PubMed Health⌕ Search

Biomedical subjects

D Wade

Publications and source records attributed to D Wade.

At least 37 records · Page 2Linked to original sources
PubMed1999

Deuterium isotope effects on noncovalent interactions between molecules.

The topic of deuterium isotope effects is usually concerned with the effects on chemical reactions that are caused by the substitution of deuterium atoms for protium, or hydrogen, atoms in a molecule. These effects include changes in the rate of cleavage of covalent bonds to deuterium, or to an atom located adjacent to deuterium, in a reactant molecule. Deuterium isotope effects on other, noncovalent, interactions between molecules are known to occur, but they are generally considered to be insignificant, especially in biological experiments where deuterium substituted molecules are used as tracers. Noncovalent interactions between molecules include hydrogen bonding, and ionic and van der Waals interactions. This article reviews evidence for deuterium isotope effects on noncovalent interactions, with an emphasis on binding interactions between molecules of biological interest, but also including examples of nonbiological molecules in order to demonstrate the generality of these effects. The reality of this effect relies on the assumption that the only difference between the isotopomers considered is the presence of deuterium or hydrogen; there are no impurities present. The physical basis of the effect may be due to differences in the polarities and/or sizes of deuterated versus nondeuterated isomers, and the extent of a deuterium isotope effect on a noncovalent interaction depends on the site of deuteration within a biomolecule. The presence of this effect requires careful interpretation of results obtained in experiments with deuterium labeled compounds.

Animals↗
PubMed1999

"Wheelchair" patients with nonorganic disease: a psychological inquiry.

We studied ten patients referred from the neurology service with severe disability associated with the use of a wheelchair, but with no organic disorder to account for their disabilities. All patients were assessed using rating scales as well as a standardized psychiatric interview (SCID), and all medical and psychiatric case notes were examined. We also interviewed key carers for their views on the information and assistance the patients had received. All but two of the ten patients were women, and the mean age was 45.4 years (SD=5.4). All had current diagnoses of conversion or somatoform disorders and six had previous episodes of major depression. Most patients expressed beliefs about their illness that were not consistent with the medical facts, and only two of the carers were satisfied with explanations they had been given by doctors. The results suggest that requests for psychiatric help once patients have become grossly disabled are unlikely to lead to recovery. The psychiatrist, however, can help the primary care doctor to formulate a plan of management aimed at preventing further deterioration.

Adult↗
PubMed1999

Does parietal cortex contribute to feature binding?

We studied the involvement of the right parietal cortex in visual conjunction search, where two features are present in the array and spatial attention and feature binding is required, and in subset search, where two features are also present but only one of them is needed in order to group stimuli together (the subset) and allow parallel processing without the need for feature binding. Six patients with right parietal lobe lesions, six age-matched controls, and three control patients with left parietal lesions were tested on these two tasks. Patients with right parietal lesions were significantly slower than normal controls in the conjunction task, especially for target-absent trials. In the subset condition, neither normal control subjects nor patients with left parietal damage showed a difference between target-present and target-absent trials whereas right parietal patients showed a significant difference between target-present and target-absent responses. The results suggest a role for the right parietal cortex in shifting attention to the next stimulus once binding of features has taken place or selecting spatial areas containing the desired feature in a subset search, but that parietal cortex is not required for binding the features of the object.

Adult↗
PubMed1998

Identification of functional domains in Efb, a fibrinogen binding protein of Staphylococcus aureus.

Staphylococcus aureus produces and secretes a protein, Efb, that binds to fibrinogen, seems to be required for virulence, and may benefit the microorganism by delaying wound healing. Interactions of Efb with fibrinogen are influenced by divalent metal cations, including Ca2+. Increasing concentrations of Ca2+ increased the binding of fibrinogen to immobilized Efb, whereas binding of Efb to immobilized fibrinogen was decreased with increasing Ca2+ concentration. Studies with synthetic peptides showed that peptides from the carboxyl terminal half of Efb bound to soluble fibrinogen and enhanced the binding of fibrinogen to Efb. A peptide corresponding to a repeated sequence in the amino terminal half of the protein also bound fibrinogen and inhibited binding of fibrinogen to Efb. These results may provide clues to the biological function of Efb and aid in the rational design of agents to block the Efb fibrinogen interaction.

