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Biomedical subjects

P Williams

Publications and source records attributed to P Williams.

At least 307 records · Page 17Linked to original sources
PubMed1993

SPROUT: a program for structure generation.

SPROUT is a new computer program for constrained structure generation that is designed to generate molecules for a range of applications in molecular recognition. It uses artificial intelligence techniques to moderate the combinatorial explosion that is inherent in structure generation. The program is presented here for the design of enzyme inhibitors. Structure generation is divided into two phases: (i) primary structure generation to produce molecular graphs to fit the steric constraints; and (ii) secondary structure generation which is the process of introducing appropriate functionality to the graphs to produce molecules that satisfy the secondary constraints, e.g., electrostatics and hydrophobicity. Primary structure generation has been tested on two enzyme receptor sites; the p-amidino-phenyl-pyruvate binding site of trypsin and the acetyl pepstatin binding site of HIV-1 protease. The program successfully generates structures that resemble known substrates and, more importantly, the predictive power of the program has been demonstrated by its ability to suggest novel structures.

Artificial Intelligence↗
PubMed1993

Food preferences and food habits of patients with chronic renal failure undergoing dialysis.

OBJECTIVE: To examine and compare the food preferences of patients undergoing maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) with those of age- and sex-matched controls. DESIGN: We administered two questionnaires, one assessing preferences for 88 food items (according to a nine-point hedonic scale) and the other assessing factors influencing dietary habits. SUBJECTS: Thirty-three patients on HD, 17 patients on CAPD, and 30 control subjects with normal renal function. MAIN OUTCOME MEASURES: The 88 foods were grouped into 14 classes to compare preferences. Taste aversions, food preparation details, and psychological and social determinants of food intake were also compared. STATISTICAL ANALYSIS: The preference ratings of the HD, CAPD, and control groups were compared using analysis of variance. The dietary habits results were examined using a chi 2 analysis. RESULTS: Sweet foods (P = .002), vegetables (P = .003), red meats (P = .010), and fish and poultry (P = .015) were less pleasant for patients on HD than for control subjects. Red meats (P = .019), fish and poultry (P = .032), and eggs (P = .005) were less pleasant for patients on HD than for patients on CAPD. Red meat was the most unpopular food group for all dialysis patients. The most common factor affecting dietary intake was a loss of interest in food and/or cooking. CONCLUSION: We conclude that chronic renal failure influences patients' food preferences and food habits. Knowledge of these preferences will help dietitians plan more adequate and enjoyable diets for such patients.

Adult↗
PubMed1993

Influence of block copolymers on the adsorption of plasma proteins to microspheres.

SDS-PAGE in combination with densitometry has been used to evaluate the adsorption of plasma and serum proteins to polystyrene microspheres (PS) coated with block copolymers of the poloxamer and poloxamine series. The protein-resistant nature of coated PS was demonstrated for these systems when incubated in dilutions of plasma and serum. The total amount of protein and the type of proteins adsorbed were dependent on the plasma and serum incubation concentration used. At 0.3% serum concentrations the total amount of protein adsorbed was found to be related to the polyoxyethylene (PEO) chain length of the block copolymer, whilst at 0.3% or 50% plasma concentrations a relationship was shown between the polyoxypropylene (PPO) chain and the plasma protein adsorption for the range of block copolymers studied. Immunoblotting studies revealed the adsorption of immunoglobulin G, complement C3, transferrin and fibronectin to all microspheres previously incubated in 50% serum and plasma, whilst fibrinogen was also adsorbed after incubation in 50% plasma; with similar quantities of each protein adsorbed to PS and block copolymer-coated PS.

Adsorption↗
PubMed1993

Changes in adolescents' knowledge and attitudes about AIDS over the course of the AIDS epidemic.

