Hepatitis A virus seroprevalence in 1,000 university students in Toronto.
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Adolescent↗
Biomedical subjects
D Smith
Publications and source records attributed to D Smith.
Requests for electroencephalography in a district general hospital: retrospective and prospective audit.
OBJECTIVES: To determine the number of inappropriate requests for electroencephalography (EEG) and whether guidelines on use could reduce this number. DESIGN: Audit with retrospective and prospective components. SETTING: EEG department in district general hospital and centre for neurology and neurosurgery. PARTICIPANTS: Retrospective: 368 at the general hospital and 143 patients at the neurology centre. Prospective: 241 patients undergoing EEG at the general hospital. INTERVENTIONS: Guidelines for EEG issued to users of service at the general hospital. OUTCOMES: Retrospective: differences in requesting practice, result in different clinical scenarios, relative roles of procedure, clinical acumen in establishing diagnosis, usefulness of procedure. Prospective: change of requesting practice, impact on use. RESULTS: There were considerable differences in requesting practice. Non-specialists seem to use EEG as a diagnostic tool, especially in patients with "funny turns," when it is much more likely to yield potentially misleading than clinically useful information. The overall proportion of procedures considered to influence management, to be justifiable, and to be inappropriate were 16% (59), 28.3% (104), and 55.7% (205), respectively. In the prospective study the total number of requests was significantly reduced (chi(2)=33.85, df=5, P<0.0001), mainly because of fewer requests in patients with non-specific "funny turns" (chi(2)=21.90, df=6, P=0.0013). There was a concomitant change in the usefulness of EEG (chi(2 )=26.99, df=2, P<0.0001). CONCLUSIONS: This original audit informed clinical practice and had potential benefits for patients, clinicians, and provision of service. Systematic replication of this project, possibly on a regional basis, could result in financial savings, which would allow development of accessible local neurophysiology services.
Electroencephalography↗
Edg2 receptor distribution in adult rat brain.
The Edg (endothelial differentiation gene) receptors are recently discovered G-protein coupled receptors which are activated by endogenous lysophospholipids. The cellular activities mediated by Edg receptors are reminiscent of those normally associated with Trk receptor activation and include modulation of cell growth, differentiation, proliferation and migration as well as apoptotic and cytoskeletal effects. In this study we have investigated immunohistochemically the distribution of one family member, the Edg2 receptor, within the adult rat brain and shown the protein expression to be most prominent in white matter tract regions. This suggests a possible role for the Edg2 receptor in nerve cell myelination.
Animals↗
Blending science and compassion: the 30th educational symposium of the Society of Critical Care Medicine, San Francisco, USA, 10-14 February 2001.
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Clinical Trials as Topic↗
Discovery of 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93), a 5HT(1B/1D) receptor partial agonist and a potent inhibitor of electrically induced plasma extravasation.
Utilizing a pharmacophoric model of binding of 3-(2-aminoethyl)indoles to 5HT(1B/1D) receptors, we identified the 3-aminocyclobutyl group as a potential ethylamine isostere. A novel multidimensional chemometric approach was used to predict the intrinsic activity (degree of agonism) at the receptor. A qualitative model for pharmacokinetic properties was then used to guide the synthesis toward molecules likely to have oral bioavailability in humans. A novel synthetic route to 3-(3-dimethylaminocyclobutyl)indoles was developed. Analogues showed generally lower intrinsic activity at 5HT(1B/1D) receptors than their ethylamine counterparts. 4-[3-(trans-3-Dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one (4991W93, 1) was identified as a partial agonist against 5HT(1B/1D) receptors, with low intrinsic activity. This molecule also has significant activity against 5HT(1F) receptors but is selective over other 5HT receptors. In addition this compound was found to be an exceptionally potent inhibitor of electrically induced plasma extravasation. Compound 1 may have utility in the treatment and prophylaxis of migraine.
Administration, Oral↗
Increased turnover of CCR5+ and redistribution of CCR5- CD4 T lymphocytes during primary human immunodeficiency virus type 1 infection.
