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Biomedical subjects

P D Williams

Publications and source records attributed to P D Williams.

At least 19 recordsLinked to original sources
PubMed2001

Interactions between sources of mortality and the evolution of parasite virulence.

A well-known result from the theory of the evolution of virulence is the prediction that the virulence of a pathogen (i.e. the rate of parasite-induced host mortality) always evolves to higher levels when host background mortality rates increase. This prediction, however, is derived from models that assume that host mortality sources combine additively to determine the overall host mortality rate. In this paper, we suggest that such additivity is probably rare for many host-pathogen systems, and explore how the predictions for the evolution of virulence are altered when interactions between host mortality sources are incorporated into the theory. Our results indicate that if mortality-source interactions are sufficiently strong then the evolutionarily stable level of virulence can actually decrease as the background mortality rate increases. Consequently, a detailed mechanistic description of how parasites and other mortality sources combine to cause host mortality is required before reliable predictions about virulence evolution can be made. Moreover, mortality-source interactions make empirical comparisons of the virulence of different parasites a much more subtle issue.

Animals↗
PubMed2001

The binding of soybean agglutinin (SBA) to the intestinal epithelium of Atlantic salmon, Salmo salar and rainbow trout, Oncorhynchus mykiss, fed high levels of soybean meal.

A lectin present in soya, soybean agglutinin (SBA), was identified in electrophoretic profiles and immunoblots of dehulled solvent-extracted soybean meal (DSSM), full-fat soybean meal (FFSM) and of aqueous extracts of feeds incorporating them in their formulation. A quantitative estimation was made of the proportion of SBA comprising the total protein in FFSM and a trial diet was prepared containing an amount of pure SBA similar to that in diets incorporating high levels of the whole soya product. Fish fed with this diet exhibited similar pathological disruption of the intestinal tract to that observed in fish given a diet with a high level of DSSM (60% of the diet). Furthermore, immuno-histochemistry revealed the binding of the SBA to the enterocytes lining the intestinal villi both of fish fed a diet incorporating pure SBA and those fed a diet containing a high-level of soya (60%). Our results suggest that SBA binds in vivo to the intestinal epithelium of fish and has a contributory role in pathological changes associated with fish feeds containing high levels of soybean proteins.

Animal Feed↗
PubMed2001

Treatment type and symptom severity among oncology patients by self-report.

Oncology patients receiving chemotherapy (n=109) and radiation therapy RT (n=161) reported symptom concerns and severity on the 25-item therapy-related symptom checklist (TRSC). Secondary analysis of the self-reports of the two treatment groups was done using the Mann-Whitney U Test. Thirteen symptoms differed significantly between the two groups. RT patients reported significantly greater severity of five symptoms (p<0.05) during therapy. Chemotherapy patients reported significantly greater severity of eight different symptoms. The other 14 items showed a heterogeneous pattern of self-reported patient symptom concerns. The TRSC appears to be a clinically useful self-report checklist that captures the more important symptom concerns of both RT and chemotherapy patients. Earlier efforts to develop this checklist are reviewed briefly.

Antineoplastic Agents↗
PubMed2001

Evolution of functionality in lattice proteins.

We study the evolution of protein functionality using a two-dimensional lattice model. The characteristics particular to evolution, such as population dynamics and early evolutionary trajectories, have a large effect on the distribution of observed structures. Only subtle differences are observed between the distribution of structures evolved for function and those evolved for their ability to form compact structures.

Evolution, Molecular↗
PubMed2000

Mothers' developmental expectations for young children in the Philippines.

The purpose of the study was to investigate the developmental timetables of rural and urban mothers in the Central Visayas, Philippines. Examined were mothers' expectations for children's development (physical/perceptual-motor, cognitive, and psychosocial) and mothers' child rearing practices, as influenced by four selected variables (child's gender and ordinal position, mother's education, and rural or urban residence). The total sample size was 303 mothers [153 of rural residence and 150 urban] in two provinces. Mothers responded to a structured questionnaire which was read to them aloud by trained interviewers who then recorded the responses. All the mothers had children between 4-6 years old; equal numbers of male and female children were included, and the entire economic and educational ranges were represented. MANOVA results showed significant main effects of all four variables on maternal expectations of child development and on maternal child rearing practices. Also, significant interaction effects of residential location and maternal education on mothers' expectations of children's physical/perceptual motor development were found (F[2, 256]=3.05, P=0.05). Significant interaction effects also were found of maternal education and the child's ordinal position (F[4,256]=2. 95, P=0.02) on maternal expectations of children's psychosocial development.

Adult↗
PubMed2000

Balinese mothers' developmental timetables for young children.

