Biomedical subjects

R H Ward

Publications and source records attributed to R H Ward.

At least 37 records · Page 2Linked to original sources

PubMed1996

Comparison of sulfasalazine and placebo in the treatment of reactive arthritis (Reiter's syndrome). A Department of Veterans Affairs Cooperative Study.

OBJECTIVE: To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective in the treatment of reactive arthritis (ReA) that has been unresponsive to nonsteroidal antiinflammatory drug (NSAID) therapy. METHODS: One hundred thirty-four patients with ReA who had failed to respond to NSAIDs were recruited from 19 clinics, randomized (double-blind) to receive either SSZ or placebo, and followed up for 36 weeks. The definition of treatment response was based on joint pain/tenderness and swelling scores and physician and patient global assessments. RESULTS: Longitudinal analysis revealed improvement in the patients taking SSZ compared with those taking placebo, which appeared at 4 weeks and continued through the trial (P = 0.02). At the end of treatment, response rates were 62.3% for SSZ treatment compared with 47.7% for placebo treatment. The Westergren erythrocyte sedimentation rate declined more with SSZ treatment than with placebo (P < 0.0001). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints. CONCLUSION: SSZ at a dosage of 2,000 mg/day is well tolerated and effective in patients with chronically active ReA.

Adult↗

PubMed1996

The intergenerational predisposition to operative delivery.

OBJECTIVE: To determine the risk of cesarean delivery for women who themselves were born via operative delivery. METHODS: A linked data base was constructed between the birth certificates of individuals born in Utah during 1947-1957 (parental cohort) and who subsequently became a parent of offspring born in Utah between 1970-1991 (offspring cohort). Parental cohort women (cases) who had been delivered operatively (cesarean delivery, mid- or high forceps) as well as women who had a sibling delivered by an operative procedure were matched (1:2) with parental-cohort women born by spontaneous vaginal delivery (controls). Both cases and controls were selected based on having a record of at least one delivery in Utah during 1970-1991. RESULTS: Women who were delivered by cesarean were at increased risk of subsequently delivering their children by cesarean (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.18-1.70; P < .001). Progressive risk was associated with parental delivery by mid- or high forceps (OR 1.72, 95% CI 1.20-2.47; P = .004), parental cesarean because of cephalopelvic disproportion alone (OR 1.83, 95% CI 1.16-2.88; P = .01), or parental cesarean for dysfunctional labor (OR 5.97, 95% CI 1.5-23.6; P < .001). The attributable risk for cesarean delivery to the contemporary population is 3.5%. CONCLUSION: An intergenerational predisposition to cesarean delivery exists.

Cesarean Section↗

PubMed1996

Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.

The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, c1, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF c1 alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 "shared epitope" (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF c1 and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, c1, d1, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR.

Arthritis, Rheumatoid↗

PubMed1996

The retrieval of ancient human DNA sequences.

DNA was extracted from approximately 600-year-old human remains found at an archaeological site in the southwestern United States, and mtDNA fragments were amplified by PCR. When these fragments were sequenced directly, multiple sequences seemed to be present. From three representative individuals, DNA fragments of different lengths were quantified and short overlapping amplification products cloned. When amplifications started from <40 molecules, clones contained several different sequences. In contrast, when they were initiated by a few thousand molecules, unambiguous and reproducible results were achieved. These results show that more experimental work than is often applied is necessary to ensure that DNA sequences amplified from ancient human remains are authentic. In particular, quantitation of the numbers of amplifiable molecules is a useful tool to determine the role of contaminating contemporary molecules and PCR errors in amplifications from ancient DNA.

Archaeology↗

PubMed1995

Association of young maternal age with adverse reproductive outcomes.

