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Biomedical subjects

R M Williams

Publications and source records attributed to R M Williams.

At least 91 records · Page 5Linked to original sources
PubMed1994

Simultaneous quantification of an anti-inflammatory compound (DuP 697) and a potential metabolite (X6882) in human plasma and urine by high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method using fluorescence detection has been developed for the simultaneous analysis of low nanogram concentrations of an anti-inflammatory drug, 5-Bromo-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (DuP 697), and a potential metabolite (X6882) in human plasma and of DuP 697 in human urine. This assay method used an EM Separations Lichrospher C18 endcapped column. The mobile phase was acetonitrile-water (75:25, v/v). The detection of DuP 697 and X6882 was by fluorescence at excitation and emission wavelengths of 256 and 419 nm, respectively. The chromatographic system could separate DuP 697 from X6882, the external standard (anthracene), and other endogenous substances present in human plasma. In human plasma the limits of quantification for DuP 697 and X6882 were 3 and 20 ng/ml, respectively; the limit of quantification for DuP 697 in human urine was 5 ng/ml. These compounds were shown to be stable in frozen (-20 degrees C) human plasma and urine for at least 9 weeks. The assay described has been used to characterize DuP 697 pharmacokinetics after oral administration in humans.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

O2-dependent cleavage of DNA by tetrazomine.

A mechanism for the reduction of molecular oxygen that results in the O2-dependent cleavage of both single-stranded and double-stranded DNA by the antitumor antibiotic tetrazomine (1) is presented. The results are discussed in the context of a redox self-disproportionation of the oxazolidine moiety of tetrazomine. Comparisons are made to the structurally analogous natural product quinocarcin (2) in which, like tetrazomine, the oxazolidine moiety is invoked in redox chemistry, which ultimately results in the reduction of molecular oxygen to superoxide.

DNA↗
PubMed1994

Inhibition of cytolytic T lymphocyte activity by oxysterols.

The objective of this study was to investigate the effects of oxysterols (OS), namely 5 alpha-hydroxy-6-ketocholestanol, 6-ketocholestanol and 25-hydroxycholesterol, on specific cell-mediated cytotoxicity by C57BL/6 spleen cells against P815-X2 (a DBA/2 mastocytoma) target cells. Cytolytic T lymphocytes (CTL) were generated by intraperitoneally injecting C57BL/6 mice with P815-X2 tumor cells 10 d prior to the cytotoxicity experiments. Preincubation of CTL with 10(-5) M 5 alpha-hydroxy-6-ketocholestanol and 6-ketocholestanol for 45 min in lipoprotein-depleted medium resulted in an inhibition of cytolytic activity (73 and 43%, respectively) as measured by 4-h 51Cr release. At a concentration of 5 x 10(-6) M, 5 alpha-hydroxy-6-ketocholestanol inhibited CTL activity by 65%, whereas 6-ketocholestanol did not elicit any inhibition. By contrast, 25-hydroxycholesterol did not inhibit CTL at either concentration, although it is known to be a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. When CTL were preincubated with OS in lipoprotein-replete medium, there was no inhibition of CTL activity at the respective concentrations. The results suggest that the inhibition of CTL activity upon short-term incubation with OS is not due to the inhibition of cholesterol synthesis, but may be due to the insertion of OS into the plasma membrane to replace cholesterol and alteration of membrane physical properties.

Animals↗
PubMed1994

Innervation and mast cells of the rat exorbital lacrimal gland: the effects of age.

The distribution of nerves and mast cells was studied in the lacrimal glands of 3-5-, 14- and 24-month-old rats, using light microscopic histochemical and immunohistochemical techniques. In 14-month and, to a greater extent, in 24-month-old rats there were signs of chronic inflammation and patchy destruction of acinar, ductal and vascular tissue. The glands of the three different age groups contained acetylcholinesterase (AChE), vasoactive intestinal polypeptide (VIP)-, neuropeptide Y (NPY)-, calcitonin gene-related peptide (CGRP)-, tyrosine hydroxylase-, substance P- and the phosphoprotein B-50-immunoreactive nerves. B-50-immunoreactive nerves were distributed around acini, blood vessels and ducts, in a similar manner to VIP and AChE. Substance P- and CGRP-immunoreactive nerves were sparsely distributed in interlobular connective tissue and around ducts and blood vessels. Tyrosine hydroxylase- and NPY-containing nerves were found around blood vessels. The 3-5- and 14-month-old rats had a similar pattern of innervation, however, by 24 months there was a reduction in the number and intensity of immunoreactive nerves. The loss of nerves was particularly associated with damage to the gland. Mast cells were also found in the lacrimal, mostly associated with neurovascular tissue. These could be histochemically labelled with alcian blue/safranin or toluidine blue and were immunohistochemically labelled with histamine and serotonin. Substance P-, CGRP-, VIP- and NPY-immunoreactive nerves were found apposed to mast cells. A large increase in mast cells was observed in 24-month compared to 3-5-month-old rats and these were found throughout the acinar tissue. These results show that a decrease in innervation and also chronic inflammation, with mast cell infiltration, occurs in aged rats. These findings may be contributing factors to reduced tear output in aging.

