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Biomedical subjects

T Smith

Publications and source records attributed to T Smith.

At least 145 records · Page 8Linked to original sources
PubMed2000

Apparent tolerance of Plasmodium falciparum in infants in a highly endemic area.

The incidence of fever among infants in the village of Idete in the Morogoro region of Tanzania was analyzed in relation to densities of Plasmodium falciparum parasites in the peripheral blood. Parasite densities in both fever cases and in asymptomatic infants, were compared and a Bayesian non-parametric mixture decomposition algorithm was used to estimate the proportion of fevers attributable to malaria and hence the incidence of clinical malaria. Age group-specific densities of peripheral parasitaemia showed little seasonality, but the clinical malaria incidence showed a clear peak in the wet season in children aged less than 9 months. Estimates of the parasitaemia-specific incidence of clinical malaria were used to quantify apparent tolerance of parasites, and indicated that clinical episodes occurred on average at lower parasite densities during the wet season than in the dry season. These patterns could reflect differences in levels of anti-toxic immunity, but the nature of the seasonal differences supports the alternative explanation that the variation in apparent tolerance may be an effect of changes in the ratio of peripheral parasite densities to the sequestered mass.

Age Factors↗
PubMed2000

Characterisation of lectin binding patterns of mouse bronchiolar and rat alveolar epithelial cells in culture.

Lung epithelial cell differentiation pathways remain unclear. This is due in part to the plasticity of these cells and the lack of markers which accurately reflect their differentiation status. The aim of this study was to determine if lectin binding properties are useful determinants of functional differentiation status in vitro. Mouse Clara cells were cultured for 5 days. During this time, no alteration in differentiation was evident by electron microscopy. No significant alteration in binding reactivity of Bauhinia purpurea (BPA), Maclura pomifera (MPA), Concanavalin A, Wheat germ or Helix pomatia lectins occurred in cultures compared with Clara cells in mouse lung tissue. In contrast, nitrotetrazolium blue reductase activity and CC10 expression declined in culture. Rat type II cells were cultured for 8 days. Between days 0 and 4, the number of type II cells identified by electron microscopy was constant at 70-80%, decreasing to 8% by day 6. In contrast, by day 4, only 42% cells retained alkaline phosphatase activity. BPA and MPA reactivity was altered at day 0 and day 4 respectively, compared with cells in situ. Therefore, the reactivity of lectins analysed here does not reflect functional differentiation status of cultured mouse Clara cells. However, BPA and MPA reactivity may be a sensitive indicator of alterations in rat type II cell differentiation in vitro.

Alkaline Phosphatase↗
PubMed2000

Autoimmune encephalomyelitis ameliorated by AMPA antagonists.

Multiple sclerosis is an immune-mediated disorder of the central nervous system leading to progressive decline of motor and sensory functions and permanent disability. The therapy of multiple sclerosis is only partially effective, despite anti-inflammatory, immunosuppresive and immunomodulatory measures. White matter inflammation and loss of myelin, the pathological hallmarks of multiple sclerosis, are thought to determine disease severity. Experimental autoimmune encephalomyelitis reproduces the features of multiple sclerosis in rodents and in nonhuman primates. The dominant early clinical symptom of acute autoimmune encephalomyelitis is progressive ascending muscle weakness. However, demyelination may not be profound and its extent may not correlate with severity of neurological decline, indicating that targets unrelated to myelin or oligodendrocytes may contribute to the pathogenesis of acute autoimmune encephalomyelitis. Here we report that within the spinal cord in the course of autoimmune encephalomyelitis not only myelin but also neurons are subject to lymphocyte attack and may degenerate. Blockade of glutamate AMPA receptors ameliorated the neurological sequelae of autoimmune encephalomyelitis, indicating the potential for AMPA antagonists in the therapy of multiple sclerosis.

Animals↗
PubMed2000

Fixing mistakes.

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Acylation↗
PubMed2000

Going green.

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Aequorin↗
PubMed2000

Functional capacity in patients with congestive heart failure.

