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S Smith

Publications and source records attributed to S Smith.

At least 253 records · Page 14Linked to original sources
PubMed1999

Asthma survey items as predictors of respiratory problems in children 2 yrs later: a longitudinal study.

The study compared the ability of characteristics defined by an asthma survey (wheeze versus cough and asthma diagnosis versus no diagnosis) to predict later respiratory problems in a cohort of 108 schoolchildren who had reported either recent wheeze or recurrent cough in a 1987 asthma survey. The children recorded daily respiratory symptoms and peak flow from April 1989 until May 1990. The frequency and severity of lower respiratory symptom episodes and peak flow dips were compared in the wheeze and cough groups and in the diagnosed versus nondiagnosed children. The independent effects of initial wheeze, atopy, diagnosis and bronchial hyperresponsiveness (BHR) on the longitudinal outcome measures were assessed using multiple linear regression. Children with initial wheeze had more chronic symptoms and peak flow variability than those with cough alone, but wheeze had only a weak effect on frequency and severity of acute lower respiratory episodes. Children with both wheeze and atopy had more acute symptomatic episodes and more chronic symptoms than did the other children. Children with diagnosed asthma (versus no diagnosis) had significantly more frequent and severe lower respiratory exacerbations, more days symptomatic and greater peak flow variability. The predictive effects of diagnosis were independent of (and stronger than the effects of) wheeze, atopy and BHR, or combinations of these variables. The results suggest that among children who report respiratory symptoms, survey-reported wheeze on its own is a weaker marker of significant respiratory disease than is a doctor's diagnosis of asthma.

Asthma↗
PubMed1999

Characterization of a mutant T-cell hybridoma line with defects in the TCR-mediated apoptotic pathway.

A mutant T-cell hybridoma line named mutant 51 was developed that, unlike the parental line, did not die after T-cell receptor (TCR) engagement and demonstrated reduced death in response to dexamethasone. Intracellular calcium measurements showed that available calcium stores were markedly reduced in the mutant cell line. Unlike control cells, secretion of IL-2 from mutant cells was also greatly reduced, although addition of exogenous IL-2 did not facilitate increased apoptosis. Although levels of the cell death gene product Nur77 were equivalent, additional studies showed that mutant cells expressed Nur77 predominantly in the cytoplasm following TCR engagement, while parental cells displayed a nuclear translocalization of Nur77. In addition, Fas levels and Fas ligand dependant killing were both markedly reduced in the mutant clone. From these data we hypothesize a role for available calcium stores and Nur77 nuclear localization in TCR-mediated apoptosis in T-cell hybridomas.

Apoptosis↗
PubMed1999

Failure to respond to treatment with typical antipsychotics is not associated with CYP2D6 ultrarapid hydroxylation.

AIMS: To investigate whether or not there is a correlation between failure to respond to typical antipsychotics and CYP2D6 ultrarapid metaboliser status. METHODS: CYP2D6 phenotype (metaboliser status) was assigned following genotyping for gene duplication, as well as for the CYP2D6*3, CYP2D6*4, and CYP2D6*5 null alleles in 235 treatment-refractory patients and 73 nonrefractory patients. RESULTS: Four (1.7%) of the 235 treatment-refractory subjects were positive on the duplication assay, but, of these, two were found to represent duplications of a null allele (CYP2D6*4 ), therefore leaving only two (0.85%) positive for duplication of a wild type allele (ultrarapid metabolisers). Three (4.1%) of the nonrefractory subjects had a genotype consistent with ultrarapid metaboliser status. Fisher's exact test gave a two-tailed P value of 0.091, i.e. a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, which was in the opposite direction to that predicted by our hypothesis. CONCLUSIONS: Although the results show a trend towards an excess of ultrarapid metabolisers in the nonrefractory group, the percentages in the two groups of patients are both within the range for ultrarapid metabolisers in Caucasian populations. Our data are not consistent with ultrarapid metaboliser status being a major cause of failure to respond to typical antipsychotics.

Alleles↗
PubMed1999

Treatment of photosensitive epilepsy using coloured glasses.

