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Biomedical subjects

R E Ferrell

Publications and source records attributed to R E Ferrell.

At least 73 records · Page 4Linked to original sources
PubMed2000

Lipoprotein lipase gene variation is associated with adipose tissue lipoprotein lipase activity, and lipoprotein lipid and glucose concentrations in overweight postmenopausal women.

Adipose tissue lipoprotein lipase (LPL) activity is under strong genetic control in both mice and humans. This study determines whether common DNA variation in the LPL gene (PvuII and HindIII polymorphisms) is associated with adipose tissue LPL activity and metabolic risk factors in a homogeneous population of 75 overweight postmenopausal women (body mass index >25 kg/m2; age: 51-69 years old). The allele frequencies for the presence of the cut-sites for LPL HindIII and PvuII were 0.71 and 0.49, respectively. There were no associations between the HindIII polymorphism and any of the measured variables. Age, body mass index, percent body fat, waist-hip ratio, visceral and subcutaneous fat area, and gluteal (GLT) and abdominal (ABD) adipocyte size did not differ by LPL PvuII genotype. However, adipose tissue LPL activity at both GLT and ABD sites was higher in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous (+/-) or homozygous (+/+) for the cut-site (P<0.05). Total and LDL cholesterol were lower in women without the LPL PvuII cut-site (-/-) compared with women who were heterozygous or homozygous for the cut-site (P<0.05), whereas triglyceride and HDL levels were similar between LPL PvuII genotypes. Fasting glucose, but not insulin, was lower in women without the LPL PvuII cut-site (-/-). These data suggest that the LPL PvuII polymorphism is a possible marker for a functional mutation that is found in the LPL gene and that alters LPL activity in older overweight women.

Adipocytes↗
PubMed2000

Complex adaptive systems and human health: the influence of common genotypes of the apolipoprotein E (ApoE) gene polymorphism and age on the relational order within a field of lipid metabolism traits.

We analyzed the influence of age, apolipoprotein E (ApoE) genotype, and their interaction on the variation of each of all possible pairwise correlations among plasma levels of ApoE, ApoB, total cholesterol, triglyceride, and HDL cholesterol. Our cross-sectional study sample included 1,876 individuals (979 females and 897 males) from the Rochester, MN population, unselected for health, with a common ApoE genotype of epsilon32, epsilon33, or epsilon43, and ranging in age from 5 to 90 years. We conducted analyses on data from female and male subjects separately, using a hierarchical set of generalized additive models. The age changes in the correlations were estimated using a 30-year sliding window across the age range. There were qualitative differences between genders in the age at which the peaks in the correlations occurred. For female subjects, peaks in correlations were mostly in the middle and older age windows, whereas in males, peaks were mostly in the younger and middle age windows. We found for both genders that for each of the possible pairwise correlations, the influence of age was significantly dependent on ApoE genotype (all Pr<0.0001). We also found for female and male subjects that the epsilon32- and epsilon43- specific age changes in the correlations were each significantly different from those for the epsilon33 genotype (Pr<0.0001), with two exceptions for males (marginally significant differences, P<0.08). We conclude that the influence of ApoE genotypic variation extends far beyond the levels of the gene product, to the dynamics of the relational order among measures of lipid metabolism with age. Moreover, age and common ApoE genotype are not independent predictors of the gender-specific changes in relational order that we observed among these measures of lipid metabolism. These results have implications for the development and application of therapeutic approaches to treat human disease and our enhanced understanding of the role of genetic variation in the dynamic actions of complex adaptive systems with age that occur in response to environmental change. These dynamic actions emerge as the phenotypes that are measures of human health in the population at large.

Adaptation, Physiological↗
PubMed2000

Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression.

The relationship of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) to antidepressant response was examined in 95 elderly patients receiving a protocolized treatment for depression with paroxetine or nortriptyline. Patients were treated for up to 12 weeks and assessed weekly with clinical ratings and measurements of plasma drug concentrations. Twenty-one of the paroxetine-treated subjects were found to have the ll genotype and 30 had at least one s allele. There were no baseline differences between these groups in pretreatment Hamilton Rating Scale for Depression (HRSD) scores or anxiety symptoms. During acute treatment with paroxetine, mean reductions from baseline in HRSD were significantly more rapid for patients with the ll genotype than for those possessing an s allele, despite equivalent paroxetine concentrations. Onset of response to nortriptyline was not affected. Allelic variation of 5-HTTLPR may contribute to the variable initial response of patients treated with a selective serotonin reuptake inhibitor.

Adrenergic alpha-Agonists↗
PubMed2000

Ambulatory blood pressure after acute exercise in older men with essential hypertension.

