Search PubMed⌕ Search

Biomedical subjects

R H Ward

Publications and source records attributed to R H Ward.

At least 19 recordsLinked to original sources
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↗
PubMed1992

Modeling the evolution of the human mitochondrial genome.

Mitochondrial DNA data have been used extensively to study evolution and early human origins. These applications require estimates of the rate at which nucleotide substitutions occur in the DNA sequence. We consider the problem of estimating substitution rates in the presence of site-to-site rate variation. A coalescent model is presented that allows for different substitution rates for purines and pyrimidines, as well as more detailed models that allow fast and slow rates within each of the purine and pyrimidine classes. A method for estimating such rates is presented. Even for these simple models of site heterogeneity, there are, typically, insufficient data to obtain reliable estimates of site-specific substitution rates. However, estimates of the average rate across all sites appear to be relatively stable even in the presence of site heterogeneity. Simulations of models with site-to-site variation in mutation rate show that hypervariable sites can produce peaks in the pairwise difference curves that have previously been attributed to population dynamics.

Biological Evolution↗
PubMed1992

HLA-DPB typing using co-digestion of amplified fragments allows efficient identification of heterozygous genotypes.

Twenty-four alleles have been defined for HLA-DPB based on their second exon sequences. This paper describes a novel method, co-digested amplified fragment length polymorphisms (CAFLP), for assigning these alleles to heterozygous patients, as well as to homozygous cell lines. The method depends on co-digestion of amplified DNA by restriction endonucleases and separation of the resultant fragments with polyacrylamide gel electrophoresis. Co-digestion by selected restriction enzymes produces a set of readily discernible fragments that are unique for a given haplotype because the selected restriction sites occur in cis. Consequently, this method provides haplotype information not available from independent digests and allows all known heterozygous genotypes to be identified. Analysis of 103 trios of mother, father, and child, plus 120 normal caucasians, demonstrates the reliability and simplicity of this procedure. This simple typing method results in unambiguous assignment of all current HLA-DPB genotypes in random samples with a high proportion of heterozygous individuals.

Adult↗
PubMed1992

Alpha thalassaemia hydrops fetalis in the UK: the importance of screening pregnant women of Chinese, other South East Asian and Mediterranean extraction for alpha thalassaemia trait.

OBJECTIVE: Alpha zero (alpha 0 or alpha-1) thalassaemia is an important genetic risk for women originating from Hong Kong, Singapore, Vietnam, Thailand, the Philippines or South China. Cypriots are also at risk. Carriers of alpha zero thalassaemia trait can be detected by routine haemoglobinopathy screening. When a couple are both carriers, in each pregnancy there is a 25% risk that the fetus will have alpha thalassaemia hydrops fetalis; this is fatal for the fetus and carries serious obstetric and psychological risks for the mother. Most informed couples at risk request prenatal diagnosis and selective abortion. This study investigates the effectiveness of screening, counselling and prenatal diagnosis for alpha thalassaemia hydrops fetalis in the UK. DESIGN: Retrospective analysis of the notes. SUBJECTS: 18 couples attending University College Hospital London for prenatal diagnosis of alpha thalassaemia hydrops fetalis since 1982. RESULTS: The study shows underdiagnosis of both alpha zero thalassaemia trait and alpha thalassaemia hydrops fetalis leading to avoidable stillbirths and complications in pregnancy. CONCLUSION: We recommend early screening for alpha zero thalassaemia trait for all women of Southeast Asian or eastern Mediterranean origin and the offer of prenatal diagnosis when indicated. The diagnosis of alpha thalassaemia hydrops fetalis should be considered in women of the relevant ethnic origin who have a stillbirth, neonatal death, abnormal ultrasound findings at fetal anomaly scanning (especially a large placenta), or who develop pre-eclampsia.

Abortion, Spontaneous↗
PubMed1992

Factors affecting the uptake of prenatal diagnosis for sickle cell disease.

Between 1979 and 1990, 170 couples at risk of having children with sickle cell disease, resident in the UK and with a continuing pregnancy, were referred for counselling at the University College Hospital Perinatal Centre. Approximately 50% of the couples, including those where one partner actually had sickle cell disease, requested prenatal diagnosis. This was requested in 82% of pregnancies when the mother was seen in the first trimester of pregnancy and in 49% when she was seen in the second trimester. More than 90% of referred couples who already had an affected child requested prenatal diagnosis. The type of sickle cell disease involved and ethnic group also influenced choice. These results show the importance of detecting and counselling couples at risk before pregnancy whenever possible.

Anemia, Sickle Cell↗
PubMed1992

CD4 immunoadhesins in anti-HIV therapy: new developments.

CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Extensive mitochondrial diversity within a single Amerindian tribe.

Sequencing of a 360-nucleotide segment of the mitochondrial control region for 63 individuals from an Amerindian tribe, the Nuu-Chah-Nulth of the Pacific Northwest, revealed the existence of 28 lineages defined by 26 variable positions. This represents a substantial level of mitochondrial diversity for a small local population. Furthermore, the sequence diversity among these Nuu-Chah-Nulth lineages is greater than 60% of the mitochondrial sequence diversity observed in major ethnic groups such as Japanese or sub-Saharan Africans. It was also observed that the majority of the mitochondrial lineages of the Nuu-Chah-Nulth fell into phylogenetic clusters. The magnitude of the sequence difference between the lineage clusters suggests that their origin predates the entry of humans into the Americas. Since a single Amerindian tribe can contain such extensive molecular diversity, it is unnecessary to presume that substantial genetic bottlenecks occurred during the formation of contemporary ethnic groups. In particular, these data do not support the concept of a dramatic founder effect during the peopling of the Americas.

Base Sequence↗
PubMed1991

Prevention of HIV-1 IIIB infection in chimpanzees by CD4 immunoadhesin.

The first step in infection by the human immunodeficiency virus (HIV) is the specific binding of gp120, the envelope glycoprotein of HIV, to its cellular receptor, CD4. To inhibit this interaction, soluble CD4 analogues that compete for gp120 binding and block HIV infection in vitro have been developed. To determine whether these analogues can protect an uninfected individual from challenge with HIV, we used the chimpanzee model system of cell-free HIV infection. Chimpanzees are readily infected with the IIIB strain of HIV-1, becoming viraemic within about 4-6 weeks of challenge, although they do not develop the profound CD4+ T-cell depletion and immunodeficiency characteristic of HIV infection in humans. CD4 immunoadhesin (CD4-IgG), a chimaeric molecule consisting of the N-terminal two immunoglobulin-like regions of CD4 joined to the Fc region of human IgG1, was selected as the CD4 analogue for testing because it has a longer half-life than CD4, contributed by the IgG Fc portion of the molecule. In humans, this difference results in a 25-fold increased concentration of CD4-IgG in the blood compared with recombinant CD4. Here we report that pretreatment with CD4-IgG can prevent the infection of chimpanzees with HIV-1. The need for a preventative agent is particularly acute in perinatal HIV transmission. As recombinant CD4-IgG, like the parent IgG molecule, efficiently crosses the primate placenta, it may be possible to set up an immune state in a fetus before HIV transfer occurs, thus preventing infection.

Acquired Immunodeficiency Syndrome↗
PubMed1991

The CD4-gp120 interaction and AIDS pathogenesis.

Infection by the human immunodeficiency virus (HIV) leads to progressive destruction of the CD4+ subset of T lymphocytes, resulting in immunodeficiency and AIDS. The selectivity of CD4+ cell destruction is due to the specific binding of gp120, the external envelope glycoprotein of HIV, to CD4, initiating viral entry. Binding of gp120 to CD4 on the cell surface may also lead to CD4+ cell depletion by inappropriate immune targeting, and may interfere with CD4+ cell function and ontogeny by disrupting CD4-mediated cell signaling. The CD4-gp120 interaction is thus an obvious target for AIDS therapeutics.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Multiple sclerosis: updated risks for relatives.

Two important characteristics of multiple sclerosis (MS) are familial clustering and a variable age of onset. There is increasing evidence for a genetically influenced susceptibility in MS. Because of this, patients and their relatives are increasingly asking about the risk for relatives of developing MS. In the MS Clinic in Vancouver, genetic histories are taken routinely for all patients and are updated annually. Patients do not attend the clinic specifically to participate in genetic studies, which could result in over-representation of familial cases. Data were available for 815 MS index cases and 11,345 of their relatives. Age-specific MS risks were calculated for first-, second-, and third-degree relatives of probands and are presented in an easy-reference format. In general, first-degree relatives of probands have a risk that is 30-50 times greater than the 0.1% risk for the general population.

British Columbia↗
PubMed1988

Changes in circulating alphafetoprotein and human chorionic gonadotrophin following chorionic villus sampling.

Chorionic villus sampling (CVS) is rapidly becoming established as a routine procedure for first-trimester fetal diagnosis. The technique can result in fetomaternal haemorrhage and this might sensitize Rhesus-negative mothers and on occasion lead to spontaneous abortion. Serial sampling indicates that there is a rapid rise in alphafetoprotein (AFP) levels following CVS; however, this is not reflected by raised levels at 16-18 weeks and does not influence the subsequent pregnancy outcome. Unlike AFP, alterations in hCG levels are small and variable. Anti-D prophylaxis for non-sensitized Rhesus negative mothers should be given after CVS and the procedure may be contra-indicated in patients who are already sensitized.

