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S Smith

Publications and source records attributed to S Smith.

At least 73 records · Page 4Linked to original sources
PubMed2003

Phase I population pharmacokinetics of irofulven.

Our aim was to develop a population pharmacokinetic model for irofulven and to assess covariates that might affect irofulven pharmacokinetics. Irofulven was administered by 5- or 30-min i.v. infusion to cancer patients during a phase I study. Blood samples were collected over 4 h. Plasma samples were analyzed to quantitate irofulven by high-performance liquid chromatography. Population pharmacokinetic analysis was performed using a non-linear mixed effects modeling program, MP2. Fifty-nine patients were available for pharmacokinetic analysis. Irofulven plasma concentration-time profiles were best described by a two-compartment pharmacokinetic model. Clearance and central volume of distribution were not significantly influenced by individual characteristics, i.e. body weight (BW), body surface area (BSA), age and gender. Final parameter estimates of clearance and central volume of distribution were 616 l/h and 37 l, respectively, resulting in a very short terminal half-life of less than 10 min. A relatively high level of variability was observed in irofulven pharmacokinetics, which was mainly due to a significant residual variability, 39%. For a 30-min irofulven infusion, the optimal sampling schedule for clearance estimation using the Bayesian method was the three time points 0.35-0.45, 0.80 and 1-1.2 h from the beginning of a 30-min infusion. We conclude that after i.v. infusion of irofulven, plasma clearance was high and not dependent upon patient age, gender, BSA or BW.

Adult↗
PubMed2003

An evidence and consensus based guideline for the management of a child after a seizure.

OBJECTIVE: An evidence and consensus based guideline for the management of the child who presents to hospital having had a seizure. It does not deal with the child who is still seizing. The guideline is intended for use by junior doctors, and was developed for this common problem (5% of all paediatric medical attenders) where variation in practice occurs. OPTIONS: Assessment, investigations (biochemistry, lumbar puncture, serum anticonvulsant levels, EEG in particular), and/or admission are examined. OUTCOMES: The guideline aims to direct junior doctors in recognising those children who are at higher risk of serious intracranial pathology including infection, and conversely to recognise those children at low risk who are safe to go home. EVIDENCE: A systematic review of the literature was performed. Articles were identified using the electronic data bases Medline (from 1966 to June 1998), Embase (from 1980 to June 1998) and Cochrane (to June 1998), and selected if they investigated the specified clinical question. Personal reviews were excluded. Selected articles were appraised, graded, and synthesised qualitatively. Statements of recommendation were made. CONSENSUS: An anonymous, postal Delphi consensus development was used. A national panel of 30 medical and nursing staff regularly caring for these children were asked to grade their agreement with the statements generated. They were sent the relevant original publications, the appraisals, and literature review. On the second and third rounds they were asked whether they wished to re-grade their agreement in the light of other panellists' responses. Consensus was defined as 83% of panellists agreeing with the statement. Recommendations in brief: For afebrile seizures all children should have their blood pressure recorded, but no other investigations are routine although a seizing or somnolent child should have blood glucose measured; all children under 1 year should be admitted. For seizures with fever, clinical signs indicating the need to treat as meningitis are given. Children should be admitted if they are under 18 months old, have had a complex seizure, or after pretreatment with antibiotics. VALIDATION: The guideline has undergone implementation and evaluation in a paediatric accident and emergency department, the results of which will be published separately. Only one alteration was made to the guideline as a result of this validation process, which is included here.

Algorithms↗
PubMed2003

Effect of on-farm commercial batch pasteurization of colostrum on colostrum and serum immunoglobulin concentrations in dairy calves.

