The stereoselective uptake of ibuprofen enantiomers into adipose tissue.
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Biomedical subjects
Publications and source records attributed to K Williams.
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A comparison has been made of the electrochemical behaviour of investment cast coupons of a 20Cr, 25Ni, Ti stabilized stainless steel (in the nitrided and un-nitrided conditions) with a cobalt-chromium alloy in order to make a preliminary assessment from the point of view of corrosion of the nitrided material for dental and other biomedical applications. Electrochemical tests have been carried out in vitro in artificial saliva and in Ringer's solution, with some additional tests carried out in natural saliva. Both the potential-time behaviour and the magnitude of the breakdown potential on anodic polarization suggest that the protective properties of the passivating film are substantially improved in the case of the nitrided stainless steel alloy.
The variation in case-mix of patients admitted for routine (non-emergency) orthopaedic surgery at a Staffordshire orthopaedic hospital over a 10-year period was studied, with the aid of the BUPA Schedule of Surgical Procedures. Over this period there was a 2% decrease in the total number of operations performed. There was a marked reduction in the number of 'minor' operations performed, and a marked increase in the number of 'major' and more complex operations performed. The overall workload, as judged by estimated surgeons' fees, rose by 43%. This study offers clear support to the claim that the complexity of orthopaedic operations performed has significantly increased over a ten-year period.
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Enzyme-linked immunosorbent asays (ELISAs) are described for determining levels of dapsone and pyrimethamine in urine. Both assays have a sensitivity of about 20 mug/l and are reproducible, but each produces some false positives. The problem of false positive reactions was partially obviated by requiring positive results in both assays. In a pilot study involving 50 children aged 3 months to 4 years who were given a single dose of Maloprim (pyrimethamine + dapsone), 75% were positive for dapsone 7 days after administration of the drug, while 25% were still positive 15 days after its administration. The corresponding proportions for pyrimethamine were 73% and 30%, respectively. Comparison of the results obtained in a larger chemoprophylaxis trial with those from the pilot study indicated that the assays described could be used to investigate whether antimalarials had been taken.
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Anion-exchange chromatography is shown to permit resolution and separation of subforms of the serum glycoprotein alpha 2-macroglobulin. The subforms differ dramatically in their stability as judged by differential scanning calorimetry, undergoing thermally induced unfolding at temperatures of 61 and 69 degrees C respectively. In addition, the proteinase-binding stoichiometry of the subforms differs by a factor of 2, with the more- and less-stable forms binding 2 and 1 mol of proteinase per mol of tetramer respectively. The calorimetric stability of the two forms is differentially affected on treatment with neuraminidase, suggesting that the nature of glycosylation may in part account for the observed differences in physical and functional properties.
Four environmental emissions samples were ranked by their genotoxic potency in several bioassays. Although the relative potency of a series of automotive emissions (diesel and gasoline) in the Ames assay correlated well with the relative potency in mammalian cell and mouse skin, this was not the case for the coke oven, roofing tar, and cigarette smoke condensate (CSC) emissions. This study examines the role of metabolic activation in determining the difference between a microbial and a mammalian bioassay in ranking the genotoxic potency of these environmental emissions. Uninduced and Aroclor 1254-induced S9 from both rat and hamster liver were compared as the metabolic activator in the Ames assay with Salmonella typhimurium TA98. The diesel emissions sample was direct-acting while the other samples required activation. The standard S9 concentration (only Aroclor-induced rat, approximately 1.25 mg protein/plate) also produced the maximum mutagenic activity. Induced S9s produced higher mutagenic activity than uninduced. The hamster S9 gave significantly higher mutagenic activities than rat S9 for the coke oven and CSC. The relative potency of these four samples was not significantly different between the microbial (Ames), mammalian cell (mouse lymphoma), and tumor initiation (mouse skin) assays. These results suggest that the differences observed between the relative mutagenic activity of these emissions in the mammalian cell and microbial assays was not due to a lack of optimization of the S9 system but may be inherent in the different response of the indicator cells to different chemical classes.
A novel family of micronuclear elements termed telomere-bearing elements (TBEs) is described. All 1900 family members are eliminated during macronuclear development. We conclude that they are transposons, first because the members are moderately conserved in sequence and probably dispersed in the genome. Second, in two cases, sequence comparison of the termini and flanks of the element with the corresponding empty site indicate that elements cause 3 bp target duplications (AAT) upon insertion; the 3 bp are part of the 5 bp target sequence, AATGA. Lastly, both elements carry 77 or 78 bp inverted terminal repeats. The tip of each inverted terminal repeat is the 17 bp telomere-like sequence 5' C1A4C4A4C4. At least half of the elements have these 17 bp or an extremely similar sequence. One possible pathway for transposition into new micronuclear sites starts in the developing macronucleus with excision to create a free linear form to which telomeres are added, followed by a low frequency of movement to the micronucleus, and insertion into the germ-line micronuclear DNA.