BACKGROUND: Six-minute walk distance (6MWd) is related to activities of daily living and is also an independent predictor of prognosis in patients with congestive heart failure (CHF). Therefore, it is important to determine factors that contribute to the variability of this test. METHODS AND RESULTS: We assessed the relationship between 6MWd and peak aerobic capacity (VO2) and dynamic muscle strength in 180 patients with CHF (age, 66+/-10 years; 146 men, 34 women; ejection fraction, .29+/-0.08). We also hypothesized that a measure of work performed during the walk test (6MWw) would be a better indicator of exercise capacity than 6MWd. The 6MWd had weak to moderate correlations with dynamic muscle strength (r = 0.33 to 0.41) and peak VO2 (r = 0.48). However, 6MWw was strongly related to dynamic muscle strength (r = 0.63 to 0.70) and peak VO2 (r = 0.77). Multivariate analysis indicated that a model combining dynamic muscle strength and peak VO2 explained 69% of the variance in 6MWw, more than with peak VO2 alone (R2 = 0.59). CONCLUSIONS: Compared with 6MWd, 6MWw correlates significantly better with peak VO2 and dynamic muscle strength, suggesting that 6MWw may be a better reflection of a patient's exercise capacity. Furthermore, these results suggest that an exercise program combining both aerobic and strength training in patients with CHF may improve 6MWw and therefore 6MWd.

Aged↗
PubMed2000

Ulnar neuropathy at the elbow: clinical and electrophysiological outcome of surgical and conservative treatment.

The objective was to evaluate and compare the clinical and electrophysiological outcome of treatment in patients with ulnar neuropathy at the elbow in 32 consecutive patients who were studied prospectively. Based on the electrophysiological findings 15 patients were treated by surgical decompression and 17 were treated conservatively. Sensory and motor nerve conduction studies across and below the elbow were done in all patients before treatment and again after one year. Postoperatively 10/15 patients (67%) improved clinically and 12 patients (80%) had improved nerve conduction results. There was clinical and electrophysiological agreement in eight patients in the surgically-treated group, all of whom improved both clinically and electrophysiologically. In the conservatively-treated group six patients (35%) showed clinical improvement, 10 patients had no improvement, and one patient was worse. The nerve conduction studies improved in six patients (35%), were unchanged in eight patients, and worse in three. There was clinical and electrophysiological agreement in 11 patients. We conclude that the electrophysiological examination was valuable in deciding which patients to operate on, and that most of the patients improved clinically or electrophysiologically postoperatively.

Adolescent↗
PubMed2000

Atlantic salmon HNF-3/forkhead: cDNA sequence, evolution, expression, and functional analysis.

We report the isolation and characterization of a cDNA encoding an HNF-3 family member (as HNF-3) from Atlantic salmon (Salmo salar L). The important functional domains of HNF-3 proteins that have been characterized previously are revealed by segments of high identity along the alignment of the asHNF-3 with winged helix/forkhead amino acid sequences isolated from other species. A comparison of asHNF-3 cDNA and genomic DNA indicated that there were no introns present in the asHNF-3 gene. Expression of asHNF-3 protein in adult salmon tissues was not exclusive to liver but was also present in the pancreas and intestine. An RT-PCR analysis performed on salmon development showed that asHNF3 expression is detectable before gastrulation at the mid blastula transition stage. Functional analysis of the asHNF-3 protein using a characterized HNF-3 consensus binding site demonstrated that the protein can recognize and bind to specific HNF-3 consensus sequences. We also report the identification of a novel HNF3 binding site in the promoter of the Atlantic salmon transferrin gene.

Amino Acid Sequence↗
PubMed2000

Spatial modelling of multinomial data with latent structure: an application to geographical mapping of human gene and haplotype frequencies.

We develop hierarchical models for spatial multinomial data with missing categories, to analyse a database of HLA-A and -B gene and haplotype frequencies from Papua New Guinea, with a highly variable number of samples per spatial unit. The spatial structure of the multinomial data is incorporated by adopting conditional autoregressive (CAR) priors for the random effects, reflecting extra-multinomial variation. Different spatial structures are investigated, and covariate effects are evaluated using a novel model selection criterion. Tables and maps reveal strong spatial association and the importance of altitude, a covariate anticipated to be significant in explaining genetic variation. Our approach can be used in identifying associations with environmental factors, linguistic or epidemiological patterns and hence potential causes of genetic diversity (population movements, natural selection, stochastic effects).