The objectives were to describe the effect of on-farm commercial batch pasteurization on immunoglobulin (IgG) concentrations and the fluid and feeding characteristics of colostrum and to compare serum IgG concentrations in calves fed fresh versus pasteurized colostrum. Newborn calves (123) were systematically allocated to dietary treatments of either fresh or pasteurized colostrum at both the first and second colostrum feedings. The IgG concentrations were measured for batches of colostrum fed fresh and in pre and postpasteurized samples for batches of colostrum fed after being pasteurized and in calf serum. Pasteurization reduced colostrum IgG concentration, with the percentage reduction averaging 58.5 and 23.6% for 95-L and 57-L batches, respectively. Pasteurizing high quality colostrum in 57-L (vs. 95-L) batches resulted in higher IgG concentrations in the end product. Pasteurization of 57-L batches produced colostrum of normal or only mildly thickened consistency that could be fed to calves. Serum IgG concentrations were higher for calves fed fresh colostrum and for calves with a shorter time interval (< or = 6 h) between first and second colostrum feedings. After controlling for the time interval between feedings, serum IgG concentrations were significantly higher for 40 calves fed unpasteurized (19.1 mg/ml) vs. 55 calves fed pasteurized colostrum (9.7 mg/ml) for calves fed 2 L at first feeding. By contrast, there was no difference in serum IgG concentrations between 8 calves fed unpasteurized (16.1 mg/ml) and 20 calves fed pasteurized colostrum (13.5 mg/ml) after calves were fed 4 L at the first feeding. While the latter results suggest that pasteurizing colostrum may work for producers with excellent colostrum management, these results are preliminary and should be interpreted with caution, given the fewer number of calves and batches of colostrum involved with this second comparison.

Animals↗
PubMed2003

A national census of Irish general practice training programme graduates 1990-1996.

We followed the career pathways of all graduates of Irish general practice training schemes between 1990 and 1996 inclusive, with specific reference to their current positions, ten year aspirations, perceived barriers to their ideal career and attitudes to out of hours work. A postal survey using a structured questionnaire was performed. Addresses were identified for 253 of the 266 graduates (95%). A total of two hundred and nine responses were received (84% of those with an identifiable address). 173 (83%) have remained in general practice; 90% in Ireland and 60% in the same health board of their training programme. The preferred career option for 79% was to be a general practice principal; this differed significantly between males (89%) and females (74%) (p=0.016). Being a single-handed general practitioner was the preferred option for 2%; 43% considered this unacceptable. A half would prefer to work in a country town; one third considered a rural location as unacceptable. 'Out of hours' commitment and availability of local posts were the most commonly perceived barriers to career progress (53% and 45% respectively). 26% were not prepared to do any out of hours work; this differed significantly between males (10%) and females (30%) (p<.001). 17% have permanently left a career in general practice. Female general practitioners were not significantly more likely than male general practitioners to have left (19% vs. 14%, p=0.3). The most common reason given for leaving general practice was other career interest (78%). The significant increase in female general practice graduates over the past twenty years is highlighted. The vast majority of these female graduates wished to be a principal in a group practice and were prepared to undertake out of hours work. There is also a mismatch between career aspirations and the present structure of general practice in Ireland. The urgent need for changes in health system organisation to ensure that these intentions can be fulfilled is emphasised.

Career Choice↗
PubMed2003

MRI brain T1 relaxation time changes in MS patients increase over time in both the white matter and the cortex.

OBJECTIVE: To test the sensitivity of whole-brain T1 relaxometry to the evolution of pathological changes in multiple sclerosis (MS). BACKGROUND: T1-weighted hypointense lesion load in the brains of patients with MS is associated with axonal loss. Other work has shown that T1 measurements may provide information complementary to existing imaging techniques, such as magnetization transfer imaging. METHODS: The authors studied 14 MS patients twice over a median time interval of 19.5 months (range, 14-22 months). Structural images and whole-brain T1 maps using a novel rapid-scanning technique (3 min/study) were performed at 3 T. Analysis focused on defining changes separately in the lesional and normal-appearing white matter (NAWM) and in the cortical gray matter. RESULTS: At baseline, there was an inverse relationship between disease duration and the NAWM T1 histogram peak height (r = -0.75, P = .03). The total white matter T1 histogram peak height decreased over time (P < .001). This could be accounted for by changes in the NAWM (P < .03). There also was a decrease (6%) in the mean (11 of 14 patients, P = .004) and in the median (7%) (13 of 14 patients, P < .001) neocortical gray matter T1 over the follow-up period. CONCLUSIONS: Brain T1 maps can be generated quickly and are sensitive to pathological changes over time. T1 values in both the gray and the white matter at the baseline visit were related to disease duration, suggesting that the T1 changes are clinically relevant. Although the absolute values will be different, it is likely that similar changes will be able to be detected at 1.5 T. The role of T1 measurement as a magnetic resonance imaging outcome measure in clinical trials now should be explored.

