Biomedical subjects
Publications and source records attributed to D R Williams.
A stereoselective synthesis of the C(28)-C(46) fragment (3) of phorboxazole A is described. Key advances include an enantioselective allylation to establish the stereochemistry of the tetrahydropyran unit and a useful SmI(2)-mediated modification of the Barbier reaction of iodomethyloxazole 15 with aldehyde 14.
A novel method for the analysis of trace element chemical speciation at parts per billion (ppb) levels in wound fluid samples both contributes to the fundamental inorganic biochemistry of the healing process and permits improved treatments. Potentiometric Stripping Analysis in combination with acid digestion has been used to quantify the total copper and zinc levels in a series of 0.5 ml samples of fluid obtained from surgical wounds. Further, the degree of blood contamination has been investigated using visible spectroscopy. The prevailing chemical speciation (chemical forms) of these total concentrations of copper and zinc amongst low molecular mass ligands in wound fluid has been investigated by computer modelling using JESS, the Joint Expert Speciation System. The model, involving 38 components, generates in the region of 3500 individual low molecular mass complexes including copper, zinc, iron, calcium and manganese species, and predicts that the majority of low molecular mass (lmm) copper complexes are electrically net-neutral, whilst those of zinc are predominantly charged. Further studies indicate that supplementing the concentrations of histidine and tryptophan may increase the net-neutral zinc fraction, the optimum effect being achieved at pH=7.4. This may be important in transporting zinc into healing cells.
[formula: see text] A mild and highly efficient cyclization of beta-hydroxy amides to oxazolines is described using DAST and Deoxo-Fluor reagents. A one-pot protocol for the synthesis of oxazoles from beta-hydroxy amides is also presented.
[formula: see text] Cyclizations of substituted (E)-1-nitro-1,7,9-decatrienes under thermal and Lewis acid conditions have led to the formation of decalin ring systems with excellent endo selectivity. This strategy has been applied to the synthesis of the AB ring system of norzoanthamine.
Insect molting hormone (ecdysteroid) inactivation occurs by several routes, including 26-hydroxylation and further oxidation to the 26-oic acids. Thus, the ecdysteroid 26-hydroxylase is a critical enzyme involved in precise regulation of ecdysteroid titers during insect development. Administration of the ecdysteroid agonist, RH-5849 (1,2-dibenzoyl, 1-tert-butyl hydrazone), or 20-hydroxyecdysone to the tobacco hornworm, Manduca sexta, results in induction of ecdysteroid 26-hydroxylase activity in midgut mitochondria and microsomes. The biochemical and kinetic properties of the ecdysteroid 26-hydroxylase were investigated. The mitochondrial enzyme was found to have optimal activity at a pH of 7. 5 in a Hepes or sodium phosphate buffer at 30-37 degrees C. The apparent K(m) of the microsomal 26-hydroxylase for 20-hydroxyecdysone substrate was lower than that of the mitochondrial enzyme for either 20-hydroxyecdysone or ecdysone substrate. The V(max) of the 26-hydroxylase in both subcellular fractions was slightly higher using 20-hydroxyecdysone as substrate compared to ecdysone. Demonstration that activity of the mitochondrial 26-hydroxylase was inhibited by incubation in a CO (or N(2)) atmosphere, taken together with the requirement for reducing cofactor and the efficacy of the P450 inhibitors, ketoconazole and fenarimol, provided strong evidence that the hydroxylase is cytochrome P450-dependent. Indirect evidence suggested that the mitochondrial and microsomal ecdysteroid 26-hydroxylase(s) could exist in a less active dephosphorylated state or more active phosphorylated state. Using Escherichia coli alkaline phosphatase to remove covalently bound phosphate groups, the activity of the 26-hydroxylase was decreased and, conversely, activity was enhanced using a cAMP-dependent protein kinase with appropriate cofactors. In addition, the protein kinase was shown to reactivate the 26-hydroxylase activity in alkaline phosphatase-treated fractions.
The convergent enantiocontrolled total synthesis of the 15-membered macrolactone (-)-amphidinolide P is reported. Key transformations include a Sakurai allylation, a Stille coupling for the formation of a fully functionalized acyclic precursor, and intramolecular transesterification.
Optical blurring in the eye prevents conventional physiological techniques from revealing the fine structure of the small parvocellular receptive fields in the primate fovea in vivo. We explored the organization of receptive fields in macaque parvocellular lateral geniculate nucleus cells by using sinusoidal interference fringes formed directly on the retina to measure spatial frequency tuning at different orientations. Most parvocellular cells in and near the fovea respond reliably to spatial frequencies up to and beyond 100 cycles/ degrees of visual angle, implying center input arising mainly from a single cone. Temporal frequency and contrast response characteristics were also measured at spatial frequencies up to 130 cycles/degrees. We compared our spatial frequency data with the frequency responses of model receptive fields that estimate the number, configuration, and weights of cones that feed the center and surround. On the basis of these comparisons, we infer possible underlying circuits. Most cells had irregular spatial frequency-response curves that imply center input from more than one cone. The measured responses are consistent with a single cone center together with weak input from nearby cones. By exposing a fine structure that cannot be discerned by conventional techniques, interferometry allows functional measurements of the early neural mechanisms in spatial vision.