Chorionic Gonadotropin↗
PubMed1988

Convergence of immigrant suicide rates to those in the destination country.

Factors influencing the 1969-1973 suicide rate in 25 immigrant groups in Canada were investigated. Standardized mortality ratios (SMRs) were calculated for each group relative to the suicide rates in the origin country populations. Compared with their origin countries, immigrant females exhibited a significant increase in suicide rates (SMR = 1.11, p less than 0.01), whereas immigrant males did not (SMR = 0.98). Another set of standardized mortality ratios were then calculated for both origin and immigrant populations using the Canadian native-born rates as the standard. For the majority of immigrant groups, the standardized mortality ratios were significantly different from the ratios of their corresponding origin country populations, with 60% of the female immigrant groups and 41% of the male immigrant groups exhibiting higher ratios. Considerable variation was observed in the immigrant standardized mortality ratios, with a significant proportion of this variability being associated with the suicide rates in the origin countries (males r = 0.60, p less than 0.01; females r = 0.47, p less than 0.05). Using the standardized mortality ratios based on the Canadian native-born rates, the degree of "convergence" of immigrant suicide rates to the Canadian native-born rates was examined. Overall, significant convergence occurred for both sexes (p less than 0.01), with the immigrant suicide rates converging 40% of the initial difference between the standardized mortality ratios for the origin country and the Canadian native-born.

Adolescent↗
PubMed1988

Chorionic villus sampling in a high-risk population--4 years' experience.

Between August 1982 and July 1986 a total of 163 pregnancies in 136 patients with a high genetic risk have had prenatal diagnosis by chorionic villus sampling. Villi were not obtained in five pregnancies (two of which subsequently miscarried), and 11 fetal losses followed successful sampling (four in pregnancies in which the fetus was shown to be affected). The rate of fetal loss fell with increasing experience of the team. Three sets of twins were all sampled successfully.

Abortion, Spontaneous↗
PubMed1987

Hypertension and the genetics of red cell membrane abnormalities.

Hypertension represents the upper 15-25% of the blood pressure distribution in industrialized countries. The trait is practically absent in primitive societies and is made manifest by diet and lifestyles in industrialized countries. High blood pressure is an important risk factor for strokes, heart disease and renal disease. The frequency of hypertension is higher among blacks than among whites in the USA. Various twin, family and adoption studies indicate a strong genetic effect on blood pressure. The genetic mechanisms are unknown. Membrane transport variability has been studied in red cells as a surrogate for analogous alterations in smooth muscle or renal cells. Among the various transport systems, erythrocyte sodium-lithium countertransport (CT) has been consistently elevated in variable proportions of Caucasian hypertensives. Genetic studies of countertransport levels have shown familial aggregation and higher concordance for monozygotic than dizygotic twins. Complex segregation analysis suggests the action of a major gene superimposed on a polygenic background. The postulated gene (B) raises CT activity and has a population frequency of 0.25. CT levels of the common AA homozygotes and AB heterozygotes cannot be distinguished from each other, whereas CT activity of BB homozygotes (6% of the population) is significantly elevated. Although the CT gene contributes only 2.7% to 3.5% of the variability of blood pressure over its entire range, 14% to 20% of persons with systolic hypertension (greater than 140 mmHg) are BB homozygotes rather than the expected 6% to 7%. A much lower frequency of elevated countertransport activity among black hypertensives suggests genetic heterogeneity in the pathogenesis of high blood pressure. Further investigations on the mechanism and genetic linkage relationships of the putative CT gene may aid in elucidating an important mechanism of blood pressure elevation and will allow molecular approaches in the future.

Antiporters↗
PubMed1987

Two unusual cases of first trimester prenatal diagnosis of cystic fibrosis using DNA probes.

There are now several DNA probes which localize the cystic fibrosis mutation (CF) to chromosome 7q2.2-q3.1. The most tightly linked probes, pJ3.11 and met, are useful for first trimester prenatal diagnosis for many families provided that there is at least one living child affected by CF (Farrall et al., 1986). We describe here two families seeking prenatal diagnosis for CF which present unusual counselling problems. The first is an extended family in which there is no living affected member with CF; the second, a consanguinous marriage at risk both for cystic fibrosis and beta-thalassaemia. In both cases first trimester chorionic villus sampling and DNA haplotype analysis predicted that the fetus is a carrier for CF, and in the doubly affected family a carrier for beta-thalassaemia as well. Both pregnancies resulted in live births and subsequent immunoreactive trypsin estimations were both in the normal range.

Chorionic Villi↗