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Biomedical subjects

Peter Smith

Publications and source records attributed to Peter Smith.

At least 19 recordsLinked to original sources
PubMed2006

Separation of adeno-associated virus type 2 empty particles from genome containing vectors by anion-exchange column chromatography.

Adeno-associated virus (AAV) empty capsids typically co-purify with genome containing AAV2 vectors purified by column chromatography. This study describes a method to remove empty capsids from genome containing vector particles by anion exchange chromatography. The separation is based on the slightly less anionic character of empty particles compared to vectors. Detailed methods to achieve AAV2 vector purification and particle separation using cation exchange resin POROS 50HS followed by anion exchange resin Q-Sepharose(xl) are described. Chromatographic separation of AAV2 particles was achieved using gradients based on sodium acetate and ammonium acetate, and was optimal at pH 8.5. Efficient removal of particle surface nucleic acid impurities was found to be important to achieve good particle separation. In a large scale experiment performed using partially purified vector containing a mixture of 1.56 x 10(14)vg and 2.52 x 10(15) empty capsids as a starting material, the optimized anion exchange chromatography method resulted in a vector peak of 1.15 x 10(14)vg containing 0.25 x 10(14) empty capsids, corresponding to 74% vector yield and 86-fold reduction in empty capsids in the vector product.

Capsid↗
PubMed2006

The effects of immunizing sheep with different BMP15 or GDF9 peptide sequences on ovarian follicular activity and ovulation rate.

The aims of these studies were to determine the abilities of antisera against different regions of ovine bone morphogenetic protein 15 (BMP15) and growth differentiation factor 9 (GDF9) to inhibit ovarian follicular activity, estrus (mating), and ovulation in sheep. The 9-15-mer peptides were conjugated to keyhole limpet hemocyanin (KLH) and used to generate antibodies against the flexible N-terminal regions of the mature protein as well as against regions in which dimerization of the protein or interaction with a type 1 BMP or a type 2 TGFB or BMP receptor was predicted to occur. Ewes (n = 10 per treatment group) were vaccinated with KLH or the KLH-BMP15 (n = 9 different peptides) or KLH-GDF9 (n = 10) peptides in Freund adjuvant at five consecutive monthly intervals. Overall, antisera generated against peptides that corresponded to amino acid residues 1-15 of the N-terminus of the BMP15 or GDF9 mature protein or GDF9 amino acid residues 21-34 were the most potent at inhibiting ovulation following primary and single booster vaccination. Several other BMP15 (8/9) or GDF9 (6/10) treatment groups, but not KLH alone, also produced significant reductions in the numbers of animals that ovulated, although 2, 3 or 4 booster vaccinations were required. Anovulation was commonly associated with the inhibition of normal ovarian follicular development and anestrus. The in vitro neutralization studies with IgG from the BMP15 or GDF9 immunized ewes showed that the mean inhibition of BMP15 plus GDF9 stimulation of (3)H-thymidine uptake by rat granulosa cells was approximately 70% for animals without corpora lutea (CL), whereas for animals with one to three CL or more than three CL, the inhibition was 24%-33% or 27%-42%, respectively. In summary, these data suggest that reagents that block the biological actions of BMP15 or GDF9 at their N-termini have potential as contraceptives or sterilizing agents.

Amino Acid Sequence↗
PubMed2006

The market for elective surgery: joint estimation of supply and demand.

This paper develops models of the demand for and supply of elective (non-emergency) surgery using a panel of quarterly data for 200 English hospitals over the period 1995-2002. Unusually, distinct measures of supply (outpatients seen and inpatient admissions) and demand (outpatient referrals and decisions to admit) are available for each observation. These offer the opportunity to estimate separate empirical models of supply and demand using ordinary least squares (OLS) regression methods. However, the strong correlation between the residuals of these models suggests some merit in the deployment of seemingly unrelated regression (SUR) methods. Although both static and dynamic SUR estimations leave the results largely qualitatively unchanged, SUR estimation can have a considerable quantitative effect relative to the OLS results. For example, SUR estimation generates a lower elasticity of inpatient demand with respect to waiting time than that obtained via OLS. The results offer an important justification for more careful econometric modelling of hospital behaviour than has traditionally been employed in the health economics literature.

Elective Surgical Procedures↗
PubMed2006

Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B.