The processes of converting new chemistry into new healthcare, environment-friendly, products are considerably facilitated when chemical speciation data are available. These identify causal links between speciation and biological responses based upon specific chemical species rather than total concentrations. The effective roles of bismuth for ulcer treatment, of Ca, Zn, Sn and F in dentifrices, and of zinc species and common cold symptoms are described. A new readily biodegradable ligand for minimising the environmental impact of washing powders, Al and Alzheimer's disease (and the absence of a causal link), and an audit of Cu and Zn flow from wound dressing through wound fluid to healing tissue, are all discussed in detail.
Depression is highly prevalent in welfare recipients, and is associated with failure to move from welfare to work. This paper examines the relationship between social and environmental factors in a large, community-based sample of mothers who currently or recently received welfare benefits. Specific and modifiable risk factors related to poverty, gender, and race were found to predict major depression beyond traditional risk factors. Research and practice implications are discussed.
AIMS: A systematic review of the literature was carried out to examine whether published evidence suggests a difference in the frequency and awareness of hypoglycaemia induced by 'human' and animal insulin. METHODS: The review identified randomized controlled trials and studies of other designs including observational comparisons, case series and case reports in which the use of 'human' insulin was compared to animal insulin in people with diabetes. These were identified from bibliographic databases and hand-searches of key journals. The main outcome measures were frequency, severity, awareness and symptoms of insulin induced hypoglycaemia. RESULTS: Fifty-two randomized controlled trials, 37 of double-blind design, were identified which included one or more of the relevant outcome measures. Of these, 21 specifically investigated hypoglycaemic frequency and awareness as primary outcomes (six in people with previously reported reduced hypoglycaemic awareness). The remainder of the identified trials reported hypoglycaemic outcomes as a secondary or incidental outcome during comparative investigations of efficacy or immunogenicity. Seven of the double-blind studies reported differences in frequency of hypoglycaemia or awareness of symptoms, although none of the studies which selected subjects on the basis of previously reported impaired awareness demonstrated significant differences between insulin species. Four of the unblinded trials reported differences in hypoglycaemia. This reached statistical significance in two of the studies. A further 56 studies of other designs and case reports were considered. In addition to the 10 case reports describing individuals with impaired hypoglycaemic awareness, nine studies reported differences in the incidence and manifestation of hypoglycaemia during 'human' insulin treatment. Notably, none of the four population time trend studies found any relationship between the increasing use of 'human' insulin and hospital admission for hypoglycaemia or unexplained death among those with diabetes. The largest case series could find no support for the hypothesis that an influence of treatment with 'human' insulin on hypoglycaemia had contributed to any of the 50 deaths investigated. When all types of studies considered are ranked in order of rigour (according to the accepted 'hierarchy of evidence'), it is the least rigorous which lend most support to the notion that treatment with 'human' insulin has an effect on the frequency, severity or symptoms of hypoglycaemia. CONCLUSIONS: Evidence does not support the contention that treatment with 'human' insulin per se affects the frequency, severity or symptoms of hypoglycaemia. However, a number of studies, mainly those of less rigorous design, describe an effect when people are transferred from animal insulin to 'human' insulin. It is not possible to state how common this is or whether the phenomenon is specific to 'human' insulin or an effect resulting from stricter glycaemic control (perhaps compounded, in some cases, by neurological complications in long-standing diabetes). This remaining uncertainty makes it essential that insulin from animal sources continues to be available so that clinicians and patients may retain this choice of treatment.
To show the feasibility of wireless pocket teleradiology, brain computed tomography scan images of five neurosurgical emergency cases were received on a pocket computer via a wireless modem link. Viewing times from turning on the pocket computer to viewing the entire image ranged from 4 to 6 minutes. The quality of the images was satisfactory. Reliability in obtaining a wireless internet connection was good, but not perfect. Wireless pocket telemedicine devices carried by specialists may improve the ability of telemedicine systems to gain access to the expertise of specialists.
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This Workshop was designed to assist in the ongoing development and application of telemedicine and medical informatics to support extended space flight. Participants included specialists in telemedicine and medical/health informatics (terrestrial and space) medicine from NASA, federal agencies, academic centers, and research and development institutions located in the United States and several other countries. The participants in the working groups developed vision statements, requirements, approaches, and recommendations pertaining to developing and implementing a strategy pertaining to telemedicine and medical informatics. Although some of the conclusions and recommendations reflect ongoing work at NASA, others provided new insight and direction that may require a reprioritization of current NASA efforts in telemedicine and medical informatics. This, however, was the goal of the Workshop. NASA is seeking other perspectives and views from leading practitioners in the fields of telemedicine and medical informatics to invigorate an essential and high-priority component of the International Space Station and future extended exploration missions. Subsequent workshops will further define and refine the general findings and recommendations achieved here. NASA's ultimate aim is to build a sound telemedicine and medical informatics operational system to provide the best medical care available for astronauts going to Mars and beyond.