The study examined Balinese mothers' expectations for children's development and mothers' child-rearing practices, as influenced by selected variables (child's gender and ordinal position, mother's education, and rural or urban residence). Rural (n = 100) and urban (n = 100) mothers responded to structured questionnaires read aloud to them by trained interviewers who recorded responses. All children were between 4 and 6 years. Equal numbers of male and female children were included, and the entire economic and educational ranges of families were represented. MANOVA results showed significant interaction effects of residential location and maternal education on mothers' expectations of children's cognitive, F(2, 170) = 4.31, p = .04, and psychosocial development, F(2, 170) = 4.35, p = .01. Significant interaction effects were found for maternal education, residential location, child's ordinal position, and gender, F(3, 170) = 5.92, p = .001, on maternal child-rearing practices. Two developmental timetables were constructed.

Adult↗
PubMed1999

Immunological, physiological and pathological responses of rainbow trout (Oncorhynchus mykiss) to increasing dietary concentrations of soybean proteins.

High concentrations of dietary soya were shown to suppress salmonid growth rates and non-specific immune capacity. The immunosuppression became evident at dietary inclusion rates of 60-70% and was coincident with a reduction in weight gains and the appearance of demonstrable pathological changes in the distal intestine. Further increases in soya concentrations to 80-89% caused a progressive decline in specific growth rates and exacerbation of the intestinal pathology. There was no evidence of circulating antibody responses to dietary soybean proteins at any of the rates of inclusion. These observations confirm the findings of other authors that, at concentrations of up to 20-30% inclusion in diets, soybean proteins can provide a partial replacement for fish meal, but at higher concentrations detrimental effects become apparent, not only through reduced weight gains, but also through other physiological and immunological changes.

Animal Feed↗
PubMed1999

A new class of simplified phorbol ester analogues: synthesis and binding to PKC and eta PKC-C1B (eta PKC-CRD2).

[formula: see text] A unique class of simplified phorbol ester analogues is described for the first time. A highly efficient retro-annelation sequence was developed in order to remove the five-membered ring from the phorbol diterpene core, allowing access to BCD ring analogues of the phorbol esters. The binding of these analogues to protein kinase C (PKC) and the truncated peptide eta PKC-C1B (eta PKC-CRD2) is also reported.

Animals↗
PubMed1999

Nonpeptide oxytocin antagonists: analogs of L-371,257 with improved potency.

Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).

Animals↗
PubMed1999

Fatigue in mothers of infants discharged to the home on apnea monitors.

A comparative study was done to determine differences in caregiver fatigue between two groups of mothers of preterm infants at baseline, in the hospital (Time 1), 1 week postdischarge (Time 2), and 1 month postdischarge (Time 3). Group 1 infants were discharged home on apnea monitors (AM) (n = 28), and Group 2 infants were not on apnea monitors (nonAM)(n = 46). Measured by the Multidimensional Assessment of Fatigue (MAF) scale, mean fatigue scores from Time 1 to Time 3 markedly increased for the monitor group and decreased for the nonmonitor group. The scores were significantly different between the two groups at Times 2 and 3 but not at baseline. Two-way analysis of variance (ANOVA) with repeated measures showed group by time interaction effects on fatigue. Monitoring and alleviation of fatigue in home caregivers of preterm infants on apnea monitors are necessary.

Adolescent↗
PubMed1999

Defining and measuring fatigue.

In response to a long history of problems with defining and measuring fatigue, the University of Kansas School of Nursing established a Center for Biobehavioral Studies of Fatigue Management to facilitate the study of fatigue in diverse populations. The purpose of this article is to review past efforts to define and measure fatigue and the conceptual problems relevant to currently used measures of fatigue. Several distinct characteristics and corresponding measures of fatigue are identified and a definition and framework for the study of fatigue are discussed. Future research on fatigue must attend to the conceptual distinctions among various measures and the measures of fatigue most appropriate to the goals of a study.

Diagnosis, Differential↗
PubMed1998

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines.

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.

Administration, Oral↗
PubMed1998

Progress in the development of oxytocin antagonists for use in preterm labor.