We compared AIDS-related attitudes of junior and senior high school students from 1988 to 1991 and across grade level to examine how effectively schools are addressing AIDS. Attitudes measured included knowledge and social anxiety about AIDS, as well as perceptions of vulnerability to HIV infection. Junior high school students (grades 7-9) were sampled three times, from 1989 to 1991. High school students (grades 10-12) were sampled four times, from 1988 to 1991. The 1991 junior high school sample had lower AIDS knowledge scores than the 1989 sample. Conversely, the 1991 high school sample had more accurate knowledge than earlier groups. With respect to grade level, 9th graders had more accurate knowledge than 7th and 8th graders, but knowledge did not increase from 10th through 12th grade. Anxiety about interacting with a person with AIDS and perceptions of vulnerability to HIV infection were unrelated to either sampling time or grade level. It is concluded that it will be important to redouble efforts to educate adolescents about AIDS and that particular attention needs to be paid to young adolescents.

Acquired Immunodeficiency Syndrome↗
PubMed1993

The attaching and effacing virulence property of enteropathogenic Escherichia coli.

Enteropathogenic Escherichia coli (EPEC) remain an important cause of infant diarrhoea in many parts of the developing world. Essential for virulence is their ability to adhere to the small intestinal mucosa and produce a striking 'attaching and effacing' (AE) lesion characterised by localised destruction of brush border microvilli, intimate attachment of bacteria to the residual apical enterocyte membrane, often in a cuplike pedestal structure, and formation of a dense plaque of actin (and other) cytoskeletal filaments beneath adherent bacteria. Fluorescence actin staining (FAS test) has turned out to be a useful diagnostic test for the AE lesion and also led to the identification of a chromosomal gene, eae, which is necessary but, by itself, not sufficient to produce the AE lesion. The 94 kDa outer membrane protein encoded by eae may be the adhesin which promotes intimate bacterial attachment. The signal transduction pathway which leads to AE lesion formation has yet to be defined although EPEC induced increased levels in intracellular calcium and phosphorylation of specific cell proteins including myosin light chain suggest that EPEC, by binding to a specific host cell receptor, may be promoting a calcium second message which would a) activate the brush border protein villin to cause microvillar breakdown and b) stimulate protein kinase activity to cause the other cytoskeletal rearrangements.

Actins↗
PubMed1993

The N-methyl-D-aspartate antagonist MK-801 fails to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium toxicity in vitro.

Recent reports suggest that NMDA receptor antagonists when administered in vivo can protect dopaminergic neurons from the toxic actions of MPP+. In the present study the possible neuro-protective effects against MPP+ toxicity of the noncompetitive NMDA receptor antagonist MK-801 was studied in primary cultures of fetal rat mesencephalic dopamine neurons. MK-801 failed to protect dopaminergic neurons from MPP+ toxicity at concentrations that completely block NMDA-induced toxicity of these same neurons. In contrast to work carried out in cerebellar granule cells, MPP+ toxicity of mesencephalic dopamine neurons was unaffected by preexposure to subtoxic concentrations of either NMDA or cycloheximide. Our findings suggest that the toxic effects of MPP+ on dopaminergic neurons are not mediated through a direct interaction with the NMDA subtype of glutamate receptor.

1-Methyl-4-phenylpyridinium↗
PubMed1993

Maternal factors that influence inadequate prenatal care.

Fifty-seven pregnant women who received inadequate prenatal care identified the factors that influenced their decisions related to prenatal care. Data were collected in an institution that serves neighborhood clinics that offer free prenatal care and can be reached by public transportation. Women were interviewed either prenatally (n = 23) or postnatally (n = 34). The interview questions were drawn from the literature on the adequacy of prenatal care. The women identified 22 personal reasons and structural barriers for receiving inadequate prenatal care. The five most frequently cited reasons were small children at home, no medical assistance card, didn't know reason, sadness or ambivalence about the pregnancy, and just moved to the area. Despite demographic risk and facing the similar barriers, some women manage to receive sufficient care and others do not. Presently, government and other policy-making groups often believe that public insurance, Medicaid, or socialized medicine is the answer to our high infant mortality rate. However, in some geographic areas where financial barriers are not factors and where services are available that meet pregnant women's needs, some women still do not enter care early and remain in care. Data that expand knowledge on why women receive inadequate prenatal care will be useful in developing community outreach programs, preparing public service announcements, and designing prenatal services.