CCR5 is the major coreceptor for human immunodeficiency virus (HIV) type 1 during primary infection. CCR5+ CD4 T lymphocytes were studied in subjects with primary HIV-1 infection (PHI) or acute Epstein-Barr virus (EBV) infection and in HIV-uninfected controls. The early decline of CD4 T lymphocytes during PHI resulted from depletion of CCR5- CD4 T lymphocytes. After antiretroviral therapy, Ki-67- CCR5- CD4 T cell counts rapidly increased in the circulation, which suggests that the initial decrease was due to an alteration in trafficking and/or sequestration. In the CCR5+ subset of CD4 T cells, there was an elevation in the proliferative (Ki-67+) fraction during PHI, yet their total number remained in the normal range. In contrast, in acute EBV infection, proliferating CCR5+ CD4 T cells accumulated to very high levels, suggesting they have an important role in the early antiviral response, which may be impaired in HIV-1 infection.
Adult↗
Three-dimensional structure of Erwinia chrysanthemi pectin methylesterase reveals a novel esterase active site.
Most structures of neutral lipases and esterases have been found to adopt the common alpha/beta hydrolase fold and contain a catalytic Ser-His-Asp triad. Some variation occurs in both the overall protein fold and in the location of the catalytic triad, and in some enzymes the role of the aspartate residue is replaced by a main-chain carbonyl oxygen atom. Here, we report the crystal structure of pectin methylesterase that has neither the common alpha/beta hydrolase fold nor the common catalytic triad. The structure of the Erwinia chrysanthemi enzyme was solved by multiple isomorphous replacement and refined at 2.4 A to a conventional crystallographic R-factor of 17.9 % (R(free) 21.1 %). This is the first structure of a pectin methylesterase and reveals the enzyme to comprise a right-handed parallel beta-helix as seen in the pectinolytic enzymes pectate lyase, pectin lyase, polygalacturonase and rhamnogalacturonase, and unlike the alpha/beta hydrolase fold of rhamnogalacturonan acetylesterase with which it shares esterase activity. Pectin methylesterase has no significant sequence similarity with any protein of known structure. Sequence conservation among the pectin methylesterases has been mapped onto the structure and reveals that the active site comprises two aspartate residues and an arginine residue. These proposed catalytic residues, located on the solvent-accessible surface of the parallel beta-helix and in a cleft formed by external loops, are at a location similar to that of the active site and substrate-binding cleft of pectate lyase. The structure of pectin methylesterase is an example of a new family of esterases.
Amino Acid Sequence↗
Relative significance of different pathways of immune reconstitution in HIV type 1 infection as estimated by mathematical modeling.
A major goal of antiretroviral HIV-1 therapy is the reversal of HIV-1-associated immunological dysfunction. However, the pathogenetic mechanisms involved and their significance are largely unknown. On the basis of the life cycle of naive, activated, and memory CD4(+) T cell subsets, a mathematical model of immune reconstitution was developed and applied to data for T cell subsets in individuals with acute or chronic HIV-1 infection receiving antiretroviral therapy. The final model that most accurately fitted the data, and resulted in realistic estimates for CD4(+) T cell turnover, considered three pathways of immune reconstitution for naive cells, including thymic production, peripheral expansion, and redistribution of naive cells from lymphoid tissue. The reconstitution of the memory compartment was fitted through differentiation and expansion of naive cells and peripheral expansion of memory cells as well as redistribution of memory cells trapped in the lymphoid tissue. Estimated median half-lives for naive and memory CD4(+) T cells were 114 and 21 days, while total production rates were 9.1 x 10(7) and 2.4 x 10(9) cells/day, respectively. Peripheral expansion and thymic production contributed equally to the regeneration of naive cells, but peripheral expansion of memory cells was larger than production of these cells by differentiation of naive cells. A comparison of immune reconstitution in acute and chronic HIV-1 infection revealed that, after adjustment for age, the main difference was the more rapid release of a larger number of naive cells in treated acute HIV-1 infection. Thymic function and peripheral expansion rates, however, were similar in both cohorts.
Acute Disease↗
A viable herd of genetically uniform cattle.