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Two experiments were performed as an initial attempt to explain age related limitations in response accuracy on a coincident anticipation task. Five- to 9-year-old boys and adult males participated in each experiment. They made horizontal arm movements in response to stimuli from a Bassin Anticipation Timer. The results of Experiment l confirmed the findings of previous studies, which showed that young children respond early to slow moving stimuli. They were most accurate at intermediate speeds; their responses deteriorated as speed was increased. older children and adults were more accurate at slow to intermediate speeds; their performances also declined at fast stimulus velocities. Experiment ll examined use of a stereotypic or default movement speed as an explanation for these results, particularly for young children. A most comfortable movement pace was determined for each subject and was used as a baseline speed for a subsequent timing task. Four other stimuli were selected in 0.8 mph increments from the baseline speed (two faster, two slower). In addition, selected trials for 6 subjects at each age were filmed at 32 fps. X-coordinates for these trials were obtained and smoothed at 5 Hz. Movement time data suggested that 5-year-olds used a preferred or stereotypic speed, since they were accurate only when responding to their baseline speed. older subjects matched stimuli up to and including their baselines. Kinematic characteristics confirmed the general notion of preferred speed for 5-year-olds. These same measures demonstrated that older subjects were increasingly adaptable in their responses, despite a failure to respond more accurately. Consequently, the term "preferred speed" lacks generality as an explanatory concept. Age-related shifts in the ability to modify components of a response, like average movement velocity and number of corrections, were used to explain accuracy differences.
Rotavirus gastro-enteritis in young Gambian children has its maximum impact on infants after the age of one month, in whom it produces short, well-defined annual winter epidemics with clinical dehydration in up to 18% of those infected. Sporadic infection was observed in neonates who were often asymptomatic, throughout one year but not in the subsequent year. In two consecutive years studied there was a major change from subgroup I, serotype 2 to subgroup II, serotypes 1 and 3. This could have contributed to the failure of children to develop protective immunity against sequential disease following an infection during infancy. If rotavirus morbidity in this community is to be notably reduced by a vaccination programme it would need to be carried out in early infancy prior to the winter season. Evaluation of a type-specific vaccine should include monitoring secular changes in rotavirus serotypes throughout subsequent epidemics.
This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/- 6% of an administered dose of R(-) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(-) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha-methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.
In a prospective, randomized study, ceftazidime monotherapy was compared with a combination of ceftazidime and flucloxacillin in 100 febrile neutropenic patients. Thirty-four bacteriologically documented infections, of which 26 were bacteremias, in 51 patients were treated with ceftazidime alone. Thirty-four bacteriologically proven infections, of which 29 were bacteremias, in 49 patients were treated with a combination of ceftazidime and flucloxacillin. The clinical response rate for ceftazidime monotherapy was 80%; the bacteriological cure rate was 90%. Efficacy against gram-negative pathogens appeared to be excellent, achieving a 100% cure rate. The clinical response and bacteriological cure rates for the combination were 76 and 86%, respectively. Three superinfections were registered in the ceftazidime group, and four, involving six pathogens, were registered in the combination group. Other side effects of ceftazidime were minimal. It is concluded that ceftazidime is an effective drug for the empiric treatment of febrile neutropenic patients. It offers the opportunity to avoid the aminoglycosides in first-line treatment. It may be appropriate to combine ceftazidime with cephalothin or vancomycin or to modify therapy if resistant gram-positive strains are encountered.
Fasting plasma insulin (PI) and glucose (PG) concentrations were measured throughout the body weight cycle of marmots. Animals gained weight during summer, and in late fall body weight peaked, after which they ceased feeding. Each month euthermic animals were injected intra-arterially with either dextrose (500 mg/kg) or porcine insulin (0.1 U/kg), and blood samples were collected over the subsequent 2 h. During weight gain fasting PI concentration and pancreatic B-cell response to injected dextrose increased markedly. Maximal insulin release to a dextrose challenge was measured during peak body weight or when body weight initially began to decline. The PG concentration after exogenous insulin administration was slight (less than 10%) in the fall but increased approximately 25% in the spring after marmots lost weight. Basal PG levels were not significantly different throughout the year. Basal fasting PI concentrations were significantly higher during the fall (P less than 0.01). It is suggested that in the fall, when marmots are obese, hyperinsulinemia and peripheral insulin resistance appear. Furthermore, in two animals with an increase in body weight of approximately 30% or less over the summer, peripheral resistance was demonstrable, albeit not as marked as in animals that appropriately doubled their body weights when given food ad libitum. Thus we hypothesize that factors other than adiposity, i.e., food intake, central nervous system input to the pancreatic B-cell, and/or changes in B-cell sensitivity to PG, may contribute to the observed peripheral insulin resistance and may be involved in body weight regulation.
The ordered asymmetry of biological macromolecules allows them to differentiate between the optical isomers of monomeric substrates. Optical isomers of drugs often have greatly different affinities at receptor sites, are metabolised at different rates, and have different affinities for tissue and protein binding sites. Despite this knowledge, many drugs are administered as their racemates. Manipulation of the enantiomeric ratio or the use of only one enantiomer of a drug may allow separation of toxicity and efficacy, and this may lead to a significant increase in therapeutic ratio and a more rational approach to therapeutics.
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