BACKGROUND: Pregnancy in adolescence is associated with an excess risk of poor outcomes, including low birth weight and prematurity. Whether this association simply reflects the deleterious sociodemographic environment of most pregnant teenagers or whether biologic immaturity is also causally implicated is not known. METHODS: To determine whether a young age confers an intrinsic risk of adverse outcomes of pregnancy, we performed stratified analyses of 134,088 white girls and women, 13 to 24 years old, in Utah who delivered singleton, first-born children between 1970 and 1990. Relative risk for subgroups of this study population was examined to eliminate the confounding influence of marital status, educational level, and the adequacy of prenatal care. The adjusted relative risk for the entire study group was calculated as the weighted average of the stratum-specific risks. RESULTS: Among white married mothers with educational levels appropriate for their ages who received adequate prenatal care, younger teenage mothers (13 to 17 years of age) had a significantly higher risk (P < 0.001) than mothers who were 20 to 24 years of age of delivering an infant who had low birth weight (relative risk, 1.7; 95 percent confidence interval, 1.5 to 2.0), who was delivered prematurely (relative risk, 1.9; 95 percent confidence interval, 1.7 to 2.1), or who was small for gestational age (relative risk, 1.3; 95 percent confidence interval, 1.2 to 1.4). Older teenage mothers (18 or 19 years of age) also had a significant increase in these risks. Even though sociodemographic variables associated with teenage pregnancy increase the risk of adverse outcomes, the relative risk remained significantly elevated for both younger and older teenage mothers after adjustment for marital status, level of education, and adequacy of prenatal care. CONCLUSIONS: In a study of mothers 13 to 24 years old who had the characteristics of most white, middle-class Americans, a younger age conferred an increased risk of adverse pregnancy outcomes that was independent of important confounding sociodemographic factors.

Adolescent↗

PubMed1995

Angiotensin-converting enzyme gene polymorphism is associated with myocardial infarction but not with development of coronary stenosis.

BACKGROUND: Although both genetic and nongenetic factors contribute to the pathogenesis of coronary artery disease, the identification of specific genetic lesions has lagged behind the identification of critical environmental risk factors. A reported association between myocardial infarction (MI) and the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in European men suggests a critical role for this genomic region. However, the generality of this association remains to be determined. It also is not clear at what stage in disease progression the association with the ACE I/D polymorphism becomes important. METHODS AND RESULTS: We evaluated the ACE I/D polymorphism in patients who had undergone coronary angiography (402 men and 295 women) and in 203 representative control subjects. After polymerase chain reaction amplification, genotypes were determined by agarose gel sizing and by hybridization with allele-specific oligonucleotides. After patients were categorized by the degree of coronary artery stenosis and the occurrence of an MI, the distribution of ACE I/D genotypes was evaluated by log linear analysis. Patients were genetically representative of the regional population, and patients with > 60% stenosis of their coronary arteries had the same distribution of ACE I/D genotypes as did patients with < 10% stenosis. However, among patients with stenosis, the occurrence of an MI was significantly associated with the D allele in all patients (odds ratio [OR], 1.59; P = .002) and in men alone (OR, 1.63; P = .006). The lack of significance in women (OR, 1.40; P = .263) is probably due to the fact that only 36 women in the present study had experienced an MI. Furthermore, the association between MI and the ACE I/D polymorphism was independent of blood pressure, smoking habits, and body mass index. CONCLUSIONS: Segregation of the ACE I/D polymorphism is a pervasive genetic risk factor for MI in whites but has no evident effect on the events leading to stenosis of the coronary arteries. This suggests that risk of MI is influenced by two independent processes--atherogenesis that leads to coronary stenosis followed by conversion to MI. The renin-angiotensin system appears to confer significant risk of infarction by influencing the conversion to MI but has no apparent effect on the development of atherostenosis.

Aged↗

PubMed1995

Immune response factors in rheumatic heart disease: meta-analysis of HLA-DR associations and evaluation of additional class II alleles.

OBJECTIVES: This study used a meta-analysis to examine HLA-DR frequencies in rheumatic heart disease and prospectively examined other class II allelic disease associations. BACKGROUND: Studies of rheumatic heart disease have reported HLA class II allelic associations, but these are inconsistent. METHODS: A meta-analysis combined all known (n = 10) studies to determine disease risk associated with HLA-DR antigen expression. Meta-analysis of studies grouped by ethnic derivation of subjects was also performed. The present study also examined DQA, DQB and DPB allele frequencies by DNA-based strategies. RESULTS: Meta-analysis showed a significant negative disease association with DR5 (odds ratio [OR] 0.67, p < 0.00003) for all combined studies. Among black patients, DR1 was increased (OR 2.80, p < 0.004); DR6 was increased (OR, 2.03, p < 0.003); and DR 8 was decreased (OR 0.32, p < 0.02). Among Eastern Indian patients, DR3 was increased (OR 2.44, p < 0.00003), with decreased expression for DR2 (OR 0.31, p < 0.00001) and DR5 (OR 0.52, p < 0.05). DR4 was increased among American whites (OR 1.74, p < 0.03), although there was significant heterogeneity among studies of whites. DQA, DQB and DPB allele frequencies were similar for control subjects and patients. CONCLUSIONS: Our findings support an association between major histocompatibility complex class II alleles and risk for rheumatic heart disease. However, heterogeneity in associations was observed among different ethnic and racial groups; regional and temporal differences in streptococcal outbreaks may compound this heterogeneity. Further studies are necessary to elucidate the respective contributions of these variables.