A recently introduced optometric technique, colorimetry, enables the perceptual effects of ophthalmic tints to be evaluated subjectively, optimized, and then prescribed in tinted spectacles. The new technique is beneficial in reducing visual stress in patients with dyslexia and migraine. We describe an open trial designed to ascertain: (1) whether the colorimetry assessment, as it is now given, is safe for the investigation of photosensitive patients in optometry clinics where colorimetry equipment is most readily available, but where EEG control is not practical; (2) what proportion of patients with photosensitive epilepsy is likely to benefit to the extent already described in individual cases; (3) whether a tint selected by colorimetry could be shown to reduce the incidence of paroxysmal epileptiform EEG activity in response to flicker and patterns, thereby validating the subjective methods and corroborating the reported seizure reduction. Twenty-four females and nine males (aged 12-43 years) took part. All the patients had suffered visually-provoked seizures, had exhibited a photoparoxysmal response on at least one previous EEG recording, and had received a diagnosis of photosensitive epilepsy. Twenty-two were currently experiencing seizures. A further EEG was recorded in all except seven cases: a routine resting record, followed by hyperventilation. Colorimetry was performed after hyperventilation and before photic stimulation. Twenty-three (70%) reported beneficial effects during colorimetry and were prescribed glasses. There was a preponderance of lenses with a rose or purple colour, in contrast to patients with dyslexia. Seventeen of the 23 patients were available at follow-up, an average of 2.4 years later. Thirteen (57%) reported benefits, and said they were still using the lenses. In six of the 13 the benefits were pronounced, including a reduction of dizziness from fluorescent lighting, elimination of aura when using computer screens etc. Only in three cases was there a reduction in seizures that could reasonably be attributed to the use of lenses; in two of these cases no medications were prescribed, and in the third the medications remained unchanged for four years, two before and two after the introduction of the glasses. In an additional four cases a reduction in seizures was observed but medication had been changed. There was a modest reduction in EEG photosensitivity with the coloured lenses but also to an equivalent or lesser extent with grey in all of the eight patients examined in this way. One patient had seizures during colorimetry, but the seizures were not accompanied by scalp EEG changes.

Adolescent↗
PubMed1999

Short-term inflammatory responses following intratracheal instillation of fine and ultrafine carbon black in rats.

Ultrafine carbon black (ufCB) 14 nm in diameter and fine carbon black (CB) 260 nm in diameter were instilled intratracheally in rats at mass of 125 microg, and the bronchoalveolar lavage (BAL) profile at 6 h was assessed. UfCB generated a 50% neutrophil alveolitis 6 h after intratracheal instillation compared to CB, which showed similar activity to the phosphate-buffered saline (PBS) vehicle control. UfCB instillation also produced a marked increase in lactate dehydrogenase (LDH) levels in BAL fluid, which was associated with increased epithelial permeability measured as total protein. In contrast, CB had much less of an effect in increasing BAL protein. Although both particle types caused a decrease in glutathione (GSH) in lung tissue compared to control, the greatest depletion was seen in ufCB-treated animals. To investigate time response, bronchoalveolar lavage was carried out at 6 h, 24 h, and 7 days after a single 125-microg instillation of ufCB. Neutrophil influx was relatively persistent and was still maintained 7 days later. Tumor necrosis factor (TNF) production by BAL leukocytes increased gradually postinstillation, whereas NO production became significantly higher at 24 h after instillation and remained at raised levels up to 7 days. Higher doses of CB caused more inflammation than the ufCB. Thus, in the instillation model, a localized dose of particle over a certain level causes the particle mass to dominate the response, rather than the surface area. In contrast to the effect of CB, which showed a dose-related increasing inflammatory response, ufCB at the highest dose caused less of a neutrophil influx than at the lower dose. Six hours after intratracheal instillation, the threshold dose for neutrophil influx occurred at 50 microg. Calculation of surface area of particles instilled suggested that this was likely to be an overload-inducing dose of particles, as gauged from recent experiments with inhaled particles. In summary, this study provides evidence in a rat instillation model that ufCB has greater ability than CB to produce lung inflammation and oxidant stress at a relatively low dose of 125 microg. At high doses, however, BAL is not a reliable indicator of pulmonary response, since the overall response seems to scale to mass or volume of instilled particulate without an influence of surface area.

