noted were also small and probably not of physiological importance. There were no significant effects of the low-iso or high-iso diets on vaginal cytology or endometrial biopsy results. These data suggest that effects of isoflavones on plasma hormones per se are not significant mechanisms by which soy consumption may exert estrogen-like effects in postmenopausal women. These data also show that neither isoflavones nor soy exert clinically important estrogenic effects on vaginal epithelium or endometrium.

Aged↗
PubMed1999

Menstrual cycle effects on urinary estrogen metabolites.

Endogenous estrogen metabolism may play an important role in the pathogenesis of hormone-related cancers, most notably breast cancer. Despite the importance of estrogen metabolism, little is known about estrogen metabolite profiles during different phases of the menstrual cycle. This study was performed to evaluate the effects of the menstrual cycle on endogenous estrogen metabolism. Twenty-four-hour urine samples were collected daily during 4 precisely defined phases of the menstrual cycle (early follicular, midfollicular, periovulatory, and midluteal phases) from 6 healthy premenopausal women. Urine samples were analyzed for 15 endogenous estrogens and their metabolites by an ion exchange chromatography and the capillary gas chromatography-mass spectrometry method. The patterns of urinary estrogen metabolites (including potentially genotoxic 16alpha-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone) followed those of plasma estradiol and estrone, showing significant increases in the periovulatory and midluteal phases. Compared to the early and midfollicular phases, the ratios of 2-hydroxyestrogens/16alpha-hydroxyestrogens and 2-hydroxyestrogens/4-hydroxyestrogens were significantly increased during the periovulatory and midluteal phases (by 28% and 72%, respectively; P < 0.05), suggesting that estrogen metabolism is significantly affected by menstrual cycle phase. These data indicate that menstrual cycle phase must be considered in studies of estrogen metabolism in premenopausal women.

Adult↗
PubMed1999

Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels.

Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition.

Angiotensin II↗
PubMed1998

Effect of the menstrual cycle on creatinine clearance in normally cycling women.

OBJECTIVE: We assessed changes in creatinine clearance during the menstrual cycle of normally cycling women. METHODS: We used a design that precisely identified the day of ovulation. Creatinine clearance was measured in 14 subjects on each of three days: cycle day 2 or 3, 1 or 2 days before the day of ovulation, and 6 or 7 days after ovulation. RESULTS: Creatinine clearance was affected significantly by the menstrual cycle (P=.02), but the degree of this effect was modest. Mean (+/-standard error of mean) early follicular, preovulatory, and midluteal creatinine clearance values were 135+/-4, 131+/-5, and 142+/-5 mL/min, respectively, and only the difference between the preovulatory and midluteal values was significant. These changes in creatinine clearance were attributable largely to changes in creatinine excretion and not to changes in plasma creatinine concentrations. CONCLUSION: Despite the statistically significant luteal phase increase, creatinine clearance does not change in a clinically important manner during the normal menstrual cycle. Specifically, there is no substantial decrease in creatinine clearance around the time of ovulation.

Adult↗
PubMed1998

Effects of neutral endopeptidase inhibition and combined angiotensin converting enzyme and neutral endopeptidase inhibition on angiotensin and bradykinin peptides in rats.

The combination of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) inhibition is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on the levels of these peptides. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, 100 mg/kg per day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg per day), to rats by 12 hourly gavage for 7 days. Ecadotril produced diuresis, natriuresis, increased urine cyclic guanosine monophosphate and BK-(1-9) levels, increased Ang II and Ang I levels in plasma, and increased Ang I levels in heart. Perindopril reduced Ang II levels in kidney, and increased BK-(1-9) levels in blood, kidney and aorta. Combined NEP/ACE inhibition produced the summation of these effects of separate NEP and ACE inhibition. In addition, perindopril potentiated the ecadotril-mediated diuresis, natriuresis and decrease in urine BK-(1-7)/BK-(1-9) ratio, which is an index of BK-(1-9) metabolism. Moreover, combined NEP/ACE inhibition increased Ang II levels in plasma and lung. These data indicate that summation of the effects of separate NEP and ACE inhibition provides the basis for the therapeutic efficacy of their combination. Whereas potentiation by perindopril of the diuretic and natriuretic effects of ecadotril may contribute to the therapeutic effects, increased Ang II levels in plasma and lung may compromise the therapeutic effects of combined NEP/ACE inhibition.