Alleles↗

PubMed1995

Reduced mtDNA diversity in the Ngöbé Amerinds of Panamá.

Mitochondrial DNA (mtDNA) haplotype diversity was determined for 46 Ngöbé Amerinds sampled widely across their geographic range in western Panamá. The Ngöbé data were compared with mtDNA control region I sequences from two additional Amerind groups located at the northern and southern extremes of Amerind distribution, the Nuu-Chah-Nulth of the Pacific Northwest and the Chilean Mapuche and from one Na-Dene group, the Haida of the Pacific Northwest. The Ngöbé exhibit the lowest mtDNA control region sequence diversity yet reported for an Amerind group. Moreover, they carry only two of the four Amerind founding lineages first described by Wallace and coworkers. We posit that the Ngöbé passed through a population bottleneck caused by ethnogenesis from a small founding population and/or European conquest and colonization. Dating of the Ngöbé population expansion using the Harpending et al. approach to the analysis of pairwise genetic differences indicates a Ngöbé expansion at roughly 6800 years before present (range: 1850-14,000 years before present), a date more consistent with a bottleneck at Chibcha ethnogenesis than a conquest-based event.

Archaeology↗

PubMed1994

Major histocompatibility complex class II gene frequencies by serologic and deoxyribonucleic acid genomic typing in idiopathic dilated cardiomyopathy.

Certain immunologic features associated with idiopathic dilated cardiomyopathy (IDC) suggest an infectious and/or autoimmune etiology. In this regard, an association between the major histocompatibility complex class II allele, DR4, and increased risk for IDC was previously identified. In the present report, 43 additional patients with IDC and 236 control subjects were studied for major histocompatibility class II allele associations. DR alleles were identified by microcytotoxicity. No significant differences between control subjects and patients with IDC were seen, although the frequency of DR4 was increased among patients. DR4 subtyping (n = 9) was performed by "dot blot" hybridization of allele-specific oligonucleotide probes to PCR-amplified genomic deoxyribonucleic acid. The DRB1*0401 and DRB1*0404 alleles were each found in 44% (n = 4) of patients with IDC, and DRB1*0407 was identified in 1 patient (11%). DQ and DP alleles were identified by restriction endonuclease codigestion of polymerase chain reaction-amplified deoxyribonucleic acid. The digested fragments were separated and identified by polyacrylamide gel electrophoresis. Differences between patients and control subjects were observed for DQA1*0501 (11% of patients vs 28% of control subjects, p < 0.05) and DQB1*0201 (13% patients vs 25% control subjects, p < 0.05). A modest difference was noted for DQA1*0301 (35% patients vs 23% control subjects, p = 0.08). These findings suggest a complex immune-related etiology for IDC that cannot be explained solely by the presence or absence of a single class II allele. However, this and other studies continue to implicate genes within the class II region in determining the risk for IDC.

Alleles↗

PubMed1994

Maternal serum human chorionic gonadotrophin and pregnancy-associated plasma protein A, markers for fetal Down syndrome at 8-14 weeks.

Maternal serum levels of human chorionic gonadotrophin and its subunits (intact, alpha, and free beta h CG) and pregnancy-associated plasma protein A (PAPP-A) were measured in 279 women between 8 and 14 weeks' gestation. This group included 23 pregnancies in which the fetus had Down syndrome (DS), diagnosed either at birth or during the second trimester (n = 17) or from chorionic villus sampling (CVS) (n = 6). Normal medians were determined from the 258 apparently normal pregnancies. The median levels of intact hCG (1.4 MOM) and free beta hCG (2.1 MOM) were significantly raised, whereas the median level of PAPP-A (0.39 MOM) was significantly lower in the DS pregnancies when compared with the control group. Levels of alpha hCG were similar in both the control and the DS pregnancies. Analysis of samples taken prior to 14 weeks' gestation demonstrated that only PAPP-A (0.34 MOM) was significantly altered in DS pregnancies. However, after the exclusion of DS cases diagnosed at CVS, the median intact hCG (1.56 MOM), free beta hCG (2.27 MOM), and alpha hCG (1.8 MOM) were all raised in DS pregnancies. This emphasizes the problem of the interpretation of biochemical markers when DS cases are diagnosed at CVS.

Biomarkers↗

PubMed1994

Apolipoprotein polymorphisms fail to define risk of coronary artery disease. Results of a prospective, angiographically controlled study.