Amino Acid Sequence↗
PubMed1998

Multiple binding sites in the interaction between an extracellular fibrinogen-binding protein from Staphylococcus aureus and fibrinogen.

Efb (previously Fib) is a fibrinogen-binding protein secreted by Staphylococcus aureus. It has previously been shown that it plays a role in a wound infection model in the rat and that antibodies against Efb reduce the number of recovered bacteria from the mammary glands in a mouse mastitis model. Efb binds to the alpha-chain of fibrinogen and does not participate in bacterial adherence to fibrinogen. The binding of Efb to fibrinogen is divalent, with one binding site within the two repeat regions in Efb at the N terminus and one binding site at the C terminus. The divalent binding nature leads to precipitation of Efb-fibrinogen complex when the proteins are added to each other at a 1:1 molar ratio. The interaction between Efb and fibrinogen is strongly enhanced by Ca2+ or Zn2+ but not by Mg2.

Animals↗
PubMed1998

Mechanism for elevated plasma lipoprotein(a) concentrations in patients on dialysis: turnover studies.

Plasma concentrations of lipoprotein (a) [Lp(a)] are increased in patients on renal replacement therapy. Lipoprotein (a) is increasingly being recognized as an independent cardiovascular risk factor. In an effort to explore the mechanism for elevation of Lp(a) in patients on dialysis we have performed turnover studies of Lp(a) with radioactive iodine. Lp(a) was isolated from 1 patient on hemodialysis (HD) and 1 patient on continuous ambulatory peritoneal dialysis (CAPD); the protein was labeled with 125I and returned to each patient. Lipoprotein (a) was subsequently isolated from the patients over a 15-day period and the decay of the specific radioactivity of Lp(a) was used to determine the fractional catabolic rate (FCR), which was 0.27 (pool/day) for the HD patient and 0.28 (pool/day) for the CAPD patient. These rates are indistinguishable from those measured in 4 patients with hypercholesterolemia (0.29, SEM = 0.01) and in 4 other familial hypercholesterolemic patients (0.29, SEM = 0.02) studied previously using the same method by Knight et al. (7). We found no difference in the FCR of patients on dialysis when compared to patients with hyperlipidemia and normal renal function. Increased plasma concentration of Lp(a) in our patients on renal replacement therapy is not due to decreased catabolism, but is caused by increased synthesis.

Adult↗
PubMed1997

Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project.

OBJECTIVE: To describe the immediate and long term risk of epileptic seizures after a first ever stroke. DESIGN: Cohort study following up stroke survivors for 2 to 6.5 years; comparison with age specific incidence rates of epileptic seizures in the general population. SETTING: Community based stroke register. SUBJECTS: 675 patients with a first stroke, followed up for a minimum of 2 years. MAIN OUTCOME MEASURES: Occurrence of single and recurrent seizures. RESULTS: 52 patients had one or more post stroke seizures; in 25 the seizures were recurrent. The 5 year actuarial risk of a post stroke seizure in survivors (excluding 19 patients with a history of epilepsy and 3 patients in whom the seizure occurred shortly before death from another cause) was 11.5% (95% confidence interval 4.8% to 18.2%). The relative risk of seizures, in comparison with the general population, was estimated at 35.2 in the first year after stroke and 19.0 in year 2. The risk of seizures was increased in survivors of subarachnoid and intracerebral haemorrhage (hazard ratio for intracranial haemorrhage v cerebral infarction 10.2 (3.7 to 27.9)). The risk of seizures after ischaemic stroke was substantial only in patients presenting with severe strokes due to total anterior circulation infarction. Only 9 of 295 patients (3%) independent one month after stroke suffered a seizure between 1 month and 5 years (actuarial risk 4.2% (0.1% to 8.3%)). CONCLUSION: Stroke patients have about an 11.5% risk of single or recurrent seizures in the first 5 years after a stroke. Patients with more severe strokes or haemorrhagic strokes are at higher risk.