In a phase I study, administration of an AAV2-FIX vector into the skeletal muscle of eight hemophilia B subjects proved safe and achieved local gene transfer and FIX expression for at least 10 months after vector injection, the last time point assessed by muscle biopsy. In hemophilia B dogs we have demonstrated FIX in both muscle biopsies and circulation >4 years following AAV2-FIX injection. Because circulating FIX levels remained less than 1% of normal in human subjects from the study, the duration of AAV2-mediated transgene expression in humans is unknown. We sought to determine if FIX gene transfer and expression persisted locally at injection sites. Muscle biopsies were obtained from one subject 3.7 years following treatment and revealed transgene FIX DNA and protein by quantitative PCR, DNA fluorescence in situ hybridization, and immunohistochemistry for FIX. These results demonstrate, for the first time, multiyear FIX expression by AAV2 vector in humans and suggest that improved muscle delivery provides effective treatment for protein deficiencies or muscle-specific diseases.

DNA↗
PubMed2006

A new standard nomenclature for proteins related to Apx and Shroom.

Shroom is a recently-described regulator of cell shape changes in the developing nervous system. This protein is a member of a small family of related proteins that are defined by sequence similarity and in most cases by some link to the actin cytoskeleton. At present these proteins are named Shroom, APX, APXL, and KIAA1202. In light of the growing interest in this family of proteins, we propose here a new standard nomenclature.

Animals↗
PubMed2006

Novel 4-anilinoquinazolines with C-6 carbon-linked side chains: synthesis and structure-activity relationship of a series of potent, orally active, EGF receptor tyrosine kinase inhibitors.

The structure-activity relationship of a novel subseries of 4-anilinoquinazoline EGFR inhibitors substituted at the C-6 position with carbon-linked side chains has been investigated. This exploration has led to the discovery of novel aminomethyl carboxamides with good biological, pharmacokinetic and physical properties.

Administration, Oral↗
PubMed2006

Biosynthesis of a 3,6-dideoxyhexose: crystallization and X-ray diffraction of CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3-dehydrase (E1) for ascarylose biosynthesis.

CDP-6-deoxy-L-threo-D-glycero-4-hexulose-3-dehydrase (E1), along with its reductase (E3), catalyzes the unusual C-3 deoxygenation of CDP-6-deoxy-L-threo-D-glycero-4-hexulose to form CDP-3,6-dideoxy-L-threo-D-glycero-4-hexulose in CDP-ascarylose biosynthesis [Chen et al. (1996), Biochemistry, 35, 16412-16420]. This dimeric [2Fe-2S] protein, cloned from the bacteria Yersinia pseudotuberculosis, is currently the only known example of an enzyme that uses a vitamin B6-derived pyridoxamine 5'-phosphate (PMP) cofactor to carry out one-electron chemistry [Agnihotri & Liu (2001), Bioorg. Chem. 29, 234-257]. It also exhibits a [2Fe-2S] cluster-binding motif (C-X57-C-X1-C-X7-C) which has not been observed previously [Agnihotri et al. (2004), Biochemistry, 43, 14265-14274] The recombinant 97.7 kDa dimer was crystallized in the trigonal space group P3(2), with unit-cell parameters a = b = 97.37, c = 142.2 A, alpha = beta = 90, gamma = 120 degrees. A data set has been collected to 1.9 A resolution. A full MAD data set was also collected at the iron absorption edge that diffracted to 2.0 A.

Crystallization↗
PubMed2006

Risk factors for 1-year mortality after postoperative mediastinitis.

OBJECTIVE: Postoperative mediastinitis after median sternotomy is associated with disability and mortality. The aim of this study was to identify risk factors for mortality 1 year after postoperative mediastinitis diagnosis. METHODS: Postoperative mediastinitis was defined as an organ-space infection involving the mediastinum and necessitating debridement. A total of 183 cases of postoperative mediastinitis were prospectively identified from infection control databases. By using univariate and multivariate analysis, clinical risk factors for 1-year mortality were identified. RESULTS: Of 183 patients, 36 (19.7%) died within 3 months of the initial operation. Overall, 51 (33%) died during the study period (the median time to death from the date of diagnosis was 37 days [interquartile range, 11,139 days]). In multivariate analysis, independent predictors of 1-year mortality were a greater than 3-day delay in sternal closure after debridement (hazard ratio, 6.27; P < .001), age greater than 65 years (hazard ratio, 2.29; P = .015), serum creatinine level greater than 2 mg/dL before debridement (hazard ratio, 2.52; P = .019), stay in an intensive care unit before sternal debridement (hazard ratio, 5.56; P < .001), and postoperative mediastinitis due to methicillin-resistant Staphylococcus aureus (hazard ratio, 2.13; P = .02). Treatment with antibiotics with in vitro activity against the infecting pathogen within 7 days of initial debridement was associated with a decreased risk for mortality (hazard ratio, 0.40; P = .03). CONCLUSIONS: Our data suggest that, to improve long-term survival, patients with postoperative mediastinitis should undergo sternal closure within 72 hours after sternal debridement and should receive effective antimicrobial therapy based on operative culture results.

