Search PubMed⌕ Search

Biomedical subjects

J Wakefield

Publications and source records attributed to J Wakefield.

At least 37 records · Page 2Linked to original sources
PubMed2000

Workshop to implement the baby-friendly office initiative. Effect on community physicians' offices.

OBJECTIVE: To assess the effect of a self-appraisal questionnaire and a workshop for office staff in promoting the baby-friendly office (BFO). DESIGN: A two-times-three factorial design with a delayed workshop for one of two groups: an early intervention group who attended a workshop for office staff in October 1997 (n = 23) and a late-intervention group who attended in April 1998 (n = 23). Self-appraisals were completed before the workshops by all participants in October 1997, by 37 offices in April 1998, and by 34 offices in October 1998. SETTING: Offices of family physicians and primary care pediatricians in Hamilton-Wentworth, Ont. PARTICIPANTS: Staff of 46 offices; 74% (34/46) completed all three assessments. MAIN OUTCOME MEASURES: Degree of change in implementing each of the "10 Steps to Baby-Friendly Office" and overall average BFO score received by each office. RESULTS: Of the 34 offices completing all assessments, none followed all 10 steps. Initial mean score was 4.4 steps (standard deviation 1.4, n = 46). The workshop intervention improved overall mean scores from 4.3 to 5.6 (P < .001, n = 37). Although office staff completed the BFO self-appraisal tool, it alone had no effect on scores. Areas of improvement were noted in providing information to patients and displaying posters to promote breastfeeding. Key steps, such as not advertising breast milk substitutes and not distributing free formula, did not change. CONCLUSION: The workshop effected a modest but positive change in breastfeeding promotion. The change was maintained at 6 and 12 months after the intervention.

Adult↗
PubMed1999

Modified-peptide inhibitors of amyloid beta-peptide polymerization.

Cellular toxicity resulting from nucleation-dependent polymerization of amyloid beta-peptide (Abeta) is considered to be a major and possibly the primary component of Alzheimer's disease (AD). Inhibition of Abeta polymerization has thus been identified as a target for the development of therapeutic agents for the treatment of AD. The intrinsic affinity of Abeta for itself suggested that Abeta-specific interactions could be adapted to the development of compounds that would bind to Abeta and prevent it from polymerizing. Abeta-derived peptides of fifteen residues were found to be inhibitory of Abeta polymerization. The activity of these peptides was subsequently enhanced through modification of their amino termini with specific organic reagents. Additional series of compounds prepared to probe structural requirements for activity allowed reduction of the size of the inhibitors and optimization of the Abeta-derived peptide portion to afford a lead compound, cholyl-Leu-Val-Phe-Phe-Ala-OH (PPI-368), with potent polymerization inhibitory activity but limited biochemical stability. The corresponding all-D-amino acyl analogue peptide acid (PPI-433) and amide (PPI-457) retained inhibitory activity and were both stable in monkey cerebrospinal fluid for 24 h.

Amino Acid Sequence↗
PubMed1999

A national facility for small area disease mapping and rapid initial assessment of apparent disease clusters around a point source: the UK Small Area Health Statistics Unit.

BACKGROUND: Reports of disease clusters are often received by district health authorities and are, in some cases, associated with concerns about a pollution source. The Small Area Health Statistics Unit (SAHSU) has developed a Rapid Inquiry Facility, which will produce an estimated relative risk for any given condition for the population within defined areas around a point source, relative to the population in a local reference region. The system can also facilitate the production of annual reports and other health studies for Departments of Public Health Medicine through the creation of ward-level maps to illustrate disease variation across small areas. METHODS: The facility uses routinely collected morbidity, mortality and population data at a small area scale, together with the computing facilities and expertise necessary to run such analyses quickly and efficiently. Using this facility SAHSU can supply a report within three working days. To aid interpretation, smoothed small area maps that account for sampling variability in the observed data can also be produced. RESULTS: The paper reports on two case studies where the pilot system has been utilized by health authorities for both point source analyses and small area disease mapping. CONCLUSIONS: We believe that this facility would be of considerable use to districts. The local knowledge and expertise of the local public health specialist is essential in the interpretation and presentation of the facility's output. Feedback from public health specialists is helping SAHSU refine the output of the facility, so as to make the information presented as comprehensive and as useful as possible.

Data Interpretation, Statistical↗
PubMed1999

Magnesium in drinking water supplies and mortality from acute myocardial infarction in north west England.