Adolescent↗
PubMed1997

Inhibition of Plasmodium falciparum proliferation in vitro by ribozymes.

Catalytic RNA (ribozymes) suppressed the growth of the human malarial parasite Plasmodium falciparum in vitro. The phosphorothioated hammerhead ribozymes targeted unique regions of the P. falciparum carbamoyl-phosphate synthetase II gene. The P. falciparum carbamoyl-phosphate synthetase II gene encodes the first and limiting enzyme in the pathway, and its mRNA transcript contains two large insert regions absent in other carbamoyl-phosphate synthetases, including that from humans. These inserts are ideal targets for nucleic acid therapy. Exogenous delivery of ribozymes to cultures reduced malarial viability up to 55% at 0.5 microM ribozyme concentrations, which is significantly greater than control levels (5-15% reduction), suggesting a sequence-specific inhibition. This inhibition was shown to be stage-specific, with optimal inhibitions being detected after 24 h, coincident with maximal production of the carbamoyl-phosphate synthetase enzyme in the course of the life cycle of the parasite. A decrease in total carbamoyl-phosphate synthetase activity was observed only in cultures treated with the ribozymes. The task of developing alternative therapeutic agents against malaria is urgent due to the evolution of drug-resistant strains of P. falciparum, the most virulent of all human malarial parasites. Another critical issue to be addressed is the possibility of eliminating or reducing any systemic toxicity to the host, which can potentially be provided by nucleic acid therapy. This work is the first reported assessment of the ability of ribozymes as antimalarials. Ribozyme inhibition assays can also aid in identifying important antimalarial loci for chemotherapy. The malarial parasite can, in turn, be a useful in vivo host to study the catalysis and function of new ribozyme designs.

Animals↗
PubMed1997

Comparison of postal version of the Frenchay Activities Index with interviewer-administered version for use in people with stroke.

OBJECTIVE: To assess the agreement between postal and interviewer-administered versions of the Frenchay Activities Index (FAI) and to assess the criterion validity of the postal version, using interviewer administration as a gold standard. DESIGN: Comparison of responses to FAI administered by post and then by interview (median delay 10 days). SUBJECTS: Forty-eight Oxfordshire residents admitted to hospital with acute stroke between 1 August 1994 and 31 January 1995 and discharged alive within six months of their stroke. RESULTS: The limits of agreement of the total FAI score are from -5.4 to 7.2. The kappa statistic for each of the 15 individual items that make up the FAI ranged from 0.35 to 1. For nine items, agreement was moderate or fair, and for six items, agreement was good or very good. The mean difference between the overall scores was 0.9 (95% confidence interval: -0.1 to 1.9). The correlation between the overall scores was 0.94 (Spearman's rank correlation coefficient). CONCLUSION: The postal version of the FAI is a satisfactory alternative to direct administration, but poor agreement in scores for individual patients emphasizes that the two approaches should not be used sequentially to monitor individual patients.

Activities of Daily Living↗
PubMed1996

The assessment of obsessive-compulsive phenomena: psychometric and normative data on the Padua Inventory from an Australian non-clinical student sample.

The Padua Inventory (PI) is a measure of obsessive-compulsive phenomena, which is used in clinical and research settings. One reason for the PI's growing acceptance is the emergence of a good deal of evidence supporting the adequacy of its reliability, convergent validity, and evidence supporting the stability of its factor structure. However, there have been some concerns about its discriminant validity. The use of the PI in Australia has been limited by the lack of local normative data and information about its psychometric properties. The cross-national validation of the PI has both theoretical and practical implications, and could add further evidence for its adequacy as a measure of obsessive-compulsive phenomena. Results from the present study found that the PI exhibited a similar but not identical factor structure compared to previous studies, consistently good reliability, adequate convergent validity, and differences in normative data compared with previous studies. Overall, while one may not necessarily assume the generalisability of normative data across different cultural contexts, there is a good deal of consistency in the psychometric properties of the PI. However, there is a need to further demonstrate the PI's discriminant validity, particularly for the "Urges and Worries" subscale.