Aged↗
PubMed2006

High-intensity red light suppresses melatonin.

Early studies on rodents indicated that the long-wavelength portion of the spectrum (orange- and red-appearing light) could influence circadian and neuroendocrine responses. Since then, both polychromatic and analytic action spectra in various rodent species have demonstrated that long-wavelength light is very weak, if not entirely inactive, for regulating neurobehavioral responses. Since testing of monochromatic light wavelengths above 600 nm is uncommon, many researchers have assumed that there is little to no effect of red light on the neuroendocrine or circadian systems. The aims of the following studies were to test the efficacy of monochromatic light above 600 nm for melatonin suppression in hamsters and humans. Results in hamsters show that 640 nm monochromatic light at 1.1 x 10(17) photons/cm2 can acutely suppress pineal melatonin levels. In normal healthy humans, equal photon density exposures of 1.9 x 10(18) photons/cm2 at 460, 630, and 700 nm monochromatic light elicited a significant melatonin suppression at 460 nm and small reductions of plasma melatonin levels at 630 and 700 nm. These findings are discussed relative to the possible roles of classical visual photoreceptors and the recently discovered intrinsically photosensitive retinal ganglion cells for circadian phototransduction. That physiology, and its potential for responding to red light, has implications for domestic applications involving animal care, the lighting of typical human environments, and advanced applications such as space exploration.

Adult↗
PubMed2006

A management approach that drives actions strategically: balanced scorecard in a mental health trust case study.

PURPOSE: Achieving excellence is a current preoccupation in U.K. public health organisations. This article aims to use a case study to explain how a mental health trust delivers excellent performance using a balanced scorecard (BSC) management approach. DESIGN/METHODOLOGY/APPROACH: Reports a project to implement a BSC approach in the South West Yorkshire Mental Health NHS Trust to achieve its "excellence" objectives. The authors were participants in the project. The design of the pilot project was informed theoretically by the work of Kaplan and Norton and practically by in-house discussions on a strategy to achieve excellence. FINDINGS: Explains the process of building a BSC strategy step-by-step. Discusses how the vision and strategies of a mental health trust can be translated into tangible measures, which are the basis for actions that are driven strategically. RESEARCH LIMITATIONS/IMPLICATIONS: There are many possibilities for a BSC management approach and this case study is specific to mental health trusts in the UK, although it is believed that the case has a universally applicable modus operandi. PRACTICAL IMPLICATIONS: This article will help healthcare managers to evaluate the benefits of a BSC management approach. ORIGINALITY/VALUE: This article explains how actions can be structured in connection with a BSC management approach.

Efficiency, Organizational↗
PubMed2006

A set probability technique for detecting relative time order across multiple neurons.

With the development of multielectrode recording techniques, it is possible to measure the cell firing patterns of multiple neurons simultaneously, generating a large quantity of data. Identification of the firing patterns within these large groups of cells is an important and a challenging problem in data analysis. Here, we consider the problem of measuring the significance of a repeat in the cell firing sequence across arbitrary numbers of cells. In particular, we consider the question, given a ranked order of cells numbered 1 to N, what is the probability that another sequence of length n contains j consecutive increasing elements? Assuming each element of the sequence is drawn with replacement from the numbers 1 through N, we derive a recursive formula for the probability of the sequence of length j or more. For n<2j, a closed-form solution is derived. For n>or=2j, we obtain upper and lower bounds for these probabilities for various combinations of parameter values. These can be computed very quickly. For a typical case with small N (<10) and large n (<3000), sequences of 7 and 8 are statistically very unlikely. A potential application of this technique is in the detection of repeats in hippocampal place cell order during sleep. Unlike most previous articles on increasing runs in random lists, we use a probability approach based on sets of overlapping sequences.

Action Potentials↗
PubMed2006

Exploring the determinants of NHS performance ratings: lessons for performance assessment systems.

