Biomedical subjects
Publications and source records attributed to L Matthews.
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
A detailed analysis of a scrapie outbreak in a flock of Cheviot sheep is described. A total of 33 cases of 1473 sheep born to the flock were reported between 1985 and 1994. The epidemiology of scrapie can only be understood with reference to sheep demography, the population genetics of susceptibility to scrapie, pathogenesis during a long incubation period, and the rate of transmission (by both horizontal and vertical routes), all of which interact in complex ways. In recent work a mathematical model incorporating these elements was developed and successfully reproduced key features of an earlier outbreak of scrapie in this flock. Here an application of the model to the second outbreak is described. The model accurately reproduces observed allele frequencies and total numbers of susceptible animals remaining at the end of the outbreak. A major difference between the two outbreaks is the very much lower force of infection in the second outbreak. This provided additional information which suggested two ways in which our existing assumptions be refined; firstly, older animals have reduced susceptibility to scrapie and secondly, homozygous and heterozygous susceptibles have different incubation periods.
The apparent persistence of scrapie in British sheep for more than 250 years is difficult to explain. Susceptibility to scrapie is associated with particular alleles at a single locus, the PrP gene. As the only known effect of these alleles is to confer susceptibility to a fatal disease, natural selection is expected to reduce their frequency, as has been observed in practice during scrapie outbreaks in single sheep flocks. Susceptibility alleles, and hence scrapie itself, are therefore expected to become rare, yet the disease remains widespread. We suggest that the paradox of scrapie's persistence can be explained by the exceptionally long time-scales inherent in the epidemiology of the disease. It is proposed that scrapie should be regarded as epidemic in British sheep but, unlike more familiar epidemics, which have time-scales of months or years, the scrapie epidemic has a time-scale of centuries. This interpretation implies that scrapie should eventually disappear from the sheep population.
To address mechanisms of corticosteroid action, one needs tools for distinguishing between the major classes of corticosteroid binding sites: neuronal membrane-associated receptors, intracellular ligand-activated transcription factors, and corticosteroid binding globulins (CBG) in plasma. We characterized the binding parameters for three classes of binding sites in an amphibian, Ambystoma tigrinum, and found that each class had a distinct pharmacological specificity. Equilibrium saturation and kinetic experiments indicated that [3H]corticosterone binds to neuronal membranes with high affinity (Kd approximately 0.37 nM). Aldosterone and two synthetic ligands for mammalian intracellular receptors, dexamethasone and RU486, displayed low affinity for brain membrane sites. In cytosol prepared from brain and liver, [3H]corticosterone bound to a single class of receptors with high affinity (Kd approximately 0.75 and 4.69 nM, respectively) and the rank order potencies for steroid inhibition of [3H]corticosterone binding was RU486 > dexamethasone approximately = corticosterone > aldosterone. In kidney and skin cytosol, [3H]corticosterone binding was best fit with a model having a high-affinity and a lower-affinity site; these sites are not consistent with the pharmacology of mammalian Type I (MR) and Type II (GR) receptors. [3H]Corticosterone also bound to presumed CBG in plasma with high affinity (Kd approximately 2.7 nM), but dexamethasone and androgens bound to plasma CBG with equivalently high affinity. These data demonstrate that pharmacological specificity can be a useful tool for distinguishing corticosteroid binding to different classes of binding sites. These data also indicate that there may be marked species differences in the specificity of corticosteroid binding sites.