Angiotensin II↗
PubMed1998

Effects of soy isoflavones on estrogen and phytoestrogen metabolism in premenopausal women.

Isoflavones and lignans are soy phytoestrogens that have been suggested to be anticarcinogenic. The mechanisms by which they exert cancer-preventive effects may involve modulation of estrogen synthesis and metabolism. To evaluate this hypothesis, a randomized, cross-over soy isoflavone feeding study was performed in 12 healthy premenopausal women. The study consisted of three diet periods, each separated by a washout of approximately 3 weeks. Each diet period lasted for three menstrual cycles plus 9 days (averaging approximately 100 days), during which subjects consumed their habitual diets supplemented with soy protein powder providing 0.16 (control diet), 1.01, or 2.01 mg of total isoflavones per kg of body weight per day (10+/-1.1, 65+/-9.4, or 129+/-16 mg/day, respectively). A 72-h urine sample was collected during the midfollicular phase (days 7-9) of the fourth menstrual cycle in each diet period. Urine samples were analyzed for 10 phytoestrogens and 15 endogenous estrogens and their metabolites by a capillary gas chromatography-mass spectrometry method. Urinary excretion of isoflavonoids and lignans significantly increased with increased isoflavone consumption. Compared with the control diet, increased isoflavone consumption decreased urinary excretion of estradiol, estrone, estriol, and total estrogens, as well as excretion of the hypothesized genotoxic estrogen metabolites, 16alpha-hydroxyestrone, 4-hydroxyestrone, and 4-hydroxyestradiol. Of importance are the observations of a significant increase in the 2-hydroxyestrone/16alpha-hydroxyestrone ratio and a decrease in the genotoxic/total estrogens ratio. These data suggest that soy isoflavone consumption may exert cancer-preventive effects by decreasing estrogen synthesis and altering metabolism away from genotoxic metabolites toward inactive metabolites.

Adult↗
PubMed1997

Amplification of CFTR exon 9 sequences to multiple locations in the human genome.

Cloning and characterization of the cystic fibrosis transmembrane conductance regulator (CFTR) gene led to the identification and isolation of cDNA and genomic sequences that cross-hybridized to the first nucleotide binding fold of CFTR. DNA sequence analysis of these clones showed that the cross-hybridizing sequences corresponded to CFTR exon 9 and its flanking introns, juxtapositioned with two segments of LINE1 sequences. The CFTR sequence appeared to have been transcribed from the opposite direction of the gene, reversely transcribed, and co-integrated with the L1 sequences into a chromosome location distinct from that of the CFTR locus. Based on hybridization intensity and complexity of the restriction fragments, it was estimated that there were at least 10 copies of the "amplified" CFTR exon 9 sequences in the human genome. Furthermore, when DNA segments adjacent to the insertion site were used in genomic DNA blot hybridization analysis, multiple copies were also detected. The overall similarity between these CFTR exon 9-related sequences suggested that they were derived from a single retrotransposition event and subsequent sequence amplification. The amplification unit appeared to be greater than 30 kb. Physical mapping studies including in situ hybridization to human metaphase chromosomes showed that multiple copies of these amplified sequences (with and without the CFTR exon 9 insertion) were dispersed throughout the genome. These findings provide insight into the structure and evolution of the human genome.

Animals↗
PubMed1997

The human mitochondrial elongation factor tu (EF-Tu) gene: cDNA sequence, genomic localization, genomic structure, and identification of a pseudogene.