OBJECTIVES: A basic tenet of effective performance management is that decision makers should be held responsible only for aspects of performance over which they have control. We examine the degree to which variations in the performance of health care organizations are explained by a range of factors that are subject to differing degrees of managerial control. METHODS: We use multiple regression methods and data on 304 National Health Service (NHS) Primary Care Trusts (PCTs) in England for 2002/03 to analyse the relationship between their performance, as measured by 'star ratings' and nine key performance targets, and a large number of explanatory variables. We classify the explanatory variables into five groups along a spectrum from 'no managerial control' to 'total managerial control'. We also analyse the relationship between PCTs that are service purchasers and their main providers to assess the degree to which their performance is linked. RESULTS: For all of the key performance targets, most of the variation in performance is unexplained, although variables in groups 1, 2 and 3 (less managerial control) explain the largest proportion of variation. We find some evidence that socioeconomic and geographic factors have an impact on performance. We also find a positive relationship between the performances of purchaser and provider organizations. CONCLUSIONS: The star ratings did not allow for the different environmental circumstances within which PCTs operate and which affect their performance. Policy-makers should exercise caution in using such performance indicators to regulate health care organizations.

England↗
PubMed2006

Oral trimethoprim-sulphamethoxazole levels in stable HIV-infected children.

BACKGROUND: Effective treatment of Pneumocystis jiroveci pneumonia (PCP) requires therapeutic serum concentrations of 5-10 microg/ml trimethoprim (TMP); consequently intravenous trimethoprim-sulphamethoxazole (TMP-SMZ) is recommended therapy. However, oral therapy is desirable as the intravenous route is costly, time-consuming, more difficult to administer and carries a risk of needlestick injury. OBJECTIVE: To investigate whether therapeutic TMP levels for treatment of PCP can be attained with oral therapy in HIV-infected children. METHODS: A prospective dose-escalation study was undertaken of serum TMP levels attained following oral doses of TMP of 5 mg/kg, 10 mg/kg or 20 mg/kg in stable HIV-infected children. Children who received a 20 mg/kg dose were randomised to get a second dose (5 or 10 mg/kg TMP) at 6 hours. TMP levels were measured at baseline, peak (3 hours), and trough (6 hours) using liquid chromatography. An additional TMP level was taken at 9 hours in those who received a second TMP dose. RESULTS: Median (25th-75th percentile) peak serum TMP levels following a 5 mg/kg, 10 mg/kg or 20 mg/kg oral loading dose were 0.93 (0.5-1.5) microg/ml, 1.94 (1.4-2.2) microg/ml and 7.68 (6.1-7.8) microg/ml respectively. Peak TMP levels at 9 hours after a second TMP dose of 5 or 10 mg/kg were 6.98 (3.4-8.8) microg/ml and 9.25 (8.2-10.3) microg/ml respectively. CONCLUSION: Therapeutic concentrations of TMP for treatment of P. jiroveci can be attained with an oral loading dose of 20 mg/kg and sustained with a second dose at 6 hours of either 5 mg or 10 mg/kg in stable HIV-infected children.

AIDS-Related Opportunistic Infections↗
PubMed2005

The effect of financial incentives on gatekeeping doctors: evidence from a natural experiment.

In many health care systems generalist physicians act as gatekeepers to secondary care. Under the English fundholding scheme from 1991/1992 to 1998/1999 general practices could elect to be given a budget to meet the costs of certain types of elective surgery (chargeable electives) for their patients and could retain any surplus. They did not pay for non-chargeable electives or for emergency admissions. Non-fundholding practices did not bear the cost of any type of hospital admissions. Fundholding is to be reintroduced from April 2005. We estimate the effect of fundholding using a differences in differences methodology on a large 4-year panel of English general practices before and after the abolition of fundholding. The abolition of fundholding increased ex-fundholders' admission rates for chargeable elective admissions by between 3.5 and 5.1%. The effect on the early wave fundholders was greater (around 8%) than on later wave fundholders. We also use differences in differences for two types of admissions (non-chargeable electives, emergencies) not covered by fundholding as additional controls for unobserved temporal factors. These differences in differences in differences estimates suggest that the abolition of fundholding increased ex-fundholders' chargeable elective admissions by 4.9% (using the non-chargeables DID) and by 3.5% (using the emergencies DID).

Algorithms↗
PubMed2005

Insight into schizophrenia: the effects of cognitive behavioural therapy on the components of insight and association with sociodemographics--data on a previously published randomised controlled trial.