Adolescent↗
PubMed1993

An epidemiological study of falls in older community-dwelling women: the Randwick falls and fractures study.

Seven hundred and four women aged between 65 and 99 years (mean age 74.6 years), who were randomly selected from the community, took part in a study to determine whether health and lifestyle factors were associated with falls. In the 12 months before the survey, 66.1 per cent of the subjects experienced no falls, 19.7 per cent fell once and 14.2 per cent fell on two or more occasions. The proportion of women who fell outside the home decreased with age, with a corresponding increase in the proportion who fell inside the home on a level surface. The most common causes of falls reported were trips, slips and loss of balance. Some (27 per cent) suffered injuries as a result of a fall, and the proportion suffering injuries increased with age. Those who rated their health and balance as impaired, those with a limitation in activities of daily living, those receiving community services, those taking psychoactive drugs, and those taking four or more drugs had significantly more falls. On the other hand, those taking part in planned exercise and those active for seven or more hours per week had fewer falls. Smoking and alcohol consumption were not significantly associated with falls. Stepwise logistic regression analysis revealed poor vision, inactivity and subjective fall risk as variables that were independently and significantly associated with falling. These findings highlight possible intervention strategies for reducing falls risk in older people.

Accidental Falls↗
PubMed1993

Co-transplantation of plasmid-transfected myoblasts and myotubes into rat brains enables high levels of gene expression long-term.

We have previously proposed the use of primary muscle cells as a "platform," or "vehicle" for intracerebral transgene expression. Brain grafts of minced muscle, or cultured muscle cells persisted in rat brains for at least 6 mo without any decrease in graft size, or tumor formation. Stable, but moderate levels of intracerebral transgene expression were obtained by transplanting plasmid-transfected myotubes in culture. In the present study, high and stable levels of intracerebral transgene expression were achieved by the co-transplantation of plasmid-transfected myoblasts and myotubes in culture. Approximately 5 X 10(5) myoblasts and myotubes were transfected with 10 micrograms pRSVL plasmid DNA, and 30 micrograms Lipofectin (BRL), respectively. They were mixed together (total cell number was 1 million), and stereotactically injected into the caudate nucleus of an adult rat brain. The activity of luciferase, the product of transgene expression, was stable for at least 4 mo, and much higher than the levels in myotube grafts, or co-grafts of myoblasts and minced muscle. Presumably, the myotubes served as a framework on which the myoblasts can form myotubes. The sections of brains transplanted with co-graft of myoblasts, and myotubes transfected with pRSVLac-Z were stained immunofluorescently for beta-galactosidase activity. The muscle grafts contained beta-galactosidase positive myofibers 4 mo after transplantation. Such high and stable levels of in vivo expression after postnatal gene transfer have rarely been achieved. Primary muscle cells are useful vehicle for transgene expression in brains, and potentially valuable for gene therapy of degenerative neurological disorders.

Animals↗
PubMed1993

Psychometric assessment of diabetic impotence.

In a study of 23 diabetic men complaining of impotence, completion of physical tests, self-report psychometric testing, a rating of marital intimacy, and a semi-structured interview revealed that, of ten patients found to be at risk of psychogenic impotence secondary to marital or psychiatric morbidity, five were thought to have adequate erectile response and to have a psychogenic component to their problem. This seems to show high sensitivity, if not specificity, of the self-report questionnaires.

Adult↗
PubMed1993

An enzyme-linked immunoadsorbent assay for human pituitary glycoprotein free alpha-subunit: evaluation and initial experience in patients with pituitary disease.