We sought to determine whether reductions in blood pressure in hypertensives after acute exercise persist for more than the 2 to 3 h found in controlled laboratory settings. Subjects (n = 11) were obese (32 +/- 4% body fat), sedentary (VO2max 27 +/- 4 mL/kg/min) 60 +/- 6-year-old men with stage 1 or 2 essential hypertension. Ambulatory blood pressure was recorded on 1 day preceded by 45 min of 70% VO2max treadmill exercise and on another day not preceded by exercise. Systolic blood pressure was lower by 6 to 13 mm Hg for the first 16 h after exercise (P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average systolic blood pressures were significantly lower on the day after exercise. There was a trend for peak systolic blood pressure to be lower during the entire 24 h and the day portion of the recording; peak systolic blood pressure was significantly lower during the night portion of the recording after exercise. Systolic blood pressure load (percent of systolic blood pressure readings >140 mm Hg) was reduced during the entire 24 h and the day portion of the recording after exercise. Diastolic blood pressure was lower for 12 of the first 16 h after acute exercise (hours 0 to 4, 5 to 8, 13 to 16) (P < .05) compared to the day without prior exercise. Twenty-four-hour, day, and night average diastolic blood pressure was also significantly lower on the recording after exercise. Peak diastolic blood pressure was lower over the entire 24-h period. Diastolic blood pressure load (percent of diastolic blood pressure readings >90 mm Hg) was lower during the entire 24 h and the day portion of the day after exercise. Preliminary data also suggest that common genetic polymorphisms at the angiotensinogen, lipoprotein lipase, and angiotensin converting enzyme loci may affect the blood pressure-lowering response after acute exercise. Thus, in sedentary, obese hypertensive men a single aerobic exercise session reduced blood pressure enough to result in significantly lower 24-h average systolic, diastolic, and mean arterial blood pressure. This could result in a reduced cardiovascular load during the 24 h after acute exercise in older hypertensive men.

Aged↗
PubMed2000

Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

Alleles↗
PubMed2000

Vitiligo is not caused by mutations in GTP-cyclohydrolase I gene.

GTP-cyclohydrolase I (GTP-CH I) is the initial and rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which regulates melanin biosynthesis. GTP-CH I is therefore a candidate gene for vitiligo. We have carried out DNA sequencing of all six exons and the promoter region of this gene, comprising 1759 base pairs, in 25 nonsyndromic vitiligo patients. However, contrary to an earlier report in which mutations were found in syndromic patients (vitiligo with dopa-responsive dystonia) belonging to two unrelated families, no mutation in the GTP-CH I gene was found.

Adolescent↗
PubMed2000

Familial nephrotic syndrome: clinical spectrum and linkage to chromosome 19q13.

BACKGROUND: Familial nephrotic syndrome (NS) has both autosomal dominant and recessive forms of inheritance. Recent studies in families with an autosomal dominant form of focal segmental glomerulosclerosis (FSGS) have been at odds concerning linkage to chromosome 19q13 (Mathis et al, Kidney Int 53:282-286, 1998; Winn et al, Kidney Int 55:1241-1246, 1999), suggesting genetic heterogeneity. This study examines the clinical features and confirms linkage to chromosome 19q13 in a family with autosomal dominant NS. METHODS: DNA samples were obtained from 16 of 17 family members. Genomic DNA was isolated, and polymerase chain reaction was performed for five markers spanning the area of interest on chromosome 19q13. Data were evaluated using two- and six-point linkage analysis. RESULTS: Clinical features included presentation of NS in childhood, steroid unresponsiveness, and slow progression to renal failure. Renal biopsy in affected family members showed lesions ranging from minimal change to mesangial proliferative glomerulonephritis to FSGS. Linkage was confirmed between the disease state and chromosome 19q13, with a maximum logarithm of odds (LOD) score of 2.41. Linkage was observed for a 7 cM region on chromosome 19q13, defined by markers D19S425 and D19S220. CONCLUSIONS: This study confirms the Mathis et al report of linkage to chromosome 19q13 in a family with autosomal dominant NS. However, there were notable differences in the presenting clinical and histopathologic features of our affected family members compared with those of Mathis et al. This suggests that the gene on chromosome 19q13 may be responsible for considerable phenotypic heterogeneity and variable expression in both clinical presentation and renal histopathology.

Adolescent↗
PubMed2000

Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency.