Insight in schizophrenia is an evolving concept with widespread use in clinical practice. Results are presented from a multicentre randomised trial in which patients with schizophrenia and carers received a short insight-focused Cognitive Behaviour Therapy (CBT) intervention from trained nurses in the community. The CBT group demonstrated significantly greater improvement in insight into compliance with treatment and the ability to re-label their psychotic symptoms as pathological compared with the control group at post-therapy assessment. Those participants who demonstrated improved insight into having a mental illness tended to become depressed. At the end of therapy and at 1-year follow-up, there was a statistically significantly increased dropout rate in African-Caribbean and Black African participants. The Black Caribbean group showed a significantly smaller change in insight compared to the white group. At 1-year follow-up, the result on total insight and compliance was durable. The change in insight in the Black African group was significantly lower compared to the white group. The study emphasizes the role of a short insight-focused CBT intervention in improving patients' insight into compliance and its implications. The results confirm previous findings of difficulties in engaging patients of Afro-Caribbean origin and their poor response to psychological therapies as currently delivered.

Adult↗
PubMed2005

Mitral valve repair versus replacement for isolated non-ischemic mitral regurgitation in patients with preoperative left ventricular dysfunction. A long-term follow-up echocardiography study.

UNLABELLED: The aim of this study was to evaluate LV function, by means of echocardiography, after mitral valve repair (MVr) or mitral valve replacement (MVR) in patients (pts) with chronic degenerative mitral regurgitation (MR) and depressed LV systolic function during a 6-years follow-up (FU) period. PATIENTS AND METHODS: Forty-five pts with moderately severe or severe MR and preoperative EF<or=50% were divided into 2 groups: MVr group (27 pts, 19 men-8 women, aged 62+/-10 years) and MVR group (18 pts, 8 men-10 women, aged 60+/-12 years). The cause of MR was myxomatous mitral valve disease (MVr/MVR: 16/8), endocarditis (0/4) and degenerative mitral valves with ruptured chordae tendineae (11/6). All pts underwent transthoracic echocardiography preoperatively, postoperatively and annually during the FU period (6+/-3 years). RESULTS: In MVr group, 5 pts died, 5 were lost to FU and 2 pts underwent MVR due to MVr failure. In MVR group, 6 pts died, 3 were lost to FU and 1 was re-operated due to prosthetic valve endocarditis. Atrial fibrillation was similar between the 2 groups. MVr pts demonstrated significant LVEDD decrease postoperatively which was persistent during FU (p<0.05). LVESD also decreased (p<0.05), VTI improved (p<0.05), while FS and EF showed a trend to improve. In MVR pts, LVEDD was decreased (p<0.05) but increased during FU (p<0.05) and LVESD remained high, resulting in a decrease of FS and EF (p<0.05). VTI remained unchanged (p=NS). CONCLUSION: MVr in pts with non-ischemic MR and preoperative LV dysfunction achieves better preservation of LV systolic indices than MVR, probably due to preservation of the subvalvular apparatus and LV geometry.

Aged↗
PubMed2005

When aspirations and achievements don't meet. A longitudinal examination of the differential effect of education and occupational attainment on declines in self-rated health among Canadian labour force participants.

BACKGROUND: To examine the association of a mismatch between educational qualifications and occupational attainment and subsequent declines in self-rated health (SRH) in a longitudinal nationally representative Canadian population sample. METHODS: This study used longitudinal data from 4045 healthy, working respondents of the Canadian National Population Health Survey. Respondents were categorized as either qualified, overqualified, or underqualified based on the match between their education and the skills required for their current occupation over a 2-year period. Logistic regression analysis estimated the odds of decline in SRH over the following 4-year period, using the match between occupation and education as the main independent variable. Analyses were controlled for a number of confounding variables including health behaviours, mental health, self-esteem, job control, and demographic information. RESULTS: Relative to respondents with university education working in occupations for which they were qualified, respondents with university education, working in occupations for which they were overqualified had a significant risk of decline in SRH between 1996 and 2000, even after adjusting for a number of potential confounders (OR = 2.08, 95% CI 1.11-3.91). In respondents with secondary education or less, differences in occupational attainment were not associated with differences in the odds of decline in SRH. CONCLUSIONS: The effect of occupational attainment on health is important for individuals who have invested the most time in their education. Conversely, differential occupational attainment is not associated with differences in the odds of decline in health for participants with lower levels of education.

Adult↗