Journal Article↗
PubMed2000

The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity.

This study identifies by microautoradiography activated microglia/macrophages as the main cell type expressing the peripheral benzodiazepine binding site (PBBS) at sites of active CNS pathology. Quantitative measurements of PBBS expression in vivo obtained by PET and [(11)C](R)-PK11195 are shown to correspond to animal experimental and human post-mortem data on the distribution pattern of activated microglia in inflammatory brain disease. Film autoradiography with [(3)H](R)-PK11195, a specific ligand for the PBBS, showed minimal binding in normal control CNS, whereas maximal binding to mononuclear cells was found in multiple sclerosis plaques. However, there was also significantly increased [(3)H](R)-PK11195 binding on activated microglia outside the histopathologically defined borders of multiple sclerosis plaques and in areas, such as the cerebral central grey matter, that are not normally reported as sites of pathology in multiple sclerosis. A similar pattern of [(3)H](R)-PK11195 binding in areas containing activated microglia was seen in the CNS of animals with experimental allergic encephalomyelitis (EAE). In areas without identifiable focal pathology, immunocytochemical staining combined with high-resolution emulsion autoradiography demonstrated that the cellular source of [(3)H](R)-PK11195 binding is activated microglia, which frequently retains a ramified morphology. Furthermore, in vitro radioligand binding studies confirmed that microglial activation leads to a rise in the number of PBBS and not a change in binding affinity. Quantitative [(11)C](R)-PK11195 PET in multiple sclerosis patients demonstrated increased PBBS expression in areas of focal pathology identified by T(1)- and T(2)-weighted MRI and, importantly, also in normal-appearing anatomical structures, including cerebral central grey matter. The additional binding frequently delineated neuronal projection areas, such as the lateral geniculate bodies in patients with a history of optic neuritis. In summary, [(11)C](R)-PK11195 PET provides a cellular marker of disease activity in vivo in the human brain.

Adult↗
PubMed2000

Fetal and maternal outcomes in Indo-Asian compared to caucasian women with diabetes in pregnancy.

Maternal and fetal complications are increased when pregnancy is complicated by diabetes, and this may be further influenced by racial and cultural differences. We examined fetal and maternal outcomes in Indo-Asian and Caucasian women attending the same antenatal diabetes service to see if there were any differences. Women with diabetes mellitus (type 1, type 2 and gestationally-acquired disease) complicating pregnancy, registered at the combined diabetes/antenatal clinic of this University teaching hospital over the period 1990-1998 were included. Fetal outcomes examined were miscarriage <24 weeks, stillbirths, neonatal deaths up to 28 days of life, perinatal mortality, congenital malformations and size for gestational age. Maternal outcomes examined were rates of caesarean section and vaginal deliveries, and number of pre-term deliveries <37 completed weeks of gestation. Outcomes for Indo-Asian and Caucasian women were similar, with a take-home baby rate of 96% and 92%, respectively. There was no perinatal mortality in Indo-Asian women, who were more likely to have a vaginal delivery and less likely to have a baby large for gestational age. Pregnancies complicated by type 2 diabetes in both groups pose the greatest threat to a successful pregnancy outcome. Indo-Asian and Caucasian women attending the same antenatal diabetes service have comparable outcomes. Attendance for pre-pregnancy care needs to be encouraged to combat the high early pregnancy loss and congenital malformation rate identified, particularly in those with type 2 disease, irrespective of ethnicity.

Bangladesh↗
PubMed2000

Evaluation of an antiseptic triple-lumen catheter in an intensive care unit.