Plasma steroid-binding globulins, for example, corticosteroid-binding globulin and sex hormone-binding globulin (SHBG), have been identified in a number of vertebrates. One possible function of these proteins is to regulate the amount of steroid delivery to target tissues, as only free steroids are believed to diffuse from the circulation to target cells. Male tree lizards, Urosaurus ornatus, exhibit alternative male reproductive tactics correlated with dewlap (throat-fan) coloration. Males with orange-blue dewlaps are aggressive and territorial, whereas males with orange dewlaps are less aggressive and employ a satellite strategy. The two types of males have similar basal levels of total plasma corticosterone and testosterone. However, testosterone levels of nonterritorial males are more sensitive than those of territorial males to negative regulation by stress-induced increases in corticosterone. We tested the hypothesis that this difference in corticosterone feedback on testosterone could be mediated, in part, by differences in binding globulin levels between the two types of males. We have identified two steroid-binding globulins in male tree lizards. The first binds androgens and estradiol with high affinity (10(-9) M) and is similar to previously described sex hormone-binding globulins. The second binds both androgens and C(21) steroids, such as progesterone and corticosterone, with higher specificity than estradiol and is best described as an androgen-glucocorticoid-binding globulin (AGBG). In both types of males, the capacity of AGBG is much higher than SHBG. In addition, AGBG capacity is significantly greater in territorial than nonterritorial males, whereas the capacity of SHBG does not differ between the two types of males. Calculations of free steroid levels based on the affinity and capacity measures suggest that although most testosterone circulates bound to binding globulins, binding capacity is high enough that binding globulins are also able to bind to other steroids such as corticosterone. Thus, differences in binding capacity between the two types of males could result in higher levels of free corticosterone in nonterritorial males than in territorial males, especially during stress-induced increases in corticosterone, and may explain why testosterone levels of nonterritorial males are more sensitive to negative feedback by corticosterone.
The consultative document, 'Our Healthier Nation' (Department of Health, 1998a), outlined areas for health improvement, and offers health professionals an opportunity to use the Government's programme to raise breast-feeding rates. This article reports the results of an audit to establish local breast-feeding prevalence rates in south Leicestershire, and when and why women stop breast-feeding. A simple questionnaire was used by health visitors to collect data on all babies born over a 3-month period (October 1997 - December 1997). The audit found that 57% of mothers were breast-feeding at birth compared with national breast-feeding figures of 64%. The rate at which women stopped breast-feeding substantially increased between 10 days and 6-8 weeks postpartum. Women stopped breast-feeding for a variety of reasons. The information provided by the audit will be used to inform health-visiting practice and in the long term will hopefully help to increase breast-feeding rates in this area.
The basic reproduction number R0 provides a quantitative assessment of the ability of an infectious agent to invade a susceptible host population. A mathematical expression for R0 is derived based on a recently developed model for the spread of scrapie through a flock of sheep. The model incorporates sheep demography, a long and variable incubation period, genetic variation in susceptibility to scrapie, and horizontal and vertical routes of transmission. The sensitivity of R0 to a range of epidemiologically important parameters is assessed and the effects of genetic variation in susceptibility are examined. A reduction in the frequency of the susceptibility allele reduces R0 most effectively when the allele is recessive, whereas inbreeding may increase R0 when the allele is recessive, increasing the chance of an outbreak. Using this formulation, R0 is calculated for an outbreak of scrapie in a flock of Cheviot sheep.
A detailed analysis of an outbreak of natural scrapie in a flock of Cheviot sheep is described. A total of 137 cases was reported over 13 years among 1307 sheep born into the flock. The epidemiology of scrapie can only be understood with reference to sheep demography, the population genetics of susceptibility to scrapie, pathogenesis during a long incubation period, and the rate of transmission (by both vertical and horizontal routes), all of which interact in complex ways. A mathematical model incorporating these features is described, parameter values and model inputs are derived from available information from the flock and from independent sources, and model outputs are compared with the field data. The model is able to reproduce key features of the outbreak, including its long duration and the ages of cases. The analysis supports earlier work suggesting that many infected sheep do not survive to show clinical signs, that most cases arise through horizontal transmission, and that there is strong selection against susceptible genotypes. However, important aspects of scrapie epidemiology remain poorly understood, including the possible role of carrier genotypes and of an environmental reservoir of infectivity, and the mechanisms maintaining alleles giving susceptibility to scrapie in the sheep population.
OBJECTIVE: With survivors of road trauma at risk of experiencing posttraumatic stress disorder (PTSD) and more routinely seeking psychosocial and vocational rehabilitation services, published research findings on the impact of PTSD on occupational functioning following road trauma are of increasing interest. This report investigates the literature in this area to highlight findings that may guide the development of public policy and interventions to improve occupational functioning post-accident. METHOD: A comprehensive search of the psychiatric and psychological literature in the subject area was undertaken for the period 1980-1998. RESULTS: In the absence of a conceptual framework empirical findings have focused on one aspect of occupational functioning, individual ability, at the expense of other contributing factors from both the individual and work environment. CONCLUSIONS: Very little research has been focused on developing a model that would explain the impact of PTSD on occupational functioning following road trauma. IMPLICATIONS: The absence of an empirically supported theoretical framework hinders the development of appropriate preventative interventions and tailored vocational rehabilitation for individuals with PTSD.