Adolescent↗
PubMed1996

Face and voice expression identification in patients with emotional and behavioural changes following ventral frontal lobe damage.

Impairments in the identification of facial and vocal emotional expression were demonstrated in a group of patients with ventral frontal lobe damage who had socially inappropriate behaviour. The expression identification impairments could occur independently of perceptual impairments in facial recognition, voice discrimination, or environmental sound recognition. The face and voice expression problems did not necessarily occur together in the same patients, providing an indication of separate processing. Poor performance on both expression tests was correlated with the degree of alteration of emotional experience reported by the patients. There was also a strong positive correlation between the degree of altered emotional experience and the severity of the behavioural problems (e.g. disinhibition) found in these patients. A comparison group of patients with brain damage outside the ventral frontal lobe region, without these behavioural problems, was unimpaired on the face expression identification test, was significantly less impaired at vocal expression identification and reported little subjective emotional change. The expression identification deficits in ventral frontal patients may contribute to the abnormal behaviour seen after frontal lesions, and have implications for rehabilitation.

Facial Expression↗
PubMed1996

Cephalometric A point changes during and after maxillary protraction and expansion.

The purpose of this study was to analyze the treatment and posttreatment maxillary changes achieved with maxillary protraction therapy. The cephalometric records of 25 consecutively treated Chinese children with Class III malocclusions (mean age 8.4 years) were analyzed for cephalometric A point changes, which were then compared with an untreated, age and sex matched Class III control sample. A cephalometric maxillary superimposition technique was used to differentiate between the skeletal and the local contributions to the total A point change. Results showed that 6 months of maxillary protraction therapy produced a mean A point advancement of 2.4 mm compared with 0.2 mm in the control group. Of this advancement, 75% was found to be due to skeletal maxillary advancement and 25% was attributed to local remodeling. Significantly less downward movement of A point was found with treatment compared with the controls, which could be related to the direction of force application. No significant differences were found in the horizontal and the vertical movements of A point between the treatment and the control groups during the 12-month posttreatment period, indicating stability of early maxillary protraction in patients with Class III malocclusions.

Case-Control Studies↗
PubMed1995

Probing the active sites of rat and human cytochrome P450 2E1 with alcohols and carboxylic acids.

Cytochrome P450 2E1 (P450 2E1) catalyzes the biotransformation of many low-molecular-weight compounds including industrial solvents, indoor pollutants, alcohol, and drugs. In order to understand the nature of the P450 2E1 active site, we studied the competitive inhibition of the P450 2E1-catalyzed N-nitrosodimethylamine demethylation by alcohols and carboxylic acids with different alkyl chain lengths. Using microsomes from acetone-treated rats as the enzyme source of P450 2E1, the Ki value for each compound was measured. With primary alcohols and secondary alcohols, the Ki decreased with the increase in the carbon chain length until the carbon number reached 6 or 7; the free energy increment of binding was 0.28 kcal/mol CH2 group. Similar inhibitory effects were also observed with human P450 2E1 heterologously expressed in Hep G2 cells. These results suggest that both rat and human P450 2E1 contain a pocket with hydrophobicity that serves as a binding site for low-molecular-weight substrates. Among a series of carboxylic acids and omega-hydroxycarboxylic acids investigated, dodecanoic acid was the strongest inhibitor (Ki = 22 microM), and 12-hydroxydodecanoic acid had the lowest Ki (320 microM) within the series of omega-hydroxycarboxylic acids. The free energy increment of binding for carboxylic acids was 0.35 kcal/mol CH2 group. 1,10-Decanedicarboxylic acid, which contains a carboxylic group at each end, showed a Ki > 20 mM. We suggest that for optimal interaction of a carboxylic acid moiety with the active site of P450 2E1, the hydrocarbon end of the molecule binds to the substrate binding site, leaving the carboxylic acid group outside of a proposed substrate access channel. The length of optimal substrates such as dodecanoic acid may reflect the length of the substrate access channel and the size of the active site. We estimate that the distance from the opening of the access channel to the oxygenation site is about 15 A. Based on the structural features of P450 2E1 substrates and competitive inhibitors, we propose a conceptual model to illustrate the binding of these molecules in the active site of P450 2E1.