Adult↗
PubMed2003

Head lice diagnosed in general practice in the West Midlands between 1993 and 2000: a survey using the General Practice Research Database.

The potential of the General Practice Research Database (GPRD) for communicable disease surveillance was explored using head lice as an example. All diagnoses of head lice and prescriptions for parasiticidal agents from 1993 to 2000 in the West Midlands were analysed. Diagnoses reached a peak of 28.2 per 1,000 patient years at risk and total prescriptions reached a peak of 27.1 per 1,000 patient years at risk in 1997. Malathion and permethrin were prescribed most often. The proportion of further parasiticidal prescriptions issued within 30 days of the initial prescription increased to a peak of 11.5% of prescriptions in 1997. The ratio of the same:different further prescriptions changed during the study period, reaching a high of 5:1 in 2000. These trends are mirrored by the Royal College of General Practitioners (RCGP) Weekly Returns Service and Prescribing Analysis and Cost (PACT) data. Use of GPRD provides additional insights into patient data, particularly on prescribing, that would not be available from other sources.

Adolescent↗
PubMed2002

Extremely low vertical-emittance beam in the accelerator test facility at KEK.

Electron beams with the lowest, normalized transverse emittance recorded so far were produced and confirmed in single-bunch-mode operation of the Accelerator Test Facility at KEK. We established a tuning method of the damping ring which achieves a small vertical dispersion and small x-y orbit coupling. The vertical emittance was less than 1% of the horizontal emittance. At the zero-intensity limit, the vertical normalized emittance was less than 2.8 x 10(-8) rad m at beam energy 1.3 GeV. At high intensity, strong effects of intrabeam scattering were observed, which had been expected in view of the extremely high particle density due to the small transverse emittance.

Journal Article↗
PubMed2002

Visualisation of hyaluronan and hyaluronan-binding proteins within ovine vertebral cartilages using biotinylated aggrecan G1-link complex and biotinylated hyaluronan oligosaccharides.

The aim of this study was to localise hyaluronan (HA)-binding proteins (HABPs) in ovine vertebral tissues using biotinylated HA oligosaccharides (bHA oligos) as novel affinity probes and to compare this with the distribution of tissue HA visualised using biotinylated aggrecan G1 domain-link protein complex. The bHA oligos, with a size of 6-18 disaccharides were prepared by partial digestion of HA with ovine testicular hyaluronidase, labelled with biotin hydrazide and purified by a combination of aggrecan G1 domain and avidin affinity chromatography. Hyaluronan and HABPs were both prominent pericellular components of hypertrophic cells of the vertebral epiphyseal growth plate and enlarged cells in the cartilaginous end plate of the disc. The bHA oligo probe also visualised HABPs intracellularly in hypertrophic cells, which also contained intracellular HA. Monolayer cultures of ovine annulus fibrosus and nucleus pulposus cells rapidly internalised the bHA oligo affinity probe which was subsequently visualised by indirect fluorescence using avidin-FITC, to cytoplasm and discrete nuclear regions. The results indicate that the abundant pericellular and intracellular HA associated with cartilaginous cells in the vertebral tissues is colocalised with HABPs. The bHA oligo affinity probe may have further applications in investigations of intracellular HABPs, HA endocytosis and the roles they play in cellular regulatory processes.