The clinical course of a 9-year-old diagnosed with attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and Tourette's disorder and treated with a combination of methylphenidate, clonidine, and fluoxetine is described. The patient experienced over a 10-month period, signs and symptoms suggestive of metabolic toxicity marked by bouts of gastrointestinal distress, low-grade fever, incoordination, and disorientation. Generalized seizures were observed, and the patient lapsed into status epilepticus followed by cardiac arrest and subsequently expired. At autopsy, blood, brain, and other tissue concentrations of fluoxetine and norfluoxetine were several-fold higher than expected based on literature reports for overdose situations. The medical examiner's report indicated death caused by fluoxetine toxicity. As the child's adoptive parents controlled medication access, they were investigated by social welfare agencies. Further genetic testing of autopsy tissue revealed the presence of a gene defect at the cytochrome P450 CYP2D locus, which results in poor metabolism of fluoxetine. As a result of this and other evidence, the investigation of the adoptive parents was terminated. This is the first report of a fluoxetine-related death in a child with a confirmed genetic polymorphism of the CYP2D6 gene that results in impaired drug metabolism. Issues relevant to child and adolescent psychopharmacology arising from this case are discussed.

Antipruritics↗
PubMed2000

Factors associated with calcium absorption efficiency in pre- and perimenopausal women.

BACKGROUND: The amount of calcium ingested by an individual may affect several chronic conditions, including osteoporosis, hypertension, and colon cancer. However, individuals vary in their ability to absorb the calcium they consume. OBJECTIVE: The purpose of this study was to examine sources of interindividual variation in the efficiency of calcium absorption in women. DESIGN: Fractional calcium absorption was estimated in 142 healthy pre- and perimenopausal women. Dietary habits, lifestyle factors, calciotropic hormones, and vitamin D receptor gene polymorphisms were also assessed. RESULTS: Calcium absorption values averaged 35% and ranged from 17% to 58%. Fractional calcium absorption was positively associated with body mass index (r = 0.22, P = 0.007), dietary fat intake (r = 0.29, P = 0.001), serum 1,25 dihydroxyvitamin D [1,25(OH)(2)D] concentrations (r = 0.23, P = 0. 006), and parathyroid hormone concentrations (r = 0.21, P = 0.015). Fractional calcium absorption was inversely associated with total calcium intake (r = -0.18, P = 0.030), dietary fiber intake (r = -0. 19, P = 0.028), alcohol consumption (r = -0.14, P = 0.094), physical activity (r = -0.22, P = 0.007), and symptoms of constipation (r = -0.16, P = 0.059). In stepwise regression analysis, dietary fat, dietary fiber, serum 1,25(OH)(2)D, and alcohol consumption emerged as independent predictors of calcium absorption, explaining 21.02% of the observed variation. Women in the lowest tertile of the ratio of dietary fat to fiber had 19% lower fractional calcium absorption values than did women in the highest tertile of ratio of dietary fat to fiber (test of trend, P < 0.001). CONCLUSIONS: There is a wide range of calcium absorption values in healthy women. The amount of dietary fat consumed relative to dietary fiber appears to have an important role in determining differences in calcium absorption performance among individuals.

Absorption↗
PubMed2000

Effects of age, gender, and myostatin genotype on the hypertrophic response to heavy resistance strength training.

BACKGROUND: Because of the scarcity of data available from direct comparisons of age and gender groups using the same relative training stimulus, it is unknown whether older individuals can increase their muscle mass as much as young individuals and whether women can increase as much as men in response to strength training (ST). In addition, little is known about whether the hypertrophic response to ST is affected by myostatin genotype, a candidate gene for muscle hypertrophy. METHODS: Eleven young men (25 +/- 3 years, range 21-29 years), 11 young women (26 +/- 2 years, range 23-28 years), 12 older men (69 +/- 3 years, range 65-75 years), and 11 older women (68 +/- 2 years, range 65-73 years) had bilateral quadriceps muscle volume measurements performed using magnetic resonance imaging (MRI) before and after ST and detraining. Training consisted of knee extension exercises of the dominant leg three times per week for 9 weeks. The contralateral limb was left untrained throughout the ST program. Following the unilateral training period, the subjects underwent 31 weeks of detraining during which no regular exercise was performed. Myostatin genotype was determined in a subgroup of 32 subjects, of which five female subjects were carriers of a myostatin gene variant. RESULTS: A significantly greater absolute increase in muscle volume was observed in men than in women (204 +/- 20 vs 101 +/- 13 cm3, p < .01), but there was no significant difference in muscle volume response to ST between young and older individuals. The gender effect remained after adjusting for baseline muscle volume. In addition, there was a significantly greater loss of absolute muscle volume after 31 weeks of detraining in men than in women (151 +/- 13 vs 88 +/- 7 cm3, p < .05), but no significant difference between young and older individuals. Myostatin genotype did not explain the hypertrophic response to ST when all 32 subjects were assessed. However, when only women were analyzed, those with the less common myostatin allele exhibited a 68% larger increase in muscle volume in response to ST (p = .056). CONCLUSIONS: Aging does not affect the muscle mass response to either ST or detraining, whereas gender does, as men increased their muscle volume about twice as much in response to ST as did women and experienced larger losses in response to detraining than women. Young men were the only group that maintained muscle volume adaptation after 31 weeks of detraining. Although myostatin genotype may not explain the observed gender difference in the hypertrophic response to ST, a role for myostatin genotype may be indicated in this regard for women, but future studies are needed with larger subject numbers in each genotype group to confirm this observation.