An enzyme-linked immunoadsorbent assay (ELISA) for measuring human pituitary glycoprotein free alpha-subunit is described. Pituitary tumours may secrete glycoprotein hormones, their free subunits (alpha, beta) or a combination of these. Non-functioning adenomas often secrete free alpha-subunit. Assays for free alpha-subunit have previously used radioimmunoassay or immunoradiometric principles. Some of these methods are time-consuming and lack specificity and sensitivity. In order to overcome these problems, we have developed a two-site ELISA for alpha-subunit which uses a monoclonal antibody to alpha-subunit as the capture antibody to provide greater specificity. An affinity-purified polyclonal anti alpha-subunit conjugated to alkaline phosphatase was the signal antibody. Detection and quantification were based on phenolphthalein monophosphate conversion to phenolphthalein. The ELISA specifically measured glycoprotein free alpha-subunit in serum or plasma, discriminating between alpha-subunit and the intact glycoprotein hormones. The assay can be completed in 4 h. The assay sensitivity was 0.03 micrograms/l, and a normal range of 0.05 to 0.22 micrograms/l was established. In a retrospective study, elevated circulating glycoprotein alpha-subunit was detected in 22% of patients with non-functioning pituitary tumours previously treated with surgery and/or radiotherapy.

Adolescent↗
PubMed1993

Autoregulation of carbapenem biosynthesis in Erwinia carotovora by analogues of N-(3-oxohexanoyl)-L-homoserine lactone.

N-(3-Oxohexanoyl)-L-homoserine lactone (HSL) (I) is the autoregulator controlling carbapenem antibiotic biosynthesis in Erwinia carotovora ATCC 39048. The chemical synthesis and biological evaluation of analogues of HSL are described. These include alterations of chirality, side-chain modifications, ring size and ring hetero atom. A number of compounds are reported which are capable of restoring the phenotype to a HSL negative mutant but at higher concentrations than HSL. A-factor, the autoregulator of streptomycin biosynthesis in Streptomyces griseus, was not active as an inducer of carbapenem biosynthesis in E. carotovora.

4-Butyrolactone↗
PubMed1993

Infection after lung transplantation.

Infections have been and still are the major cause of morbidity and mortality after lung transplantation. Nevertheless, the negative impact of infection on outcome has lessened considerably over the last decade because of lessons learned in the prevention, identification, and treatment of infection. Antibiotics tailored to the results of cultures and stains of respiratory-tract secretions obtained from both the donor and recipient have markedly decreased the prevalence of bacterial pneumonia early after lung transplantation. Ganciclovir treatment has reduced the mortality of cytomegalovirus (CMV) disease from 27% to 1%. Ganciclovir as prophylaxis has modestly reduced the prevalence of CMV illness from 80% to 60%. Pneumocystis infection has been nearly eliminated with low-dose trimethropin/sulfamethoxazole prophylaxis. Treating all Candida/Aspergillus isolates from respiratory-tract secretions with fluconazole or itraconazole has reduced the prevalence of fungus infections from 14% to 5%. Challenges still remain. The ideal regimen to prevent CMV illness is yet to be determined, and treating all fungal isolates from the allograft is not cost effective. Recurrent airway infection and late bacterial pneumonia caused by Pseudomonas species when obliterative bronchiolitis is present remain a major cause of concern. Surely the next decade will provide new insights into these problems.

Anti-Bacterial Agents↗
PubMed1992

N-(3-oxohexanoyl)-L-homoserine lactone regulates carbapenem antibiotic production in Erwinia carotovora.