Aggrecans↗
PubMed2002

White matter and lesion T1 relaxation times increase in parallel and correlate with disability in multiple sclerosis.

Previous studies have established the clinical relevance of hypointense lesions ("black holes") on T1-weighted MRI as a surrogate marker for pathological change [36]. In contrast to measuring the volume of "black holes", the direct measurement of T1 values allows an objective assessment of the changes contributing to hypointensity both in the focal lesions and in the normal appearing white matter (NAWM). The aims of this study were first, to determine the relationship between T1 values in the NAWM and in discrete lesions, second, to test the relationship between white matter T1 changes and measures of disability and third, to determine whether pathology leading to T1 change occurred in thalamic grey matter of patients with multiple sclerosis. 24 patients with clinically definite multiple sclerosis (13 with relapsing-remitting multiple sclerosis and 11 with secondary progressive multiple sclerosis) and 11 controls participated. White matter T1 histograms and mean T1 values for the thalamus were generated from whole brain T1 relaxation time maps measured using a novel echo-planar imaging based MRI sequence at 3Tesla. Tissue segmentation based on T2- and T1-weighted images allowed independent study of changes in lesions and NAWM. White matter T1 histograms from the patient group showed a reduced peak height and a shift towards higher T1 values (p = 0.028) relative to controls. The mean thalamic T1 was greater for secondary progressive patients than for healthy controls (p = 0.03). Mean white matter T1 values correlated significantly with disability (r = 0.48, p = 0.02). The mean T1 value in the T1-hypointense lesions correlated strongly with the mean T1 value in the NAWM (r = 0.80, p < 0.001). No significant relationship was found between mean white matter T1 value and cerebral volume (r = -0.23, p = 0.31). The T1 measurements extend previous observations suggesting that changes in the NAWM occur in parallel with pathology in lesions of MS. T1 measurements of either the total or NAWM therefore may provide a potentially observer- and scanner- independent marker of pathology relevant to disability in MS.

Adult↗
PubMed2002

Mitigation of chlorpyrifos runoff using constructed wetlands.

Constructed wetlands have been proposed as a potential best management practice (BMP) to mitigate effects of pesticide-associated agricultural runoff. Wetland mesocosms (14 m x 59-73 m) were amended with chlorpyrifos to simulate a storm runoff event at concentrations of 73, 147 and 733 microg/l. Water, sediment and plant samples collected weekly for 12 weeks indicated that chlorpyrifos rapidly sorbed to sediment and plant material, with approximately 47-65% of measured chlorpyrifos mass retained within the first 30-36 m of wetland mesocosms. Of the measured mass, approximately 55% and 25% were retained by sediments and plants, respectively. A field-scale evaluation of a constructed wetland's mitigation capability was performed in the Lourens River watershed of Cape Town, South Africa. Results indicate that the wetland was able to retain and considerably decrease the concentration (and hence toxicity) of chlorpyrifos and suspended sediment entering the receiving waterbody (Lourens River). This research provides fundamental answers concerning constructed wetland capabilities that are necessary for constructing field-scale systems within agricultural watersheds.

Agriculture↗
PubMed2002

A comparison of the plaque-inhibitory properties of stannous fluoride and low-concentration chlorhexidine mouthrinses.

