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Biomedical subjects

Peter Wood

Publications and source records attributed to Peter Wood.

13 recordsLinked to original sources
PubMed2006

Tripodal borate ligands from tris(dimethylamino)borane: the first synthesis of a chiral tris(methimazolyl)borate ligand, and the crystal structure of a single diastereomer pseudo-C3-symmetric Ru(II) complex.

The activation of tris(dimethylamino)borane towards reaction with a chiral methimazole by N-methylimidazole has been used to prepare the first example of a chiral tris(methimazolyl)borate ligand. Coordination of this neutral ligand to Ru(II) has been achieved by reaction with [(p-cymene)RuCl(2)](2) to provide a single diastereomer complex in which the chirality of the methimazolyl substituents dictate the chirality of the bicyclo[3.3.3]cage formed by the ligand on coordination to the metal. The alternative approach to chiral tris(methimazolyl)borate ligands involving the introduction of a chiral group onto the boron atom has been explored by replacing N-methylimidazole in the above reaction by chiral oxazolines as activating bases in reaction with simple methimazole. However, although the B(NMe(2))(3) is activated to reaction with methimazole by these oxazolines, an intramolecular oxazoline ring-opening by a coordinated methimazolyl sulfur occurs and prevents the successful synthesis of these ligands.

Journal Article↗
PubMed2006

Fetal growth and the adrenocortical response to psychological stress.

CONTEXT: Experimental studies in animals show that adverse prenatal environments lead to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal axis, which mediates the stress response through secretion of glucocorticoid hormones. The extent to which such prenatal hypothalamic-pituitary-adrenal axis adaptations occur in humans is unknown. OBJECTIVE: The objective of the study was to determine whether smaller but otherwise healthy term babies are more likely to demonstrate increased glucocorticoid responses to psychological stress in childhood. DESIGN AND PARTICIPANTS: This was a cross-sectional study of 68 boys and 72 girls (aged 7-9 yr) who have been followed up since 12 wk gestation when their mothers took part in a study of healthy children born in Southampton, United Kingdom. MAIN OUTCOME MEASURE: Salivary cortisol responses to psychological stress were measured. RESULTS: In boys, birth weight was inversely related to salivary cortisol responses to stress (r = -0.56, P < 0.001) but not morning cortisol levels, whereas in girls, morning peak cortisol was inversely related to birth weight (r = -0.36, P < 0.05). These associations were independent of gestational age and potential confounding factors including obesity, social class, and educational achievement. CONCLUSIONS: This study suggests that processes occurring during fetal life, resulting in smaller newborns, have a lasting effect on adrenocortical responses to stress in boys and on basal adrenocortical activity in girls. Given the known associations between small alterations in adrenocortical activity and features of the metabolic syndrome such as raised blood pressure and glucose intolerance, these effects warrant further investigation of their potential impact on the future health of prepubertal children.

Adrenal Cortex↗
PubMed2005

The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen.

Current dosing algorithms do not account for genetic and environmental factors for warfarin dose determinations. This study investigated the contribution of age, CYP2C9 and VKORC1 genotype, and body size to warfarin-dose requirements. Studied were 297 patients with stable anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0. Genetic analyses for CYP2C9 (*2 and *3 alleles) and VKORC1 (-1639 polymorphism) were performed and venous INR and plasma R- and S-warfarin concentrations determined. The mean warfarin daily dose requirement was highest in CYP2C9 homozygous wild-type patients, compared with those with the variant *2 and *3 alleles (P < .001) and highest in patients with the VKORC1 (position -1639) GG genotype compared with those with the GA genotype and the AA genotype (P < .001). Mean warfarin daily dose requirements fell by 0.5 to 0.7 mg per decade between the ages of 20 to 90 years. Age, height, and CYP2C9 genotype significantly contributed to S-warfarin and total warfarin clearance, whereas only age and body size significantly contributed to R-warfarin clearance. The multivariate regression model including the variables of age, CYP2C9 and VKORC1 genotype, and height produced the best model for estimating warfarin dose (R2 = 55%). Based upon the data, a new warfarin dosing regimen has been developed. The validity of the dosing regimen was confirmed in a second cohort of patients on warfarin therapy.

Adult↗
PubMed2005

MOLE: a data management application based on a protein production data model.