BACKGROUND: Because genetic factors are believed to contribute to the etiology of coronary artery disease (CAD), it has been suggested that DNA polymorphisms at candidate loci might identify individuals at high risk for developing disease. In this regard, apolipoprotein genes represent extremely promising loci because levels of apolipoproteins and their associated lipoproteins represent a major risk factor for CAD, and rare dysfunctional mutations in these genes result in a significant risk for CAD. To date, although some reports indicate that DNA polymorphisms at these loci are associated with increased risk of CAD, other reports have failed to find such associations. METHODS AND RESULTS: To resolve the question of whether genetic polymorphisms at apolipoprotein loci can be used to identify individuals at increased risk for CAD, we evaluated the distribution of apolipoprotein genetic polymorphisms in a large series of subjects (n = 848) undergoing coronary angiography. Blinded assessment of angiograms was used to discriminate between patients with CAD (> or = 60% stenosis of any major branch, n = 444) and control subjects without disease (< or = 10% stenosis, n = 404). A total of 12 polymorphisms were evaluated at the following loci: apolipoprotein (apo) A-I/C-III/A-IV (five restriction site polymorphisms--Msp I, Pst I, Sst I, Pvu IIa, Pvu IIb), apo B (three restriction site polymorphisms--Xba I, EcoRI, Msp I, plus an insertion/deletion polymorphism), apo A-II (Msp I polymorphism), apo C-II (Taq I polymorphism), and apo E (protein isoforms revealed by DNA analysis). All subjects were of Northern European (primarily Angloscandinavian) descent, and, within each sex, patients and control subjects were of comparable age. All 12 loci were in Hardy-Weinberg equilibrium, with no indication of population heterogeneity. As expected, patients were distinguished from control subjects by their lipid profiles and a higher frequency of known risk factors for CAD. However, analysis by log-linear models indicated that there were no significant associations between apolipoprotein polymorphisms and the risk of CAD (P = .10 to .90). The lack of association was maintained irrespective of whether the analysis was carried out for the entire sample or the contrast was made more stringent by comparing patients most likely to have a genetic component to their disease (ie, young patients with early-onset CAD) with the control subjects least likely to have genetic susceptibility (ie, older control subjects who had ample time to develop CAD). CONCLUSIONS: Despite the fundamental role of apolipoprotein genes in lipid metabolism, we find no evidence that common genetic polymorphisms of the major apolipoprotein loci have a significant influence on the risk of developing angiographically defined CAD in this representative population. Therefore, at this time we find no support for the hypothesis that mass screening for genetic polymorphisms at candidate loci can reduce the burden of CAD by identifying a substantial proportion of high-risk individuals. Instead, it appears more appropriate to direct attention toward modifying high-risk behaviors to alleviate the consequences of traditional environmental risk factors.

Adult↗

PubMed1994

mtDNA variation in the Chibcha Amerindian Huetar from Costa Rica.

The genetic variation in a Chibcha-speaking Amerindian tribe from lower Central America, the Huetar, was analyzed using nucleotide sequences of the hypervariable segments of the mitochondrial DNA (mtDNA) control region, the frequencies of 10 Amerindian-specific mtDNA haplotypes, and the regional distribution of private protein polymorphisms. The sequencing of 713 base pairs (bp) in the control regions of 27 individuals revealed 11 distinct lineages. These were defined by 24 variable sites and a 6-bp deletion between nucleotide pairs (np) 106 and 111. The 6-bp deletion is a new mtDNA marker that will be valuable for Amerindian taxonomic research. Control region sequences and mtDNA haplotype analyses reveal that Huetar mtDNAs are distributed in "Amerindian clusters" A, B, and D. A maximum-likelihood phylogenetic tree suggests a single origin for the 6-bp Huetar deletion in the sample. mtDNA haplotype analysis and the presence of previously characterized private protein variants (PEPA*F, TF*DCHI, and the absence of DI*A) show that the Huetar harbor polymorphisms of considerable antiquity, suggesting an early divergence from the regional founder gene pool for this population. The data also reflect a drastic constriction in population size, an evolutionary event with a proposed central effect on Huetar genetic structure.

Base Sequence↗

PubMed1994

HLA-linked rheumatoid arthritis.

Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the susceptibility allele frequency as 2.16%, and estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-half of familial RA, although it accounts for only approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically.

Adolescent↗

PubMed1993

Genetic and linguistic differentiation in the Americas.