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Mathematical models of the transmission dynamics of scrapie are used to explore the expected course of an outbreak in a sheep flock, and the potential impacts of different control measures. All models incorporate sheep demography, a long and variable scrapie incubation period, horizontal and vertical routes of transmission and genetic variation in susceptibility. Outputs are compared for models which do and do not incorporate an environmental reservoir of infectivity, and which do and do not incorporate carrier genotypes. Numerical analyses using parameter values consistent with available data indicate that, in a closed flock, scrapie outbreaks may have a duration of several decades, reduce the frequency of susceptible genotypes, and may become endemic if carrier genotypes are present. In an open flock, endemic scrapie is possible even in the absence of carriers. Control measures currently or likely to become available may reduce the incidence of cases but may be fully effective only over a period of several years.
Visceral left-right asymmetry occurs in all vertebrates, but the inversion of embryo turning (inv) mouse, which resulted following a random transgene insertion, is the only model in which these asymmetries are consistently reversed. We report positional cloning of the gene underlying this recessive phenotype. Although transgene insertion was accompanied by neighbouring deletion and duplication events, our YAC phenotype rescue studies indicate that the mutant phenotype results from the deletion. After extensively characterizing the 47-kb deleted region and flanking sequences from the wild-type mouse genome, we found evidence for only one gene sequence in the deleted region. We determined the full-length 5.5-kb cDNA sequence and identified 16 exons, of which exons 3-11 were eliminated by the deletion, causing a frameshift. The novel gene specifies a 1062-aa product with tandem ankyrin-like repeat sequences. Characterization of complementing and non-complementing YAC transgenic families revealed that correction of the inv mutant phenotype was concordant with integration and intact expression of this novel gene, which we have named inversin (Invs).
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In the present longitudinal study of 330 married men and 300 married women, we use a comprehensive structural equation model to investigate how occupation is linked to physical health. Results show that occupational quality influences health-risk behavior (measured by composite indices) for both men and women through a series of mediating variables: social integration, marital integration, and psychological control. Health-risk behavior is related to adverse change in physical health status over a two-year period. Occupational quality influences social and marital integration and psychological control for both husbands and wives. Social integration and marital integration also enhance husbands' psychological control, but marital integration is the only factor contributing to wives' psychological control. In turn, psychological control is associated with health-risk behaviors for both husbands and wives. In addition, both social and marital integration directly deter husbands' health-risk behaviors, while social integration is the only variable to directly influence wives' health-risk behaviors.
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Nuclear transfer (NT) procedures were used to determine the in vivo developmental capacity of bovine embryonic cell lines derived from both morula- and blastocyst-stage embryos. These cell lines differed in morphology from trophoblast and endoderm-like cells. Regardless of initial donor embryo stage, cells in the resulting bovine embryonic cell lines had a small cytoplasmic/nuclear volume ratio and contained cytoplasmic vesicles. Developmental rates to blastocyst stage for NT embryos were improved when smaller cells (15 microns) rather than larger cells (18 microns or 21 microns) were used in the NT procedure and the recipient oocyte was activated after the cell fusion step. NT embryos produced from these embryonic cell lines, both morula- and blastocyst-derived, initiated pregnancies following transfer into recipient females. However, all of these pregnancies were lost prior to 60 days of gestation. These NT embryos were able to direct development through organogenesis, with one NT fetus reaching 55 days before death. When viable NT embryos were recovered during early gestation (38 days), an absence of cotyledons and a hemorrhagic response in the caruncles were observed. A chimera produced by aggregating an NT embryo with two 8-cell-stage blastomeres from in vitro-produced embryos developed through the 85th day of gestation. However, this conceptus was also deficient of cotyledons. DNA markers indicated that 50% of the chimera conceptus tissues were derived from the embryonic cell line. Blastocyst- and morula-derived embryonic cell line nuclei are pluripotent in that they can direct development through organogenesis, with subsequent pregnancy loss due, at least in part, to a deficiency in placentome development.