The human mitochondrial elongation factor Tu (EF-Tu) is nuclear-encoded and functions in the translational apparatus of mitochondria. The complete human EF-Tu cDNA sequence of 1677 base pairs (bp) with a 101 bp 5'-untranslated region, a 1368 bp coding region, and a 207 bp 3'-untranslated region, has been determined and updated. The predicted protein from this cDNA sequence is approximately 49.8 kDa in size and is composed of 455 amino acids (aa) with a putative N-terminal mitochondrial leader sequence of approximately 50 aa residues. The predicted amino acid sequence shows high similarity to other EF-Tu protein sequences from ox, yeast, and bacteria, and also shows limited similarity to human cystolic elongation factor 1 alpha. The complete size of this cDNA (1677 bp) obtained by cloning and sequencing was confirmed by Northern blot analysis, which showed a single transcript (mRNA) of approximately 1.7 kb in human liver. The genomic structure of this EF-Tu gene has been determined for the first time. This gene contains nine introns with a predicted size of approximately 3.6 kilobases (kb) and has been mapped to chromosome 16p11.2. In addition, an intronless pseudogene of approximately 1.7 kb with 92.6% nucleotide sequence similarity to the EF-Tu gene has also been identified and mapped to chromosome 17q11.2.

Amino Acid Sequence↗
PubMed1997

Physical and transcription map in the region 14q24.3: identification of six novel transcripts.

The region of chromosome 14q24 has been of particular interest as it is known to contain one of the early-onset Alzheimer disease genes (AD3). Other genes of medical interest, such as arrhythmogenic right ventricular cardiomyopathy, have been mapped to this region by linkage analysis or chromosome rearrangements. We have focused on the region of a balanced translocation (2;14)(p25;q24). Members of a family with this translocation all have anterior polar cataracts, suggesting the presence of a gene involved in lens integrity at the vicinity of the breakpoint. The chromosome 14 breakpoint has been defined between the short tandem repeats D14S289 and D14S277, a region of overlap for yeast artificial chromosomes (YACs) 888b2 and 934d4. We have extended the study of the region to 2 Mb on chromosome 14 and present a physical map of this region, including several sequence-tagged sites. New probes were generated using several end clones and inter-Alu PCR fragments from YACs. cDNA selection was used to identify transcribed sequences. Mapping and alignment of 17 nonoverlapping cDNAs completed by sequence and expression pattern analysis suggested that a minimum of eight putative transcription units is present in this region: six of these units correspond to five new genes and one member of a new gene family.

Blotting, Northern↗
PubMed1997

A report of recurrent anencephaly with trisomy 2p23-2pter: additional evidence for the involvement of 2p24 in neural tube development and evaluation of the role for cytogenetic analysis.

A woman carrying a balanced reciprocal translocation, 46,XX,t(2;5)(p23;p15)pat, was ascertained following the delivery of an anencephalic fetus whose karyotype was 46,XY,5p+. She subsequently had two pregnancies with a similar unbalanced karyotype (trisomy 2p23-2pter and monosomy 5p15-5pter), one of which was also anencephalic. She has three living children, two of whom are balanced translocation carriers. This history raises questions regarding the necessity of cytogenetic assessment of cases identified by ultrasound with 'isolated' neural tube defects. The observation of duplication of the 2p23-2pter region in conjunction with anencephaly also adds to the growing body of evidence suggesting an association of this region and neural tube development.

Adult↗
PubMed1997

Evidence that skewed X inactivation is not needed for the phenotypic expression of Aicardi syndrome.

Aicardi syndrome is a rare disorder characterized by absent corpus callosum, infantile spasms, and choriorentinal lacunae. It is sporadic in nature and affects only females, resulting in severe mental and physical handicap. It has been suggested that the disease is caused by a dominant X-linked mutation which occurs de novo in females, and is lethal in hemizygous male embryos. This mode of inheritance has been observed in a number of other rare syndromes. In these syndromes, when X inactivation is studied, a non-random pattern is usually found. We have studied the X inactivation pattern in ten female patients with Aicardi syndrome and their parents using the highly polymorphic, differentially methylated androgen receptor gene. The results showed an unexpected random X-inactivation pattern in these patients. Previous clinical and cytogenetic evidence suggests that Aicardi syndrome is caused by an X-linked dominant mutation, de novo in females and lethal in males. However, unlike most other known X-linked disorders inherited in this fashion, Aicardi syndrome patients have a normal (i.e., random) X-inactivation pattern. A number of possible explanations is proposed for this apparently contradictory evidence.