OBJECTIVE: To evaluate a decrease in catheter-related bloodstream infection rate in patients with antiseptic triple-lumen catheters in an intensive care unit. DATA SOURCES: Retrospective review of surveillance records, patient medical records, laboratory and microbiological reports, and antibiotic administration records. STUDY SELECTION: Patients admitted to the intensive care unit with triple-lumen catheters. DATA EXTRACTION: A subset of one entry per patient was extracted from 2 yrs of primary bloodstream infection surveillance data. Data collection included risk factors, laboratory and microbiological data, and insertion sites and dates of all intravascular catheters present during triple-lumen catheterization. DATA SYNTHESIS: The catheter-related bloodstream infection rate was 5.4 and 11.3 per 1000 catheter days in antiseptic and nonantiseptic triple-lumen catheter groups, respectively (p = .06). By multivariate analysis using a Cox Proportional Hazards Model, the antiseptic triple-lumen catheters were associated with a significant reduction in catheter-related bloodstream infection (p = .03). Model expansion to include intrajugular site was significant by a likelihood ratio test [2(log likelihood diff) = 4.26 P<.05 chi2(1)] CONCLUSIONS: The use of antiseptic triple-lumen catheters may substantially reduce catheter-related bloodstream infections in an intensive care population and may be subsequently associated with a decrease in length of stay.

Aged↗
PubMed2000

Morphogenesis and release of fowlpox virus.

Release of fowlpox virus (FWPV) as extracellular enveloped virus (EEV) appears to proceed both by the budding of intracellular mature virus (IMV) through the plasma membrane and by the fusion of intracellular enveloped virus (IEV) with the plasma membrane. Based on the frequency of budding events compared to wrapping events observed by electron microscopy, FWPV FP9 strain seems to exit chick embryo fibroblast cells predominantly by budding. In contrast to vaccinia virus (VV), the production of FWPV extracellular virus particles is not affected by N(1)-isonicotinoyl-N(2)-3-methyl-4-chlorobenzoylhydrazine (IMCBH). Comparison of the sequence of the VV F13L gene product with its FWPV orthologue showed a mutation, in the fowlpox protein, at the residue involved in IMCBH resistance in a mutant VV. Glucosamine, monensin or brefeldin A did not have any specific effect on FWPV extracellular virus production. Cytochalasin D, which inhibits the formation of actin filaments, reduces the production of extracellular virus particles by inhibiting the release of cell-associated enveloped virus (CEV) particles from the plasma membrane. Involvement of actin filaments in this mechanism is further supported by the co-localization of actin with viral particles close to the plasma membrane in the absence of cytochalasin D. Actin is also co-localized with virus factories.

Actins↗
PubMed2000

Comparative model building of interleukin-7 using interleukin-4 as a template: a structural hypothesis that displays atypical surface chemistry in helix D important for receptor activation.

Using a combination of theoretical sequence structure recognition predictions and experimental disulfide bond assignments, a three-dimensional (3D) model of human interleukin-7 (hIL-7) was constructed that predicts atypical surface chemistry in helix D that is important for receptor activation. A 3D model of hIL-7 was built using the X-ray crystal structure of interleukin-4 (IL-4) as a template (Walter MR et al., 1992, J Mol Biol. 224:1075-1085; Walter MR et al., 1992, J Biol Chem 267:20371-20376). Core secondary structures were constructed from sequences of hIL-7 predicted to form helices. The model was constructed by superimposing IL-7 helices onto the IL-4 template and connecting them together in an up-up down-down topology. The model was finished by incorporating the disulfide bond assignments (Cys3, Cys142), (Cys35, Cys130), and (Cys48, Cys93), which were determined by MALDI mass spectroscopy and site-directed mutagenesis (Cosenza L, Sweeney E, Murphy JR, 1997, J Biol Chem 272:32995-33000). Quality analysis of the hIL-7 model identified poor structural features in the carboxyl terminus that, when further studied using hydrophobic moment analysis, detected an atypical structural property in helix D, which contains Cys 130 and Cys142. This analysis demonstrated that helix D had a hydrophobic surface exposed to bulk solvent that accounted for the poor quality of the model, but was suggestive of a region in IL-7 that maybe important for protein interactions. Alanine (Ala) substitution scanning mutagenesis was performed to test if the predicted atypical surface chemistry of helix D in the hIL-7 model is important for receptor activation. This analysis resulted in the construction, purification, and characterization of four hIL-7 variants, hIL-7(K121A), hIL-7(L136A), hIL-7(K140A), and hIL-7(W143A), that displayed reduced or abrogated ability to stimulate a murine IL-7 dependent pre-B cell proliferation. The mutant hIL-7(W143A), which is biologically inactive and displaces [125I]-hIL-7, is the first reported IL-7R system antagonist.

Alanine↗