BACKGROUND: Plaque inhibition by chlorhexidine (CHX) rinses is dose related with a relatively flat dose-response curve above 5-6 mg twice daily. Low dose regimens could therefore reduce local side effects but maintain reasonable efficacy. AIMS: To compare the plaque inhibitory properties of two low-dose CHX rinse products with more conventional levels delivered from proprietary rinses. A secondary outcome was a comparison with a stannous fluoride/amine fluoride (SFAF) rinse product. METHODS: The study was a five-treatments, negative controlled, randomised, single blind crossover design balanced for residual effects, involving 20 healthy subjects in a 24-h plaque re-growth model. On day 1 of each study period, subjects were rendered plaque free, suspended tooth cleaning and followed the appropriate rinse regimen. On day 2, subjects were scored for plaque by index and area. The rinse codes and rinsing regimens were: (A) 15 mg CHX 2 x daily for 30 s (0.1% CHX), (B) 9 mg CHX 2 x daily for 60 s (0.06% CHX), (C) 10 ml SFAF rinse 1 x daily for 30 s, (D) 15 ml placebo 2 x daily for 60 s, and (E) 6 mg CHX 2 x daily for 30 s (0.06% CHX). RESULTS: Average mouth plaque indices and areas were highly significantly different between rinsing regimens. All test rinses were significantly more effective than the placebo rinse. There was a mean dose-response pattern for the CHX rinses, but there were no statistically significant differences between any of the test rinses. CONCLUSIONS: Lower doses of chlorhexidine in rinses can be used to exert plaque inhibition comparable with products used at higher doses and equivalent to benchmark products such as the SFAF rinse. However, the availability of chlorhexidine from formulations has to be considered as in part explaining the results.

Adult↗
PubMed2002

A comparison of oral transmucosal fentanyl and oral midazolam for premedication in children.

Oral transmucosal fentanyl citrate (OTF) was compared with midazolam as a premedicant in a prospective, randomised, placebo-controlled, double-blind trial. Eighty children (ASA grade 1 or 2, aged 3-9 years) who presented for tonsillectomy were randomly allocated to receive either 2.5 ml OTF (15-20 microg.kg(-1)) in a lollipop format and 0.5 ml.kg(-1) placebo syrup, or midazolam syrup (0.5 mg.kg(-1)) and a placebo lollipop (2.5 ml). The acceptability of sedation, anxiety and compliance with anaesthetic induction were assessed. The children were given an 'emergence' score for their recovery. Analgesia requirements, the incidence of vomiting, itching and any behavioural changes were assessed for 6 h postoperatively. Oral transmucosal fentanyl citrate was as effective as midazolam in aiding compliance with anaesthesia, but is significantly better in its appeal to children (p < 0.001) and emergence (p < 0.001) characteristics. In conclusion, OTF may be particularly useful as a premedicant in paediatric practice.

Administration, Oral↗
PubMed2002

Human T cell responses to peptides of the Mycobacterium leprae 45-kD serine-rich antigen.

In order to identify T cell epitopes within the Mycobacterium leprae 45-kD serine-rich antigen, we analysed responses to overlapping 17-mer peptides encompassing the whole antigen in non-exposed UK controls, Pakistani leprosy patients and tuberculosis patients in both the United Kingdom and Pakistan. This antigen has been described as M. leprae-specific, although it has a hypothetical homologue in M. tuberculosis. Human peripheral blood mononuclear cells were stimulated with peptide for 5 days and IFN-gamma measured in supernatants by ELISA. Some peptides were recognized more frequently by T cells from tuberculoid leprosy patients than those from UK controls, suggesting that such T cell epitopes might have diagnostic potential, while other peptides induced greater responses among UK control subjects. Short-term cell lines confirmed that these assays detected specific T cell recognition of these peptides. However, many tuberculosis patients also recognized these potentially specific peptides suggesting that there could be a true homologue present in M. tuberculosis.

Amino Acid Sequence↗
PubMed2002

Growth factor rescue of cytokine mediated trophoblast apoptosis.