Abnormalities, Multiple↗
PubMed1997

Angiotensin and bradykinin peptides in rats with myocardial infarction.

BACKGROUND: Angiotensin II (Ang II) stimulates cardiac hypertrophy and fibrosis, whereas bradykinin [BK-(1-9)] has cardioprotective actions and reduces infarct size following myocardial infarction. METHODS AND RESULTS: We investigated whether myocardial infarction and cardiac failure are associated with changes in circulating and tissue levels of angiotensin and bradykinin peptides. Myocardial infarction was produced in rats by coronary artery ligation and confirmed by electrocardiogram. Ang II, Ang I, BK-(1-9), and its metabolite BK-(1-7) were measured 1, 2, 3, 7, and 28 days after myocardial infarction. In comparison with sham operated rats, myocardial infarction reduced blood pressure and body weight, and produced cardiac hypertrophy and cardiac failure. Myocardial infarction increased plasma renin and ACE activity, reduced plasma angiotensinogen, and increased Ang II levels in plasma, aorta, kidney, and lung. Ang II levels in whole cardiac ventricles were similar in infarct and sham operated rats, but were positively correlated with heart weight/body weight ratio in infarct rats 3, 7, and 28 days after infarction. In a separate study of cardiac regions, Ang II levels were similar in infarct and sham operated rats, except at 7 days post surgery when right ventricular Ang II levels were higher in infarct rats. In infarct rats, Ang II levels were higher in the right ventricle and in the infarct than in the non-infarcted left ventricle at 7 days, but these differences were not apparent at 28 days after infarction. BK-(1-9) levels were increased in the heart and lung on days 2 and 3 post infarction, but not in the aorta or kidney. A decrease in BK-(1-7)/BK-(1-9) ratio suggested reduced metabolism of BK-(1-9) to BK-(1-7) in infarcted hearts. CONCLUSIONS: The transient activation of the circulating renin angiotensin system, and increased Ang II levels in the aorta, kidney, and lung may contribute to the systemic responses to myocardial infarction and cardiac failure. The correlations between cardiac Ang II levels and heart weight/body weight ratio noted for whole cardiac ventricles support a role for local Ang II levels in the process of myocardial remodeling post infarction. The increased cardiac BK-(1-9) levels in the acute phase of myocardial infarction were consistent with a role for this peptide in cardioprotection and limitation of infarct size.

Angiotensin II↗
PubMed1997

Chromosomal localization of the human liver form cytochrome c oxidase subunit VIIa gene.

The chromosomal loci corresponding to human cytochrome c oxidase (COX) subunit VIIa Liver (VIIa-L) isoform genes were determined utilizing a combined approach of genomic cloning, in situ hybridization, and somatic hybrid genetics. In contrast to the proposal of E. Arnaudo et al. (Gene (Amst.), 119: 299-305, 1992) that COX VIIa-L sequences are located on chromosomes 4 and 14, we found that COX VIIa-L related sequences reside on chromosome 6, while an additional COX VIIa-L cross-reacting sequence psi-gene) was located on chromosome 4.

Animals↗
PubMed1997

Cloning, characterization, and chromosomal localization of human liver form cytochrome c oxidase subunit VIa related genes.

The chromosomal location of human cytochrome c oxidase (COX) subunit VIa Liver (VIa-L) isoform related sequences has been determined by a combination of in situ hybridization and analysis of human-hamster somatic cell hybrid panels. COX VIa-L related sequences were present on chromosomes 6 and 12. It has been verified that at least two COX VIa-L genes are on chromosome 6, one of which is a pseudogene. In total, four COX VIa-L related sequences have been cloned and their nucleotide sequences analyzed. At least three of the sequences represent pseudogenes; their relatedness to the COX VIa-L cDNA is discussed.

Animals↗