Animals↗
PubMed1999

Meningioangiomatosis. A comprehensive analysis of clinical and laboratory features.

Meningioangiomatosis (MA) is a rare, benign, focal lesion of the leptomeninges and underlying cerebral cortex characterized by leptomeningeal and meningovascular proliferation. It may occur sporadically or in association with neurofibromatosis type 2. Previous reports have emphasized histological and imaging features. Data on the management of these patients are sparse, and electrophysiological features of MA lesions have not been published. We assessed the clinical, electrophysiological, histopathological and imaging features as well as the surgical outcome in MA, and compared MA with and without neurofibromatosis. Seven patients with MA at our centre were investigated and their outcome was assessed. A review of the literature is included. MA exhibits a wide range of clinical, imaging, histopathological and electrophysiological features, making the diagnosis difficult. Sporadic MA cases are not associated with neurofibromatosis and the two disorders are genetically distinct. Medically refractory, localization-related epilepsy is the commonest presentation in sporadic cases, but atypical presentations also occur. Unlike sporadic cases, MA with neurofibromatosis is often found incidentally, does not produce seizures, occurs less frequently (ratio of 1:4), and is multifocal. MRI findings in MA correspond to the histological picture. However, the appearance on imaging is non-specific and may suggest cystic atrophy, angioma and tumours. Several abnormalities have been found in close proximity to MA lesions, i.e. meningioma, oligodendroglioma, arteriovenous malformation, encephalocoel and orbital erosion. In spite of histopathological diversity, MA lesions are either predominantly cellular or vascular. Immunohistochemical results are inconsistent among cases, add little to the diagnosis, and do not support a meningeal origin. Electrocorticographic recordings from the surface and within MA lesions revealed a spectrum of electrophysiological expressions. Intrinsic epileptogenicity of MA lesions was documented in some cases. Epileptogenicity was confined to the perilesional cortex in some patients and it was complex (extralesional, multifocal, generalized) in others. Only 43% of our patients became seizure-free postoperatively compared with 68% previously reported, and >70% of our patients and those in the literature continued to require antiepileptic drugs. This is in keeping with the diverse electrophysiology of MA and suggests a less optimistic postoperative outcome than previously recognized.

Adolescent↗
PubMed1999

Spatial mapping of T2 and gadolinium-enhancing T1 lesion volumes in multiple sclerosis: evidence for distinct mechanisms of lesion genesis?

It is generally believed that most T2-weighted (T2) lesions in the central white matter of patients with multiple sclerosis begin with a variable period of T1-weighted (T1) gadolinium (Gd) enhancement and that T1 Gd-enhancing and T2 lesions represent stages of a single pathological process. Lesion probability maps can be used to test this hypothesis by providing a quantitative description of the spatial distribution of these two types of lesions across a patient population. The simplest prediction of this hypothesis would be that the spatial distributions of T1 Gd-enhancing and T2 lesions are identical. We generated T1 Gd-enhancing and T2 lesion probability maps from 19 patients with relapsing-remitting multiple sclerosis. There was a significantly higher probability (P = 0.001) for T2 lesions to be found in the central relative to the peripheral white matter (risk ratio 4.5), although the relative distribution of T1 Gd-enhancing lesions was not significantly different (P = 0.7) between central and peripheral white matter regions (risk ratio 0.6). Longitudinal data on the same population were used to demonstrate a similar distribution asymmetry between new T1 Gd-enhancing and new T2 lesions that developed over the course of 1 year. Alternative hypotheses to explain this observation were tested. We found no spatial difference in the likelihood of development of persistent T2 lesions following T1 Gd enhancement. The relative distribution of T1 Gd-enhancing lesions was shown to be independent of the dose of Gd contrast agent and the frequency of scanning. Our findings suggest that a proportion of the periventricular T2 lesion volume may arise from mechanisms other than those associated with early breakdown of the blood-brain barrier leading to T1 Gd enhancement.