MOLE (mining, organizing, and logging experiments) has been developed to meet the growing data management and target tracking needs of molecular biologists and protein crystallographers. The prototype reported here will become a Laboratory Information Management System (LIMS) to help protein scientists manage the large amounts of laboratory data being generated due to the acceleration in proteome research and will furthermore facilitate collaborations between groups based at different sites. To achieve this, MOLE is based on the data model for protein production devised at the European Bioinformatics Institute (Pajon A, et al., Proteins in press).

Algorithms↗
PubMed2005

Design of a data model for developing laboratory information management and analysis systems for protein production.

Data management has emerged as one of the central issues in the high-throughput processes of taking a protein target sequence through to a protein sample. To simplify this task, and following extensive consultation with the international structural genomics community, we describe here a model of the data related to protein production. The model is suitable for both large and small facilities for use in tracking samples, experiments, and results through the many procedures involved. The model is described in Unified Modeling Language (UML). In addition, we present relational database schemas derived from the UML. These relational schemas are already in use in a number of data management projects.

Algorithms↗
PubMed2004

Transition planning and recidivism among mentally ill juvenile offenders.

OBJECTIVES: To determine the extent to which transition planning and community service would predict lower levels of recidivism among mentally ill juvenile offenders. DESIGN: Review of legal, medical and social service records including examination of 3-month period following community release. PARTICIPANTS: Juvenile offenders incarcerated for 6 months or more (N = 44) transitioning to community. MEASURES: Child and Adolescent Functional Assessment Scale (CAFAS), sum of different documented pre- and post-release discharge planning contacts, documented community service contacts. OUTCOMES: Re-offense during the first year post-release. RESULTS: Documented community service contacts in the 3 months following discharge were rare for mental health (20.5%), substance abuse (38.6%), financial assistance (29.5%), and school placement (34.1%). The average number of different pre-release and post-release discharge planning contacts was also low, M(SD)=1.86(1.68) and M(SD)= 2.34(1.71) respectively. Post-release discharge planning and the receipt of financial assistance and mental health services were all associated with lower levels of reoffending. CONCLUSIONS: Community transition planning, including the coordination and provision of community services, is an essential component of community reintegration for juvenile offenders and is associated with lower rates of recidivism during the first year post-discharge.

Adolescent↗
PubMed2004

Point-of-care testing shows clinically relevant variation in the degree of inhibition of platelets by standard-dose abciximab therapy during percutaneous coronary intervention.

Administration of GP IIb/IIIa inhibitors during percutaneous coronary intervention (PCI) has proven clinical benefit, but is administered at a dose allowing for the patients' weight but not other variables. This study of 75 patients evaluated platelet inhibition achieved by standard-dose abciximab therapy during PCI as measured by two point-of-care (POC) instruments, Plateletworks (PW) and whole blood aggregation (WB). Results were related to the decrease of platelet activation produced as well as patients' return of angina within 30 days. Flow cytometric measurement showed abciximab suppressed platelet-monocyte aggregates (P < 0.001) and activated glycoprotein IIb/IIIa (P < 0.001) but not P-selectin. Greater POC-measured inhibition corresponded to less postabciximab expression of platelet-monocyte aggregates (P < 0.01). Patients above the lowest quartile of POC inhibition with PW demonstrated a relative risk of experiencing return of angina within 30 days of 0.48 (0.23-0.99). In conclusion, POC measurements reflect platelet activation suppression, higher PW measurements being associated with a decreased risk of return of angina.

Abciximab↗
PubMed2004

Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin.

OBJECTIVE: Our objective was to assess the contribution of CYP2C9 genotype, age, body size, and vitamin K and lipid status to warfarin dose requirements. METHODS: Patients with stable warfarin dose requirements and an international normalized ratio (INR) of the prothrombin time within the target range of 2.0 to 3.0 were recruited to the study. On arrival at the clinic in the morning, after an overnight fast, a blood sample was taken from each patient for CYP2C9 genotyping and for determination of venous INR and plasma vitamin K, R- and S-warfarin, and triglyceride concentrations. RESULTS: A total of 121 patients were recruited to the study. CYP2C9 genotyping showed that 74 patients were homozygous wild-type (*1/*1), 30 were heterozygous *1/*2, and 15 were heterozygous *1/*3 genotype. One patient was found to have the genotype *2/*3, and another was found to have the genotype *3/*3. The mean warfarin daily dose requirement in milligrams fell from 4.06 +/- 1.72 mg in homozygous wild-type patients to 3.63 +/- 1.78 mg for *1/*2-positive patients and 2.70 +/- 1.36 mg for *1/*3-positive patients. The multiple linear regression model for warfarin dose indicated significant contributions from age (r = 0.41, P <.001), genotype (r = 0.24, P <.005), and age and genotype together (r = 0.45, P <.005). Although there were significant linear correlations between warfarin dose and body surface area (r = 0.21, P =.02), body weight (r = 0.25, P =.005), and plasma vitamin K concentration (r = 0.18, P <.05), none of these variables made a significant contribution to the regression model for warfarin dose. CYP2C9 genotype had a significant effect on S-warfarin clearance (r = 0.34, P <.0001) but none on R-warfarin clearance. CONCLUSION: This study showed that age and CYP2C9 polymorphism affect warfarin dose requirements in patients receiving long-term therapy and having stable control of anticoagulation. It is anticipated that using dosing regimens modified to take into account the contribution of age and CYP2C9 genotype has the potential to improve the safety of warfarin therapy.