OBJECTIVES: To examine whether higher concentrations of magnesium in drinking water supplies are associated with lower mortality from acute myocardial infarction at a small area geographical level; to examine if the association is modified by age, sex, and socioeconomic deprivation. DESIGN: Small area geographical study using 13,794 census enumeration districts. Water constituent concentrations (magnesium, calcium, fluoride, lead) measured at water supply zone and assigned to enumeration districts. SETTING: 305 water supply zones in north west England. SUBJECTS: Resident population of 1,124,623 men and 1,372,036 women (1991 census) aged 45 years or more. MAIN OUTCOME MEASURE: Mortality from acute myocardial infarction, International Classification of Diseases, ninth revision (ICD-9) 410. Subsidiary analysis examined deaths from ischaemic heart disease, ICD 410-414. RESULTS: There were 21,339 male and 17,883 female deaths from acute myocardial infarction in 1990-92. Drinking water magnesium concentrations in water zones ranged from 2 mg/l to 111 mg/l (mean (SD) 19 (20) mg/l, median 12 mg/l); 24% of variation in magnesium concentrations was within zone and 76% was between zone. The relative risk of mortality from acute myocardial infarction (standardised for age, sex, and Carstairs deprivation quintile) for a quadrupling of magnesium concentrations in drinking water (for example, 20 mg/l v 5 mg/l) was 1.01 (95% confidence interval (CI) 0.99 to 1.03). When adjusted for north-south and east-west trends in mortality from acute myocardial infarction and for drinking water calcium, fluoride, and lead concentrations, this relative risk was 1.01 (95% CI 0.96 to 1.06). There was no evidence of a protective effect for acute myocardial infarction even among age, sex, and deprivation groups that were likely to be relatively magnesium deficient. For ischaemic heart disease mortality there was an apparent protective effect of magnesium and calcium (with calcium predominating in the joint model), but these were no longer significant when the geographical trends were incorporated. CONCLUSIONS: No evidence was found of an association between magnesium concentrations in drinking water supplies and mortality from acute myocardial infarction. These results do not support the hypothesis that magnesium is the key water factor in relation to mortality from heart disease.

Age Factors↗
PubMed1999

Population modelling in drug development.

In this paper we discuss the vital role that population (hierarchical) modelling can play within the drug development process. Specifically, population pharmacokinetic/pharmacodynamic models can provide reliable predictions of an individualized dose-exposure-response relationship. A predictive model of this kind can be used to simulate and hence design clinical trials, find initial dosage regimens satisfying an optimality criterion on the population distribution of responses, and individualized regimens satisfying such a criterion conditional on individual features, such as sex, age, etc. Throughout we emphasize prediction and advocate mechanistic as opposed to empirical modelling, and argue that the Bayesian approach is particularly natural in this setting.

Bayes Theorem↗
PubMed1998

Vpx is required for dissemination and pathogenesis of SIV(SM) PBj: evidence of macrophage-dependent viral amplification.

The viral accessory protein Vpx is required for productive in vitro infection of macrophages by simian immunodeficiency virus from sooty mangabey monkeys (SIV(SM)). To evaluate the roles of Vpx and macrophage infection in vivo, we inoculated pigtailed macaques intravenously or intrarectally with the molecularly cloned, macrophage tropic, acutely pathogenic virus SIV(SM) PBj 6.6, or accessory gene deletion mutants (deltaVpr or deltaVpx) of this virus. Both wild-type and SIV(SM) PBj deltaVpx viruses were readily transmitted across the rectal mucosa. A subsequent 'stepwise' process of local amplification of infection and dissemination was observed for wild-type virus, but not for SIV(SM) PBj deltaVpx, which also showed considerable impairment of the overall kinetics and extent of its replication. In animals co-inoculated with equivalent amounts of wild-type and SIV(SM) Pbj deltaVpx intravenously or intrarectally, the deltaVpx mutant was at a strong competitive disadvantage. Vpx-dependent viral amplification at local sites of initial infection, perhaps through a macrophage-dependent mechanism, may be a prerequisite for efficient dissemination of infection and pathogenic consequences after exposure through either mucosal or intravenous routes.

Animals↗
PubMed1998

Statistical methods for population pharmacokinetic modelling.

A principal aim of population pharmacokinetic studies is to estimate the variance components associated with intra- and inter-individual variability in observed drug concentrations. The explanation of the inter-individual variability in terms of subject-specific covariates is also of great importance. Pharmacokinetic models are nonlinear in the parameters and estimation is not straightforward. Within this paper we review a number of estimation approaches which have been suggested for population pharmacokinetic analyses. We distinguish between Bayesian and non-Bayesian and fully-parametric, semi-parametric and nonparametric methods.

Analysis of Variance↗
PubMed1997

A population approach to initial dose selection.