Adult↗
PubMed1999

The patient-related costs of care for sepsis patients in a United Kingdom adult general intensive care unit.

OBJECTIVE: To determine the patient-related costs of care for critically ill patients with severe sepsis or early septic shock. DESIGN: Retrospective, longitudinal, observational study during a 10-month period. SETTING: Adult general intensive care unit (ICU) in a university hospital located in the United Kingdom. PATIENTS: The study population consisted of 213 patients admitted consecutively to the ICU during a 10-month period. Thirty-six patients were identified using standard definitions as having developed sepsis and analyzed by group (according to the day on which sepsis was diagnosed): Group 1 patients were septic at admission to ICU (n = 16); group 2 patients were septic on their second day in the ICU (n = 10); and group 3 patients developed sepsis after their second day in the ICU (n = 10). One hundred and seventy-seven ICU patients without sepsis were used as the comparative group (group 4). INTERVENTIONS: None. MAIN RESULTS: Patient-related costs of care, length of ICU stay, and ICU and hospital mortality rates were compiled. The median daily costs of care for patients in groups 1, 2, and 3 were $930.74 (interquartile range $851.59-$1,263.96); $814.47 ($650.89-$1,123.06), and $1,079.39 ($705.02-$1,295.96), respectively; these were significantly more than the group 4 patient's daily cost of $750.38 ($644.10-$908.55) (p < .01). The median total cost of treating the group 4 patients was $1,666.87 ($979.71-$2,772.03), significantly less than for the patients with sepsis (p < .01). The difference in total costs of care between the sepsis groups was also significant (p < .05), with a group 1 patient costing $3,801.55 ($1,865.28-$11,676.08), a group 2 patient costing $13,089.17 ($5,792.94-$22,235.18), and a group 3 patient costing $17,962.78 ($13,030.83-$28,546.73). Patients in groups 1, 2, and 3 stayed in the ICU for 3.3 days (1.3-11.3), 16.5 days (8.9-22), and 16.1 days (10.9-9), respectively. Significant differences were found among the three groups (p < 0.05), as well as between the patients with sepsis and those without (p < 0.001), whose median length of stay was 1.9 days (0.9-3.6). The ICU mortality rates were 50% each for groups 1 and 2, 60% for group 3, and 20% for group 4. Only one patient with sepsis and 16 patients without sepsis died in the hospital ward, producing overall mortality rates of 56% for group 1 and 29% for group 4. CONCLUSIONS: Patients with severe sepsis or early septic shock had a high mortality rate, spent prolonged periods of time in the ICU, and were significantly more expensive to treat than nonsepsis ICU patients.

APACHE↗
PubMed1999

Generation and analysis of 25 Mb of genomic DNA from the pufferfish Fugu rubripes by sequence scanning.

We have generated and analyzed >50,000 shotgun clones from 1059 Fugu cosmid clones. All sequences have been minimally edited and searched against protein and DNA databases. These data are all displayed on a searchable, publicly available web site at. With an average of 50 reads per cosmid, this is virtually nonredundant sequence skimming, covering 30%-50% of each clone. This essentially random data set covers nearly 25 Mb (>6%) of the Fugu genome and forms the basis of a series of whole genome analyses which address questions regarding gene density and distribution in the Fugu genome and the similarity between Fugu and mammalian genes. The Fugu genome, with eight times less DNA but a similar gene repertoire, is ideally suited to this type of study because most cosmids contain more than one identifiable gene. General features of the genome are also discussed. We have made some estimation of the syntenic relationship between mammals and Fugu and looked at the efficacy of ORF prediction from short, unedited Fugu genomic sequences. Comparative DNA sequence analyses are an essential tool in the functional interpretation of complex vertebrate genomes. This project highlights the utility of using the Fugu genome in this kind of study.

Animals↗
PubMed1999

Once-daily therapy for H. pylori infection: a randomized comparison of four regimens.