INTRODUCTION: Apoptosis can be induced in cytotrophoblasts and syncytiotrophoblast in culture by a combination of TNF-alpha and IFN-gamma (Yui et al., 1994a; Garcia-Lloret et al., 1996). This apoptotic action of TNF-alpha and IFN-gamma can be inhibited/'rescued' by EGF (Garcia-Lloret et al., 1996). Additional 'survival' factors have been sought which might protect cells against apoptosis induced by TNF-alpha/IFN-gamma. The survival factors investigated were bFGF, IGF-1, PDGF-AA, VEGF and PLGF. These cytokines were chosen specifically because in common with EGF, the receptors for these molecules are all direct protein tyrosine kinases. MATERIALS AND METHODS: All the experiments were carried out using a standard cell culture protocol (Yui et al., 1994a, b; Garcia-Lloret et al., 1996). Apoptosis was induced using TNF-alpha/IFN-gamma, and rescue was attempted using the various cytokines. Apoptosis was identified using the TUNEL technique and quantified by counting 3000 cells in each experimental well. RESULTS: As in previous studies EGF produced a complete inhibition of the apoptotic action of TNF-alpha/IFN-gamma. bFGF, IGF-1, and PDGF-AA produced a partial but significant inhibition of the apoptotic action of TNF-alpha/IFN-gamma. VEGF and PLGF in these experiments had no protective effects against TNF-alpha/IFN-gamma induced apoptosis. DISCUSSION: Previous studies relating to EGF have been confirmed. bFGF, IGF-1, and PDGF have all been shown to provide partial protection against TNF-alpha/IFN-gamma induced apoptosis. VEGF and PLGF did not protect against apoptosis, and the mechanisms of action remain unclear.

Apoptosis↗
PubMed2002

HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis.

BACKGROUND: The association between multiple sclerosis and class II alleles of the major histocompatibility complex, in particular the DRB1*1501-DQB1*0602 haplotype, is well established but their role in determining specific features of this clinically heterogeneous disease is unknown as few studies involving large sample sizes have been performed. METHODS: 729 patients with multiple sclerosis were typed for the HLA DR15 phenotype. All patients underwent clinical assessment and a detailed evaluation of their clinical records was undertaken. RESULTS: The presence of DR15 was associated with younger age at diagnosis and female sex but there was no association with disease course (relapsing-remitting or secondary progressive v primary progressive type), disease outcome, specific clinical features (opticospinal v disseminated form), diagnostic certainty (clinically and laboratory supported definite v clinically probable multiple sclerosis), and paraclinical investigations including the presence of oligoclonal bands in the CSF or characteristic abnormalities on MRI imaging of the central nervous system. CONCLUSION: Even though DR15 carriers are more likely to be female and prone to an earlier disease onset, the results indicate that there is no association with other specific clinical outcomes or laboratory indices examined here. This suggests that DR15 exerts a susceptibility rather than disease modifying effect in multiple sclerosis.

Adolescent↗
PubMed2002

Do mental disorders matter? A study of absenteeism among care seeking Gulf War veterans with ill defined conditions and musculoskeletal disorders.

AIMS: To investigate the extent that common psychological conditions contribute to lost work among individuals with musculoskeletal and ill defined conditions. METHODS: Cross sectional health and work related survey evaluating Gulf War veterans seeking Department of Defense health care for Gulf War related health concerns. Ordered probit models were used to study whether a provider diagnosed musculoskeletal condition (ICD-9 codes 710-739) or "signs, symptoms, and ill defined conditions" (ICD-9 codes 780-799) have an effect on recent lost work over the previous 90 days in the presence of one or more psychological conditions (ICD-9 codes 290-320) after controlling for sociodemographic variables. RESULTS: Bivariate analyses revealed that musculoskeletal conditions, ill defined conditions, and psychological conditions were positively associated with lost work. Multivariate analyses showed an independent effect of both psychological conditions and musculoskeletal conditions. A significant interaction existed between psychological conditions and musculoskeletal conditions: the presence of a coexisting psychological condition considerably increased the likelihood that a musculoskeletal disorder resulted in lost work, or vice versa. CONCLUSIONS: Psychological conditions appear to be an important contributor to absenteeism among individuals with musculoskeletal and ill defined conditions. A limitation of the cross sectional design was the inability to sequence the onset of conditions.

Absenteeism↗