Acetylcholinesterase↗
PubMed1994

Two-photon molecular excitation provides intrinsic 3-dimensional resolution for laser-based microscopy and microphotochemistry.

With the development of sensitive and specific fluorescent indicators, modern laser scanning microscopies enable visualization and measurement of submicron, dynamic processes inside living cells and tissues. Here we describe the working principles of new, nonlinear laser microscopies based on two-photon molecular excitation. In these techniques, a pulsed laser produces peak photon densities high enough that when focused into an appropriate medium, excitation by photon energy combinations can occur. For example, two red photons interacting simultaneously with a fluorescent molecule can excite within it a UV electronic transition, one corresponding to twice the energy of each single photon. Because the amount of two-photon excitation depends on the square of the local illumination intensity, this process exhibits a unique localization to the diffraction-limited spot of the beam focus. Elsewhere along the beam, excitation of background and photodamage is virtually nonexistent. Focal point localization of two-photon excitation lends to all visualization, measurement, and photopharmacology studies an intrinsic, three-dimensional resolution. We describe some preliminary biological applications, specifically, imaging of vital DNA stains in developing cells and embryos, imaging of cellular metabolic activity from NADH autofluorescence, spatially resolved measurements of cytoplasmic calcium ion activity, and optically induced micropharmacology using caged bioeffector molecules.

Animals↗
PubMed1994

Sudden death caused by giant cell myocarditis following coronary artery bypass.

An unusual case of idiopathic giant cell myocarditis (GCM) is described. The patient had a 5-year history of stable and unstable angina, poorly controlled by medical treatment. He underwent a successful coronary artery bypass, but 2 months later died suddenly at home. A coroner's autopsy revealed isolated GCM. This newly described possible association between the surgery and the condition is discussed and the pertinent literature is reviewed. We suggest that the list of causes of GCM in postoperative patients should also include foreign-body reaction. Our findings support the view that myocarditis occasionally masquerades as fatal acute myocardial infarction.

Coronary Artery Bypass↗
PubMed1994

Some effects of zona pellucida glycoproteins and sulfated polymers on the autoactivation of boar sperm proacrosin and activity of beta-acrosin.

The effects of zona pellucida glycoproteins, sulfated polymers and non-sulfated polymers on the activation kinetics of boar sperm proacrosin to beta-acrosin have been investigated. The aim has been to understand more about the behaviour and function of this protein after it has been released from the acrosome at the time of fertilization. Purified proacrosin was allowed to autoactivate at pH 8.0 in the presence of different concentrations of homologous zona glycoproteins, sulfated polymers (fucoidan, chondroitin sulfates A, B and C, dextran sulfate, polyvinylsulfate and heparin) and non-sulfated polymers (dextran, polyvinylphosphate and hyaluronic acid). Enzyme activity was measured against N-benzoyl-L-arginine p-nitroanalide substrate and changes in molecular mass of the protein monitored by SDS-PAGE. Results show that zona pellucida glycoproteins, fucoidan, dextran sulfate and polyvinylsulfate all potentiate the conversion of proacrosin to beta-acrosin but subsequently inhibit its amidase activity. Dextran, polyvinylphosphate, chondroitin sulfates A, B and C and glucose-6-sulfate, on the other hand, either have no effect on autoactivation and beta-acrosin activity, or enhance it slightly. SDS-PAGE analysis confirmed these observations and further indicated that binding of sulfated polymers to proacrosin inhibited staining by Coomassie Blue. These results are consistent with the hypothesis that binding of zona pellucida glycoproteins and sulfated compounds to proacrosin/acrosin is stereospecific and that contact activation onto soluble 'surfaces' causes conformational changes that are responsible for potentiation or inhibition of activation. The implications of these findings for sperm binding and penetration of the zona pellucida are discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrosin↗
PubMed1993

Specificity of binding of zona pellucida glycoproteins to sperm proacrosin and related proteins.