Adult↗
PubMed2000

Apolipoprotein E gene polymorphism and bone loss: estrogen status modifies the influence of apolipoprotein E on bone loss.

The identification of genes that contribute to bone mineral density (BMD) and bone loss has widespread implications for the understanding and prevention of osteoporosis. The objective of this study was to examine the relationship between the presence and absence of the apolipoprotein E*4 (APOE*4) allele and both BMD and annualized percentage rate of change in BMD at the lumbar spine and hip in a population of 392 healthy, pre-, peri-, and postmenopausal white women participating in the Women's Healthy Lifestyle Project. APOE genotype was analyzed by restriction enzyme analysis from genomic DNA. BMD at the lumbar spine and hip was measured at baseline and after a mean of 2.5 years using dual-energy X-ray absorptiometry (DXA). In premenopausal women, there were no significant differences in BMD or in the annualized percentage rate of change in BMD at the spine or hip when comparing women with and without the APOE*4 allele. In contrast, spine bone loss was significantly greater in peri- and postmenopausal women having an APOE*4 allele than in women without this allele (-1.75 + 1.5% per year vs. -0.98 +/- 1.4% per year, respectively, p = 0.018). Among peri- and postmenopausal women currently using hormone replacement therapy (HRT), there were no differences in the annualized percentage rate of change in spine BMD; whereas, among non-HRT users, there was a 2-fold higher rate of spine bone loss in women with an APOE*4 allele compared with women without this allele (-2.31 +/- 1.5% per year vs. -1.27 +/- 1.3% per year, respectively, p = 0.033; APOE*4 x HRT interaction, p = 0.076). In conclusion, this study shows the importance of APOE*4 allele in spine bone loss in peri- and postmenopausal women and, more importantly, it provides evidence for a genetic and lifestyle interaction in modulating spine bone loss.

Adult↗
PubMed2000

Plasma lipoprotein(a) distribution and its correlates among Samoans.

Plasma lipoprotein(a) [Lp(a)]-consisting of a disulfide-linked complex of apolipoprotein B and apolipoprotein (a)--levels are considered to be an independent risk factor for coronary heart disease. There are considerable ethnic group differences in the distribution of plasma Lp(a) levels that raise public health concerns. Although plasma Lp(a) distribution has been determined in various ethnic groups, no such information is available in Pacific Islanders. In this study we have determined the distribution and correlates of plasma Lp(a) in population-based samples of 361 American Samoans (145 men, 216 women) and 560 Western Samoans (265 men, 295 women), aged 20-70 years. Plasma Lp(a) levels were measured using a commercial enzyme-linked immunosorbent assay. The distribution of plasma Lp(a) levels in both groups was highly skewed with 73% and 65% of values in the 0-5 mg/dl range in American Samoans and Western Samoans, respectively. The mean (6.4 mg/dl) and median (2.2 mg/dl) Lp(a) levels in pooled Samoans were significantly lower when compared with other ethnic groups using the same measurement kit. Plasma Lp(a) correlated significantly with total and LDL cholesterol in both genders after correcting for the contribution of Lp(a) cholesterol, and with apolipoprotein B in women after the correction for Lp(a)-apoB, but not with age, smoking, alcohol intake, or body mass index. Our data show that Samoans, Polynesians of Pacific Islands, have strikingly lower Lp(a) levels than all other reported population groups. These data are consistent with the hypothesis that genetic factors account for interethnic group variation in plasma Lp(a) levels.

Adult↗
PubMed1999

Comprehensive transcript analysis in small quantities of mRNA by SAGE-lite.