There is currently a need for new therapeutic agents for treating preterm labor which could offer improved safety and efficacy beyond what has been achieved with the widely employed beta-mimetics. In this regard, the longstanding hypothesis of oxytocin receptor blockade as representing a potentially more selective method of tocolysis has continued to gain support from results obtained in clinical studies with the peptide oxytocin antagonist, atosiban. Our laboratory has focussed on the identification of non-peptide oxytocin antagonists with properties suitable for both oral and intravenous administration. We have previously described the development of potent, camphor-based oxytocin antagonists, including L-368,899 which entered phase I human studies. More recently we have pursued a new structural class of oxytocin antagonists based on the 1-(N-benzoylpiperidin-4-yl)-4H-3,1-benzoxazin-2(1H)-one template. L-372,662 is a new member of this structural class and in our preclinical assays possesses an attractive overall profile from the standpoint of human oxytocin receptor affinity (Ki = 4.9 nM), human oxytocin vs. vasopressin receptor selectivity (> 500-fold), potency as an antagonist of oxytocin-induced uterine contractions in late gestation pregnant rhesus monkeys (AD50 = 36 micrograms/kg), oral bioavailability (F = 90% in dogs), and aqueous solubility (10 mg/mL).

Animals↗
PubMed1998

Comparative effects of heparin and the sulfatoid GM1474 on coagulation parameters in plasma and blood from various species.

1. The discovery and development of novel carbohydrate molecules based on heparin biology and pharmacology requires consideration of coagulation effects in evaluating the therapeutic potential of these agents. A novel sulfatoid compound, GM1474, possessing potent antiproliferative and antiangiogenic properties similar to those of heparin, was evaluated for comparative coagulation effects. 2. In vitro and in vivo effects of GM1474 on plasma-activated partial prothromboplastin time (aPTT) and whole-blood clotting time (WBCT) were monitored in plasma and blood from various species and compared with those of heparin. GM1474 possessed approximately 21.7% of the in vitro aPTT and 4.3% of the in vitro WBCT effects relative to heparin, utilizing human plasma and blood. 3. Similar differences between GM1474 and heparin were observed in plasma and blood from mice, rats, dogs and nonhuman primates. The concentrations of GM1474 producing a two-fold increase in aPTT and WBCT in vitro in the various species ranged from 2.95 to 11.4 times the concentrations of heparin producing similar effects. 4. In in vivo evaluations in mice, the intravenous doses of GM1474 producing 50% of the maximal elevation in plasma aPTT and bleeding time (IC50s) were 2.1 and 12.0 mg/kg, respectively. These doses represented approximately 6.4- and 27.9-fold the in vivo IC50, doses of heparin causing elevations in aPTT and bleeding times, respectively. 5. The results of this study demonstrate that GM1474 possesses significantly reduced effects on coagulation relative to heparin, as determined by in vitro and in vivo testing. 6. Species differences in sensitivity to GM1474 and heparin were also observed in in vitro profiling. The order of species sensitivity to GM1474 and heparin was similar (mice>human beings>rats>non-human primates>dogs) and indicates that the mouse may be the most predictive species with respect to coagulation effects in human beings.

Animals↗
PubMed1998

Effects of beta-blockers on the concentration and oxidizability of plasma lipids.

1. beta-blockers improve morbidity and mortality after myocardial infarction, probably by several mechanisms. We investigated potentially relevant effects of beta-blockers in vivo and in vitro on plasma lipid oxidizability. Forty-two healthy men were randomized to receive placebo (13), metoprolol (14) or propranolol (15). 2. At 4 weeks, the effects on heart rate, blood pressure and lipids appeared similar and subjects taking a beta-blocker were combined. Compared with placebo, those on a beta-blocker gained 0.5 kg in weight (P = 0.04), heart rate fell from 63 to 52 beats/min (P < 0.0001) and blood pressure fell from 116/74 to 113/69 mmHg (P < 0.005); high-density lipoprotein (HDL)-cholesterol fell from 1.26 to 1.11 mmol/l (P = 0.005), there being no change in the ratio of free to esterified cholesterol in HDL, and there was an apparent rise in serum triacylglycerols from 1.18 to 1.43 mmol/l (P = 0.15 when adjusted for weight gain). Low-density lipoprotein (LDL)-cholesterol and lipoprotein (a) did not change. In this study, the oxidizability of LDL was unaffected by beta-blocker therapy. beta-blockade was not associated with any change in LDL fatty acid profile, or beta-carotene or alpha-tocopherol content which might account for the reduced LDL oxidizability previously reported in patients treated with beta-blockers. Furthermore, neither atenolol nor propranolol, at concentrations up to 100 mumol/l, had any effect on in vitro oxidizability of LDL obtained from healthy volunteers. 3. In contrast to the favourable haemodynamic effects conferred by beta-blockers, the effects on weight and serum triacylglycerols and HDL-cholesterol appear to be adverse and we did not demonstrate any changes in lipid oxidizability which might be relevant to the protective effects of beta-blockers in patients with coronary disease.

Adrenergic beta-Antagonists↗