BACKGROUND: This qualitative study aimed to explore the views of key stakeholders regarding the role that public health professionals have or should have in the provision of effective health care within the National Health Service. METHODS: A national (England) questionnaire survey generated a sample for qualitative telephone interviews and two site case studies. The interviews were conducted in three stages: first, 27 interviews were based on assessed reported levels of organizational activity, including non-respondents; next, views in six areas were consolidated by extra interviews; finally, two extra areas were visited for individual and group interviews. The interviews were analysed for salient themes. RESULTS: There was a widespread view that public health had not delivered its potential. Many Trusts currently wanted public health to have influence over commissioning, provide health needs assessments and epidemiological skills, and provide a strategic focus and unbiased advice. Evaluation of actual activity varied widely; local history and congruent personalities seemed to be associated with perceived success. In some cases there was mutual suspicion between Health Authorities and Trusts. Public health was often perceived by Trusts to have been marginalized. This perception was not shared by Public Health Consultants, who highlighted lack of resources as a reason for lack of involvement. The contribution of public health professionals working in Trusts was highly regarded. Barriers included overcoming initial prejudice and combating isolation within Trusts. There were four categories of response in respect of the potential future role for public health in implementing effective health care: no role; collaborative working between Health Authority Public Health Departments and Trusts; deployment of public health workers within Trusts, and an undecided group. Overall, the skills of public health, especially strategic vision and population perspectives, were seen as valuable but as yet unrealized. CONCLUSIONS: Public health skills (but not necessarily professionals) may be valuable in implementing effective health care in Trusts. However, public health professionals must refocus and market their skills to Trusts if the discipline is to play a key role in this task.
We examine the problem of a grafted rod or rods compressed by a sphere, concentrating on the steric force exerted by the rods on the sphere. We show that this problem can be solved exactly to yield simple and nontrivial expressions for the repulsive force. In particular, there are several different regimes and in some of these the force exhibits surprising maxima and minima as a function of compression. This has applications to systems of stiff grafted polymers, particularly biopolymers. One experimental realization of our system might be a rod-coil diblock copolymer with the coil grafted to a solid surface.
The functional receptor for insect ecdysteroid hormones is a heterodimer consisting of two nuclear hormone receptors, ecdysteroid receptor (EcR) and the retinoid X receptor homologue Ultraspiracle (USP). Although ecdysone is commonly thought to be a hormone precursor and 20-hydroxyecdysone (20E), the physiologically active steroid, little is known about the relative activity of ecdysteroids in various arthropods. As a step toward characterization of potential differential ligand recognition, we have analyzed the activities of various ecdysteroids using gel mobility shift assays and transfection assays in Schneider-2 (S2) cells. Ecdysone showed little activation of the Drosophila melanogaster receptor complex (DmEcR-USP). In contrast, this steroid functioned as a potent ligand for the mosquito Aedes aegypti receptor complex (AaEcR-USP), significantly enhancing DNA binding and transactivating a reporter gene in S2 cells. The mosquito receptor also displayed higher hormone-independent DNA binding activity than the Drosophila receptor. Subunit-swapping experiments indicated that the EcR protein, not the USP protein, was responsible for ligand specificity. Using domain-swapping techniques, we made a series of Aedes and Drosophila EcR chimeric constructs. Differential ligand responsiveness was mapped near the C terminus of the ligand binding domain, within the identity box previously implicated in the dimerization specificity of nuclear receptors. This region includes helices 9 and 10, as determined by comparison with available crystal structures obtained from other nuclear receptors. Site-directed mutagenesis revealed that Phe529 in Aedes EcR, corresponding to Tyr611 in Drosophila EcR, was most critical for ligand specificity and hormone-independent DNA binding activity. These results demonstrated that ecdysone could function as a bona fide ligand in a species-specific manner.
Surgery for the repair of a type I aortic dissection presents several difficulties for the surgeon and the perfusionist. One must safely support the patient, while at the same time provide the surgeon with a bloodless field in which to operate. Often, this requires cessation of the circulation for varying amounts of time. Deep hypothermia allows for an extension of the arrest period, while other techniques-- retrograde cerebral perfusion and antegrade cerebral perfusion--provide an additional degree of cerebral protection. Recently, we utilized these techniques concurrently on a 43-year-old female who presented for a reoperation for a type I aortic dissection. Combining these techniques allowed us to adequately support the patient during an anticipated lengthy period of circulatory arrest and insured a successful operation without any adverse cerebral or other organ dysfunction.
We analyzed the ratio of L:M cone photopigment mRNA in the retinas of Old World monkeys, using the method of rapid polymerase chain reaction-single-strand conformation polymorphism. The L:M cone pigment mRNA ratio in whole retina ranged from 0.6 to 7.0, with a mean of approximately 1.6 (standard deviation, +/- 0.56; n = 26). There was no change in this ratio with eccentricity up to 9 mm (approximately 45 degrees), though the ratio was approximately 30% greater in temporal than in nasal retina. The mRNA ratios are in good agreement with the L:M cone ratio in these same retinas, inferred from electrophysiological recordings of cone signal gain in horizontal cell interneurons. The correlation between mRNA ratios and physiological cone gain ratio supports the conclusion that both measures reflect the relative number of L and M cones.