Serial analysis of gene expression (SAGE) is a powerful technique that can be used for global analysis of gene expression. Its chief advantage over other methods is that SAGE does not require prior knowledge of the genes of interest and provides quantitative and qualitative data of potentially every transcribed sequence in a particular tissue or cell type. Furthermore, SAGE can quantify low-abundance transcripts and reliably detect relatively small differences in transcript abundance between cell populations. However, SAGE demands high input levels of mRNA which are often unavailable, particularly when studying human disease. To overcome this limitation, we have developed a modification of SAGE that allows detailed global analysis of gene expression in extremely small quantities of tissue or cultured cells. We have called this approach 'SAGE-Lite'. This technique was used for the global analysis of transcription in samples of normal and pathological human cerebrovasculature to study the molecular pathology of intracranial aneurysms. These samples, which are obtained during operative surgical repair, are typically no bigger than 1 or 2 mm and yield <100 ng of total RNA. In addition, we show that SAGE-Lite allows simple and rapid isolation of long cDNAs from short (15 bp) SAGE sequence tags.

Cell Line↗
PubMed1999

The heritability of otitis media: a twin and triplet study.

CONTEXT: Anatomical, physiological, and epidemiological data indicate that there may be a significant genetic component to prolonged time with and recurrent episodes of otitis media in children. OBJECTIVE: To determine the genetic component of time with and episodes of middle ear effusion and acute otitis media (AOM) during the first 2 years of life. DESIGN: Prospective twin and triplet cohort study with enrollment from 1982 through 1995. SETTING: Otitis Media Research Center in the ear, nose, and throat clinic of Children's Hospital of Pittsburgh, Pittsburgh, Pa. PATIENTS: A total of 168 healthy same-sex twin and 7 triplet sets were recruited within the first 2 months of life; zygosity results were available for 140 sets; 138 (99%) of these were followed up for 1 year and 126 (90%) for 2 years. MAIN OUTCOME MEASURES: Proportion of time with middle ear effusion, episodes of middle ear effusion, and episodes of AOM by zygosity status. RESULTS: At the 2-year end point, the estimate of heritability of time with middle ear effusion was 0.73 (P<.001). The estimates of discordance for 3 or more episodes of middle ear effusion were 0.04 for monozygotic twins and 0.37 for dizygotic twins (P = .01). The estimate of discordance of an episode of AOM in monozygotic twins was 0.04 compared with 0.49 in dizygotic twins (P = .005). CONCLUSIONS: Our study suggests there is a strong genetic component to the amount of time with middle ear effusion and episodes of middle ear effusion and AOM in children.

Acute Disease↗
PubMed1999

Frequent sequence variation in the human myostatin (GDF8) gene as a marker for analysis of muscle-related phenotypes.

Myostatin is a recently identified member of the transforming growth factor-beta family of regulatory factors, also known as growth and differentiation factor 8 (GDF8). The nucleotide sequence of human myostatin was determined in 40 individuals. The invariant promoter contains a consensus MyoD binding site, and the coding sequence contains five missense substitutions in conserved amino acid residues (A55T, K153R, E164K, P198A, and I225T). Two of these, A55T in exon 1 and K153R in exon 2, are polymorphic in the general population with significantly different allele frequencies in Caucasians and African Americans (P < 0.001). Neither of the common polymorphisms had a significant impact on muscle mass response to strength training in either Caucasians or African Americans, although skewed allele frequencies preclude detection of small effects. These allelic variants provide markers for examining association between the myostatin gene and interindividual variation in muscle mass and differences in loss of muscle mass with aging.

Amino Acid Substitution↗
PubMed1999

A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease.

Using a combination of polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing techniques, we identified a unique missense mutation (T-->C) in exon 3 of the APOE gene which resulted in the substitution of pro-28 for leu-28. We screened 1118 White cases of late-onset (>60 years) Alzheimer's disease (AD) from three independent centers (Pittsburgh = 489, Indiana = 319, Mayo Clinic Rochester = 310) and 1123 controls (607 clinically assessed and 516 individuals randomly ascertained from the general population). Two of the 1123 control subjects had the pro-28 mutation (0.18%). However, this mutation was observed in heterozygous state in 2.66, 2.51 and 1.94% of the AD cases from Pittsburgh, Indiana and Mayo Clinic Rochester, respectively, with an overall frequency of 2.42%. All individuals with this mutation were carriers of the APOE*4 allele and hence the mutation was denoted as APOE*4 Pittsburgh (APOE*4P). Compared with the non-E*4P carriers, the E*4P carriers were associated with an increased risk of AD (odds ratio (OR) 13.2) and this risk remained significant even after adjusting for the known effect of APOE*4 (OR 5.4). The risk associated with the E*4P/E*4 combination was about five times (OR 29.1) the risk attributed to APOE*4 carriers alone (OR 5.7). Our data indicates that the new mutation most likely exists in cis-orientation with APOE*4 and is associated with increased risk of developing AD.

Adult↗