Alcohols↗
PubMed1995

Damage to cerebellocortical pathways after closed head injury: a behavioural and magnetic resonance imaging study.

The objective was to investigate the anatomical substrate of ataxia seen after severe head injury. Five patients were recruited from present and former inpatients at Rivermead Rehabilitation Centre. All patients had had a closed head injury and all had cerebellar type ataxia. Four normal controls were also studied. Brain MRI, clinical examination, computer based recording, and analysis of visuomotor tracking were carried out. Focal damage was found in the superior cerebellar peduncle in all five ataxic patients. The patients' tracking movements showed profound tremor, and unusual reliance on visual feedback. Ataxia seen after severe head injury can arise from damage to the superior cerebellar peduncle, which may interfere with the cerebellocortical circuits involved in coordinated movement.

Adult↗
PubMed1994

Formation of 50 kbp chromatin fragments in isolated liver nuclei is mediated by protease and endonuclease activation.

Isolated rat liver nuclei were incubated in the presence of divalent cations, and the mechanisms underlying the subsequent chromatin fragmentation were investigated. Either of the two cations, Ca2+ or Mg2+ was sufficient to produce chromatin fragments with sizes between 700 and 300 kbp. The formation of chromatin fragments of 50 kbp as well as the following internucleosomal DNA cleavage--which are characteristic of apoptosis--were markedly stimulated in the presence of Ca2+. Chromatin degradation to 50 kbp and smaller (oligonucleosome-size) fragments was prevented by inhibitors of endonucleases and serine proteases. We suggest a mechanism whereby the concerted activity of both proteases and endonucleases results in the widespread chromatin cleavage observed in cells undergoing apoptosis.

Animals↗
PubMed1994

Structure-immunogenicity relationship of melittin, its transposed analogues, and D-melittin.

Melittin, a 26-residue bee venom peptide, is known to induce murine Abs specific for its hydrophilic C-terminus of residues 20-26 and T cell responses specific for its hydrophobic mid-region of residue 11-19. Synthetic melittin analogues with transposed sequences of Ac(21-26) (1-20) and Ac(26-21) (1-20) are found to induce murine Abs specific for the transposed peptide segment and to induce T cell responses that are cross-reactive with melittin. Compared with melittin, the transposed melittin analogues are weaker immunogens and have lower hemolytic activities, lower helical contents, and a lower degree of association in micelles. A melittin analogue with a lactoside group at its C-terminus was found to induce lactoside-specific murine Abs. Present studies show that another analogue with a lactoside group at its N-terminus induces only Abs specific for the C-terminal region of melittin, and no lactoside-specific Abs are detected. These immunochemical observations suggest that the immunogenicity of melittin or its analogues is a consequence of its binding to cell membranes with subsequent oligomer formation in lipid bilayers. Apparently melittin or its analogues bind to cell membrane in an asymmetric manner with the exposed and the buried segments functioning as B and T cell epitopes, respectively. D-melittin is non-immunogenic in mice, although D-melittin has the same hemolytic activity as melittin. This finding may be correlated with the known resistance of D-melittin to proteolysis and hence to processing for Ag presentation to T lymphocytes.

Amino Acid Sequence↗