Before a drug can be marketed, an initial dose must be established. Sheiner et al. argue that a population approach leads to the most informed and rational decision making. We discuss the choice of an initial dose from both a predictive and estimative viewpoint. Our criteria are based upon evaluating the probabilities that a patient from the specified population obtains a response that is at least of a specified size. We demonstrate the approach using a simulation study and compare estimation of population parameters and initial dose using Bayesian and likelihood-based methods.

Bayes Theorem↗
PubMed1997

Bayesian nonparametric population models: formulation and comparison with likelihood approaches.

Population approaches to modeling pharmacokinetic and/or pharmacodynamic data attempt to separate the variability in observed data into within- and between-individual components. This is most naturally achieved via a multistage model. At the first stage of the model the data of a particular individual is modeled with each individual having his own set of parameters. At the second stage these individual parameters are assumed to have arisen from some unknown population distribution which we shall denote F. The importance of the choice of second stage distribution has led to a number of flexible approaches to the modeling of F. A nonparametric maximum likelihood estimate of F was suggested by Mallet whereas Davidian and Gallant proposed a semiparametric maximum likelihood approach where the maximum likelihood estimate is obtained over a smooth class of distributions. Previous Bayesian work has concentrated largely on F being assigned to a parametric family, typically the normal or Student's t. We describe a Bayesian nonparametric approach using the Dirichlet process. We use Markov chain Monte Carlo simulation to implement the procedure. We discuss each procedure and compare our approach with those of Mallet and Davidian and Gallant, using simulated data for a pharmacodynamic dose-response model.

Bayes Theorem↗
PubMed1996

The SH3 domain of Src tyrosyl protein kinase interacts with the N-terminal splice region of the PDE4A cAMP-specific phosphodiesterase RPDE-6 (RNPDE4A5).

The PDE4A (type IV) cAMP-specific, rolipram-inhibited phosphodiesterase RPDE-6 (RNPDE4A5), when transiently expressed in COS7 cells, could be complexed with the v-Src-SH3 domain expressed as a glutathione S-transferase (GST) fusion protein. RPDE-6 did not interact with GST itself. This complex was not disrupted by treatment with high NaCl concentration together with Triton X-100. Interaction was apparently determined by the N-terminal splice region of RPDE-6, as the PDE4A splice variant RPDE-39, which differs from RPDE-6 at the extreme N-terminus, failed to associate with v-Src-SH3; met26RD1 (where RD1 is rat 'dunc-like' PDE), which has the N-terminal splice region deleted, failed to associate with v-Src-SH3, and the association of RPDE-6 and v-Src-SH3 was blocked by a fusion protein formed from the N-terminal splice region. RDPE-6 showed binding to GST fusion proteins of both the intact Src kinase and an SH2-SH3 construct but did not bind to the Src-SH2 domain or to the adaptor protein Grb-2. RPDE-6 could be co-immunoprecipitated from cytosol extracts of transfected cells by using anti-Src antiserum. RPDE-6 exhibited selectivity in binding to the SH3 domains of c-Abl, Crk, Csk, Lck, Lyn, Fyn and v-Src, with binding to the SH3 regions of the Src-related tyrosyl kinases Lyn and Fyn being the most effective. The binding of RPDE-6 to the SH3 domains of Crk, Csk and Lck led to a marked reduction in PDE activity, but no change was apparent in complexes with other species. Endogenous RPDE-6 from brain, but not endogenous RPDE-39 from testis, bound to the Src-SH3 domain. We suggest that the PDE4A splice variant RPDE-6 has a propensity for interaction with selective SH3 domains, in particular those from Src and the Src-related tyrosyl kinases Lyn and Fyn. This interaction seems to be governed by alternative splicing of the PDE4A gene, because RPDE-39, a splice variant that lacks the proline-rich N-terminal splice region of RPDE-6, does not interact with these SH3 domains. It is proposed that the binding site on RPDE-6 for SH3 domains lies within the unique first 102 residues of its N-terminal splice domain, where two motifs representing Class I SH3 binding sites with selectivity for Src kinase SH3 domains can be identified and one motif for a putative Class II SH3 binding site.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1996

Bayesian individualization via sampling-based methods.

We consider the situation where we wish to adjust the dosage regimen of a patient based on (in general) sparse concentration measurements taken on-line. A Bayesian decision theory approach is taken which requires the specification of an appropriate prior distribution and loss function. A simple method for obtaining samples from the posterior distribution of the pharmacokinetic parameters of the patient is described. In general, these samples are used to obtain a Monte Carlo estimate of the expected loss which is then minimized with respect to the dosage regimen. Some special cases which yield analytic solutions are described. When the prior distribution is based on a population analysis then a method of accounting for the uncertainty in the population parameters is described. Two simulation studies showing how the methods work in practice are presented.

Algorithms↗