OBJECTIVE: We sought to determine the efficacy and tolerability of novel, once-daily therapies in the treatment of Helicobacter pylori infection. METHODS: One hundred sixty subjects with H. pylori infection documented by endoscopic biopsy or serology plus 13C-urea breath test were randomly assigned to omeprazole 80 mg q.d. and metronidazole extended-release formulation 750 mg q.d. for 10 days (OM); OM plus amoxicillin 1.5 g q.d. for 10 days (OMAm); OM plus azithromycin 500 mg q.d. for 7 days (OMAz); or OM plus clarithromycin 1 g q.d. for 10 days (OMCI). A repeat breath test was done 6 wk after the completion of therapy. Subjects were considered compliant if they took > or = 80% of each study medication as prescribed. RESULTS: Intent-to-treat eradication rates were OM = 8% (95% confidence interval [CI], 2-20%), OMAm = 35% (95% CI, 21-52%), OMAz = 65% (95% CI, 48-79%), and OMCI = 78% (95% CI, 62-89%). Lack of compliance was seen in 5% of subjects given OM, 8% given OMAm, 3% given OMAz, and 15% given OMCI. CONCLUSIONS: This pilot study demonstrated that once-daily triple therapy with high-dose omeprazole, metronidazole extended-release formulation, and clarithromycin achieved an eradication rate approaching 80%. Further study may permit development of optimal once-daily dosing and enhance eradication rates.

Adult↗
PubMed1999

Neuroendocrine differentiation of a metastatic basal cell carcinoma in a patient with basal cell nevus syndrome.

A 48 year-old white male with basal cell nevus syndrome presented with a metastatic basal cell carcinoma with neuroendocrine features. The tumor manifested aggressive behavior, having deep local invasion and metastases to para-aortic lymph nodes and bone. Neuroendocrine differentiation has rarely been associated with basal cell carcinoma. The histologic, immunohistochemical, and electron microscopic studies of this rare tumor are described.

Antineoplastic Agents↗
PubMed1999

The bovine papillomavirus E5 protein requires a juxtamembrane negative charge for activation of the platelet-derived growth factor beta receptor and transformation of C127 cells.

The bovine papillomavirus E5 gene encodes a 44-amino-acid, homodimeric transmembrane protein that is the smallest known transforming protein. The E5 protein transforms cultured fibroblasts by forming a stable complex with the endogenous platelet-derived growth factor (PDGF) beta receptor through transmembrane and juxtamembrane interactions, leading to sustained receptor activation. Aspartic acid 33 in the extracellular juxtamembrane region of the E5 protein is important for cell transformation and interaction with the PDGF beta receptor. A. N. Meyer et al. (Proc. Natl. Acad. Sci USA 91:4634-4638, 1994) speculated that this residue interacted with lysine 499 on the receptor. We constructed E5 mutants containing all possible substitutions at position 33, as well as several double mutants containing substitutions at aspartic acid 33 and at glutamic acid 36, and we examined the ability of these mutants to transform C127 mouse fibroblasts and to bind to and induce activation of the PDGF beta receptor. There was an excellent correlation between the transformation activities of the various mutants and their ability to bind to and activate the PDGF beta receptor. Analysis of the mutants demonstrated that a juxtamembrane negative charge on the E5 protein was required for cell transformation and for productive interaction with the PDGF beta receptor and indicated that aspartic acid 33 was more important for these activities than was glutamic acid 36. These results are consistent with the existence of an essential juxtamembrane salt bridge between lysine 499 on the PDGF beta receptor and an acidic residue in the C terminus of the E5 protein and lend support to our proposed model for the complex between the E5 dimer and the PDGF beta receptor.

Amino Acid Sequence↗
PubMed1999

Disruption of muREC2/RAD51L1 in mice results in early embryonic lethality which can Be partially rescued in a p53(-/-) background.

muREC2/RAD51L1 is a radiation-inducible gene that regulates cell cycle progression. To elucidate the biological function of muREC2/RAD51L1, the gene was disrupted in embryonic stem cells by homologous recombination. Mice heterozygous for muREC2/RAD51L1 appear normal and fertile; however, no homozygous pups were born after interbreeding of heterozygous mice. Timed pregnancy studies showed that homozygous mutant embryos were severely retarded in growth as early as ca. 5 days gestation (E5.5) and were completely resorbed by E8.5. Mutant blastocyst outgrowth was also severely impaired in a double-knockout embryo, but embryonic development did progress further in a p53-null background. These results suggest that muREC2/RAD51L1 plays a role in cell proliferation and early embryonic development, perhaps through interaction with p53.