Adult↗
PubMed2002

Absence of Cushingoid phenotype in a patient with Cushing's disease due to defective cortisone to cortisol conversion.

Cushing's syndrome invariably presents with a classical phenotype comprising central adiposity, prominence of dorsal, supraclavicular and temporal fat pads, bruising, abdominal striae, proximal myopathy, and hypertension. We report the case of a 20-yr-old student with pituitary-dependent Cushing's syndrome who was spared this classical phenotype because of a defect in the peripheral conversion of cortisone to cortisol. She presented to her general practitioner with secondary amenorrhea. Clinical examination revealed normal fat distribution (body mass index, 20.9 kg/m(2)), absence of hirsutism, myopathy, or bruising; her blood pressure ranged from 115/70 to 122/82 mm Hg. She was investigated for biochemical hypercortisolemia because of a mildly elevated random circulating cortisol (serum cortisol, 661 nmol/liter). Cushing's syndrome was confirmed on the basis of repeatedly elevated urinary free cortisols (831-1049; reference range, <350 nmol/24 h), failure of low-dose dexamethasone suppression (611 nmol/liter) and loss of circadian cortisol secretion. Investigations suggested Cushing's disease; there was suppression after high-dose dexamethasone (<20 nmol/liter) and a 950% increase in ACTH after stimulation with CRH. Pituitary magnetic resonance imaging revealed a 3-mm adenoma within the pituitary gland. Urinary corticosteroid metabolites were analyzed by gas chromatography-mass spectrometry and demonstrated a decreased THF+allo-THF/THE ratio of 0.66 (mean +/- SE in Cushing's disease, 1.74 +/- 0.24) suggesting a defect in 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), an enzyme that converts the inactive glucocorticoid cortisone to active cortisol. Transphenoidal microadenomectomy was performed, and histology confirmed the diagnosis of a corticotroph adenoma. Postoperatively, serum cortisol was undetectable and replacement therapy was commenced. Subsequent investigations revealed a significantly impaired ability to convert an oral dose of cortisone acetate (25 mg) to cortisol, reduced serum cortisol to cortisone ratios, and a reduced serum half-life for cortisol (57.3 min). These results provide strong evidence for a partial defect in 11beta-HSD1 activity and concomitant increase in cortisol clearance rate. We have described a case of Cushing's disease that failed to present with a classical phenotype, and we postulate that this is due to a partial defect of 11beta-HSD1 activity, the defect in cortisone to cortisol conversion increasing cortisol clearance and thus protecting the patient from the effects of cortisol excess. This observation may help to explain individual susceptibility to the adverse effects of glucocorticoids.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2002

Hormone replacement therapy (oestradiol-only preparations): can the laboratory recommend a concentration of plasma oestradiol to protect against osteoporosis?

Target concentrations of plasma oestradiol to protect against osteoporosis have now been published in at least one textbook and are increasingly discussed by clinicians. A survey of the literature revealed that many reports do not give details of oestradiol assay methods, despite the fact that there is a wide range of biases. Plasma oestradiol measurements made after ingestion of equine oestrogen preparations are not valid, and for oral oestradiol and oestradiol valerate preparations a single untimed sample does not give a reliable estimate of the average exposure over 24 h. Oestradiol measurements in plasma from women using patch, gel or implant preparations could be useful provided that consideration is given to the time of sampling and to the assay method used, although target levels have not been established. Further studies are required in this area.

Administration, Oral↗