Erwinia carotovora A.T.C.C. 39048 produces the antibiotic 1-carbapen-2-em-3-carboxylic acid. A number of mutants with a carbapenem-non-producing phenotype were selected as part of an investigation into the molecular and genetic basis of carbapenem biosynthesis. Cross-feeding studies revealed that the mutants fell into two discrete groups. Group 1 mutants were found to secrete a diffusible low-molecular-mass compound which restored carbapenem production in group 2 mutants. This compound was isolated from the spent culture supernatant of a group 1 mutant using solvent extraction, hydrophobic-interaction chromatography and silica-gel chromatography, and finally purified by reverse-phase semipreparative h.p.l.c. M.s. and n.m.r. spectroscopy revealed that the compound was N-(3-oxohexanoyl)homoserine lactone. Both D- and L-isomers were synthesized, and subsequent analysis by c.d. established that the natural product has the L-configuration. Although carbapenem production was restored by both isomers, dose-response curves indicated that the L-isomer has greater activity, with an induction threshold of about 0.5 micrograms/ml. N-(3-Oxohexanoyl)-L-homoserine lactone is, therefore, an autoregulator of carbapenem biosynthesis rather than a biosynthetic intermediate. This compound is already known for its role in autoinduction of bioluminescence in the marine bacterium Vibrio fischeri. It is also structurally-related to the A- and I-factors which are known to regulate production of antibiotics in some Streptomyces species. Its association in this work with the regulation of carbapenem biosynthesis implies a broader role for autoregulator-controlled gene expression in prokaryotes.

4-Butyrolactone↗
PubMed1992

Small molecule-mediated density-dependent control of gene expression in prokaryotes: bioluminescence and the biosynthesis of carbapenem antibiotics.

Sophisticated signal transduction systems enable prokaryotes to sense their growth environment and mount an appropriate adaptive response. Signal transduction and gene regulation through the phosphorylation of two regulatory components is now recognised as one of the major global regulatory networks in bacteria. However, not all types of sensor-regulator circuits relay information via phosphoryl transfer. The Vibrio fischeri LuxR protein which has previously been characterised as a member of the response-regulator superfamily responds to a small diffusible signal molecule N-(3-oxohexanoyl)homoserine lactone (HSL). Biosynthesis of HSL in V. fischeri is dependent on the expression of the luxI gene. Until recently, the role of HSL as an 'autoinducer' was thought to be restricted to V. fischeri and a few related marine bacteria in which it controls the onset of bioluminescence. However, we have discovered that a diverse group of terrestrial bacteria: (1) produce HSL; (2) possess genes analogous to luxI; and (3) exhibit cell density-dependent induction of bioluminesence when transformed with a recombinant plasmid carrying V. fischeri lux genes but lacking luxI. In one of these, Erwinia carotovora, HSL is shown to mediate the cell density-dependent biosynthesis of a carbapenem antibiotic.

4-Butyrolactone↗
PubMed1992

sar: a genetic mouse model for human sarcosinemia generated by ethylnitrosourea mutagenesis.

A mouse mutant with sarcosinemia was found by screening the progeny of ethylnitrosourea-mutagenized mice for aminoacidurias. Paper chromatography, column chromatography, and gas chromatography-mass spectrometry identified high levels of sarcosine in the urine of the mutant mice. While sarcosine cannot be detected in the urine of plasma of normal mice, the urinary sarcosine level of 102 +/- 58 mmol per g of creatinine in the mutant mice was at the upper range of the urinary levels (1.5-4.5 mmol of sarcosine per g of creatinine) observed in humans with sarcosinemia. Similarly, the plasma sarcosine level of 785 +/- 153 mumol/liter in the sarcosinemic mice was at the upper range of the plasma sarcosine levels (53-760 mumol/liter) observed in affected humans. Sarcosine dehydrogenase [sarcosine:(acceptor) oxidoreductase (demethylating), EC 1.5.99.1] activity was deficient in sarcosinemic mice. The sarcosinuria phenotype in these mice was inherited as an autosomal recessive trait. This mouse mutant provides a useful genetic model for human sarcosinemia and for development of therapeutic approaches for genetic disease.

Amino Acid Metabolism, Inborn Errors↗