Animals↗
PubMed1999

Trithorax and ASH1 interact directly and associate with the trithorax group-responsive bxd region of the Ultrabithorax promoter.

Trithorax (TRX) and ASH1 belong to the trithorax group (trxG) of transcriptional activator proteins, which maintains homeotic gene expression during Drosophila development. TRX and ASH1 are localized on chromosomes and share several homologous domains with other chromatin-associated proteins, including a highly conserved SET domain and PHD fingers. Based on genetic interactions between trx and ash1 and our previous observation that association of the TRX protein with polytene chromosomes is ash1 dependent, we investigated the possibility of a physical linkage between the two proteins. We found that the endogenous TRX and ASH1 proteins coimmunoprecipitate from embryonic extracts and colocalize on salivary gland polytene chromosomes. Furthermore, we demonstrated that TRX and ASH1 bind in vivo to a relatively small (4 kb) bxd subregion of the homeotic gene Ultrabithorax (Ubx), which contains several trx response elements. Analysis of the effects of ash1 mutations on the activity of this regulatory region indicates that it also contains ash1 response element(s). This suggests that ASH1 and TRX act on Ubx in relatively close proximity to each other. Finally, TRX and ASH1 appear to interact directly through their conserved SET domains, based on binding assays in vitro and in yeast and on coimmunoprecipitation assays with embryo extracts. Collectively, these results suggest that TRX and ASH1 are components that interact either within trxG protein complexes or between complexes that act in close proximity on regulatory DNA to maintain Ubx transcription.

Amino Acid Sequence↗
PubMed1999

Northern region asplenia register--analysis of first two years.

OBJECTIVES: To assess the feasibility of setting up a register of patients with asplenia within a defined geographical area; to ensure that guidelines on best practice were implemented; to obtain information on antibody levels to pneumococcal capsular polysaccharides and Haemophilus influenzae type b capsular polysaccharide, before and after immunisation and annually thereafter; to raise awareness of risks among clinicians and to offer advice on management. DESIGN: Prospective recruitment using multiple sources of recruitment. Annual follow up reminders sent from Registration Centre. SUBJECTS: Population of (old, pre-1995) Northern Health Region: approximately 3.1 million. MAIN OUTCOME MEASURES: Data were obtained on reasons for asplenia, duration of asplenia, use of prophylactic antibiotics, Medic-Alert bracelets, immunisations, antibody levels, death. RESULTS: The register was initiated at the beginning of April 1995 and ran to the end of March 1997. After two years of operation, 1111 cases had been registered but the response from some health districts was poor. Major primary causes of asplenia were trauma (264), other surgical (198), lymphoproliferative disease (154), and idiopathic thrombocytopenic purpura (147). There were 664 patients on prophylactic antibiotics, of whom 498 were on continuous antibiotics. Only 18 had any type of warning bracelet. Antibody measurements were carried out at least once on 75% of patients; 306 patients had satisfactory antibody levels on first blood sample in year 1, rising to 405 in year 2; 43 patients failed to make any antibody response to Pneumovax despite multiple immunisations, and three patients failed to respond to Hib vaccine. Sixteen patients with satisfactory antibody levels in year 1 had low levels in year 2 requiring vaccine boosters. Sixteen deaths were reported, two of which were directly attributable to overwhelming sepsis. CONCLUSIONS: Registration has been successful and has raised awareness of the management of asplenia. Compliance with antibiotic prophylaxis and immunisation was initially poor. A potential high risk group of vaccine non-responders has been identified and poor persistence of pneumococcal antibodies has been identified which is likely to alter approaches to immunisation in asplenic patients.

Anti-Bacterial Agents↗