The relationship between linguistic differentiation and evolutionary affinities was evaluated in three tribes of the Pacific Northwest. Two tribes (Nuu-Chah-Nulth and Bella Coola) speak Amerind languages, while the language of the third (Haida) belongs to a different linguistic phylum--Na-Dene. Construction of a molecular phylogeny gave no evidence of clustering by linguistic affiliation, suggesting a relatively recent ancestry of these linguistically divergent populations. When the evolutionary affinities of the tribes were evaluated in terms of mitochondrial sequence diversity, the Na-Dene-speaking Haida had a reduced amount of diversity compared to the two Amerind tribes and thus appear to be a biologically younger population. Further, since the sequence diversity between the two Amerind-speaking tribes is comparable to the diversity between the Amerind tribes and the Na-Dene Haida, the evolutionary divergence within the Amerind linguistic phylum may be as great as the evolutionary divergence between the Amerind and Na-Dene phyla. Hence, in the New World, rates of linguistic differentiation appear to be markedly faster than rates of biological differentiation, with little congruence between linguistic hierarchy and the pattern of evolutionary relationships.

Alaska↗

PubMed1993

Serum PAPP-A measurements in first-trimester screening for Down syndrome.

Serum PAPP-A measurements taken from 254 women in the first trimester are reported. Eleven chromosomal abnormalities were detected. The mean serum PAPP-A levels in cases of Down syndrome were 0.44 MOM at 9 weeks gestation, 0.15 MOM at 10 weeks, and 0.29 MOM at 11 weeks. The PAPP-A level at 10 weeks was below those of pregnancies which aborted spontaneously. At 11 weeks, the pregnancies with Down syndrome recorded the lowest PAPP-A levels at that gestation. On this small sample, offering chorionic villus sampling to women with singleton pregnancies and a PAPP-A level below 0.3 MOM (approximately 6.5 per cent of this at-risk group) would have detected all the Down syndrome fetuses at 10 weeks and 50 per cent at 11 weeks without selecting those cases destined to abort. This suggests that serum PAPP-A should continue to be investigated as a potential first-trimester screening test for Down syndrome.

Adult↗

PubMed1993

Immunoadhesins.

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Animals↗

PubMed1993

mtDNA sequences suggest a recent evolutionary divergence for Beringian and northern North American populations.

Conventional descriptions of the pattern and process of human entry into the New World from Asia are incomplete and controversial. In order to gain an evolutionary insight into this process, we have sequenced the control region of mtDNA in samples of contemporary tribal populations of eastern Siberia, Alaska, and Greenland and have compared them with those of Amerind speakers of the Pacific Northwest and with those of the Altai of central Siberia. Specifically, we have analyzed sequence diversity in 33 mitochondrial lineages identified in 90 individuals belonging to five Circumpolar populations of Beringia, North America, and Greenland: Chukchi from Siberia, Inupiaq Eskimos and Athapaskans from Alaska, Eskimos from West Greenland, and Haida from Canada. Hereafter, we refer to these five populations as "Circumarctic peoples." These data were then compared with the sequence diversity in 47 mitochondrial lineages identified in a sample of 145 individuals from three Amerind-speaking tribes (Bella Coola, Nuu-Chah-Nulth, and Yakima) of the Pacific Northwest, plus 16 mitochondrial lineages identified in a sample of 17 Altai from central Siberia. Sequence diversity within and among Circumarctic populations is considerably less than the sequence diversity observed within and among the three Amerind tribes. The similarity of sequences found among the geographically dispersed Circumarctic groups, plus the small values of mean pairwise sequence differences within Circumarctic populations, suggest a recent and rapid evolutionary radiation of these populations. In addition, Circumarctic populations lack the 9-bp deletion which has been used to trace various migrations out of Asia, while populations of southeastern Siberia possess this deletion. On the basis of these observations, while the evolutionary affinities of Native Americans extend west to the Circumarctic populations of eastern Siberia, they do not include the Altai of central Siberia.

Alaska↗

PubMed1992

Estimating substitution rates from molecular data using the coalescent.

A coalescent model is used to estimate the rate at which neutral substitutions occur in a DNA sequence, without the necessity for an independent estimate of divergence times. Given a random sample of molecular sequences from a finite population, the distribution of the time to a common ancestor can be obtained from the coalescent model. With this principle, summary statistics are developed that use the distribution of molecular diversity within the sample to estimate the relative magnitude of nucleotide substitution rates. If, in addition, the effective population size is known, absolute substitution rates can also be estimated. These techniques are illustrated by estimating the transition rates that underlie the evolution of the first 360 nucleotides of the mitochondrial control region in an Amerindian tribal population.

Biological Evolution↗