A major regulatory site for species specificity of fertilization in mammals lies at the level of sperm binding to the zona pellucida. This implies a high degree of complementarity between gamete receptor molecules. One putative receptor molecule on spermatozoa is proacrosin/acrosin which binds to zona pellucida glycoproteins (ZPGPs) non-enzymically and with high affinity. The mechanism of recognition involves polysulphate groups in a particular stereochemical orientation and it has been suggested that this may contribute to species specificity of sperm-egg binding. In the present work this hypothesis has been tested by challenging 125I-labelled ZPGPs from pig, cow, and hamster eggs to recognize heterologous sperm proacrosins as well as a variety of sequence-related and unrelated proteins. Results show that pig and cow 125I-ZPGPs bind readily to boar, ram, and bull proacrosin but do not recognize guinea-pig proacrosin or any of the polysulphate binding proteins from rat, hamster, or mouse spermatozoa. Hamster 125I-ZPGPs also recognise boar, ram, and bull proacrosin as well as a range of unidentified proteins in pH3 extracts of hamster, rat, and mouse spermatozoa. The binding of ZPGPs to a variety of proteins not related to proacrosin is strongest to those with a high content of basic residues (i.e., pI > 8.5), although the secondary folding of the target protein is of major importance as boar proacrosin (pI 6.75) has the highest binding capacity of all proteins tested. Cross-reaction of ZPGP probes was not observed to guinea-pig proacrosin, suggesting that in this species the conformation of the protein is different to other sperm proacrosins.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrosin↗
PubMed1993

Tobacco and alcohol use among Australian secondary school students in 1990.

OBJECTIVE: To obtain up-to-date prevalence estimates of tobacco smoking and alcohol drinking among Australian secondary students, and to compare these estimates with those obtained from similar studies conducted in 1984 and 1987. DESIGN: Data were collected from 24,892 secondary students aged 12 to 17 years from all Australian States and the Northern Territory. A stratified two-stage sample design was used. First, a random sample of schools was selected and second, for each school a sample of 80 students was randomly selected from predetermined year levels. A total of 351 schools participated in the survey. Students completed an anonymous, self-administered questionnaire on their smoking and drinking behaviours. RESULTS: The prevalence of current smoking (defined as having smoked at least one cigarette in the week preceding the survey) was found to increase with age to reach a peak of 25% among 16-year-old boys and 29% among girls aged 15 years. From the age of 13, smoking was more prevalent among girls than boys. Among current smokers, boys were heavier smokers than were girls. Unlike smoking, drinking was slightly more prevalent among boys than girls; boys were heavier drinkers. The proportion consuming at least one alcoholic drink in the week before the survey rose with age to a peak of 51% of boys and 46% of girls aged 17 years. Comparisons with data obtained from a similar survey conducted in 1987 showed that there had been a decrease in the proportion of 12 to 15 year olds smoking. The prevalence of drinking among both 12 to 15 year olds and 16 to 17 year olds was significantly lower in 1990 than 1987. CONCLUSIONS: While the continuing downward trends in smoking and drinking among younger students is encouraging, the results show that there are still large numbers of students smoking and drinking.

Adolescent↗
PubMed1993

A new high frequency polymorphism in the HER-2/neu oncogene in normal tissue and breast tumors.

The HER-2/neu (erbB-2) oncogene, if amplified and/or overexpressed in breast and ovarian cancers, is associated with a poor prognosis. Employing direct DNA sequencing, we have discovered and sequenced an 80 base pair intron from human placenta which contains an A to G polymorphism. This polymorphism lends itself to restriction fragment length polymorphism analysis of the PCR product spanning this intron. All three genotypes, homozygous A, heterozygous, and homozygous G appear in normal control populations and breast tumors. Also, no difference was seen between the polymorphic form found in five breast cancers and the corresponding normal tissue.

Base Sequence↗
PubMed1993

National health reform and emergency medicine.

I accept the responsibility of the office of President of ACEP today with great pride--not in myself at having achieved this prestigious office, but rather in the specialty of emergency medicine. I am honored to have the privilege and pleasure of your association and support, and I am immensely proud of being an emergency physician. I have presented these ideas and challenges in a spirit of enthusiasm and optimism for emergency medicine and ACEP. Innovation, courage, and determination are our heritage and will hopefully forever be our legacy. Emergency physicians truly are on the leading edge of the great issues of our society. I believe the time has come for us to assume a leadership position in medicine that reflects the dedication, compassion, and pioneering spirit on which this specialty was founded nearly 25 years ago--and which is so evident in this room today. Please join me in this exciting and worthwhile endeavor.

Cost Control↗
PubMed1993

Health care reform and emergency department services.

EDs are the access of last resort for many Americans, and cost-driven reform initiatives that restrict ED utilization could deter people from seeking necessary and timely medical services. The experience in Canada under universal coverage suggests that major reform could lead to a substantial increase in ED utilization, especially in view of the relative shortage of primary care physicians in the United States. Many hospitals could face short-term overcrowding problems that compromise the quality of care provided in EDs, and rural hospital EDs face specific and unique problems relative to competition and cost efficiency. Integration of emergency services into comprehensive health delivery systems under the concept of managed competition is essential to ensure access and cost-effective delivery of services. The hospital ED may well serve as an important focal point in the development of alternative physician-hospital relationships.

Emergency Service, Hospital↗