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Animals↗
Assessment of commercial laboratories performing hair mineral analysis.
CONTEXT: Hair mineral analysis is being used by health care practitioners and promoted by laboratories as a clinical assessment tool and to identify toxic exposures, despite a 1985 study that found poor reliability for this test. OBJECTIVE: To assess whether the reliability of data from commercial laboratories advertising multimineral hair analyses for nutritional or toxicity assessment has improved since the 1985 study. DESIGN, SETTING, AND PARTICIPANTS: A split hair sample taken from near the scalp of a single healthy volunteer was submitted for analysis to 6 commercial US laboratories, which analyze 90% of samples submitted for mineral analysis in the United States. MAIN OUTCOME MEASURES: Agreement of test results for each analyte, laboratory reference ranges, laboratory characteristics, and interpretation of health implications. RESULTS: Laboratory differences in highest and lowest reported mineral concentrations for the split sample exceeded 10-fold for 12 minerals, and statistically significant (P<.05) extreme values were reported for 14 of the 31 minerals that were analyzed by 3 or more laboratories. Variations also were found in laboratory sample preparation methods and calibration standards. Laboratory designations of normal reference ranges varied greatly, resulting in conflicting classifications (high, normal, or low) of nearly all analyzed minerals. Laboratories also provided conflicting dietary and nutritional supplement recommendations based on their results. CONCLUSIONS: Hair mineral analysis from these laboratories was unreliable, and we recommend that health care practitioners refrain from using such analyses to assess individual nutritional status or suspected environmental exposures. Problems with the regulation and certification of these laboratories also should be addressed.
Biomarkers↗
Medium-chain acyl coenzyme A dehydrogenase deficiency: occurrence in an infant and his father.
BACKGROUND: Autosomal recessive inborn errors of metabolism often present as life-threatening disease in infancy and have adverse effects on the nervous system. Parents are usually heterozygotes. This is true of most disorders of fatty acid oxidation, which are rare and present with hypoketotic hypoglycemia. However, the gene for medium-chain acyl coenzyme A dehydrogenase (MCAD) deficiency is common in white people, raising the possibility that a parent may be homozygous. OBJECTIVE: To document the occurrence of MCAD deficiency in a 12-month-old boy and his father, both of whom were homozygous for the A985G mutation. DESIGN: Clinical observations and definitive biochemical testing. SETTING: Children's hospital and university laboratory. PARTICIPANTS: One child and one adult. INTERVENTIONS: Diagnosis and treatment. MAIN OUTCOME MEASURES: Clinical outcome; analysis results of plasma and urine for carnitine and organic acids. RESULTS: An infant admitted with an acute illness requiring intensive care was found to have carnitine deficiency and dicarboxylic aciduria; MCAD deficiency was diagnosed by assay of his DNA for the common mutation. Test results of the father revealed him also to be homozygous. CONCLUSION: In MCAD deficiency, as opposed to the usual rare autosomal recessive metabolic disease, a parent may also be an affected homozygote.
Acyl-CoA Dehydrogenase↗
On-line determination of the deuterium abundance in breath water vapour by flowing afterglow mass spectrometry with applications to measurements of total body water.
We have developed a new method for the on-line quantification of deuterium in water vapour. We call this method flowing afterglow mass spectrometry (FA-MS). A swarm of H3O+ precursor ions is created in flowing helium carrier gas by a microwave discharge. These precursor ions react with the H2O, HDO, H2(17)O and H2(18)O molecules in a water vapour sample that is introduced into the carrier gas/H3O+ ion swarm. The hydrated ions, H3O+.(H2O)3 at m/z 73, and their isotopic variant ions H8DO4(+) and H9(17)OO(3)(+) at m/z 74 and H9(18)OO(3)(+) at m/z 75, are thus formed. By adopting the known fractional abundance of 18O in water vapour, and accounting for the contribution of the isotopic ions H9(17)OO(3)(+) to the ion signal at m/z 74, a measurement of the 74/75 ion signal ratio under equilibrium conditions provides the fractional deuterium abundance in the water vapour sample. Using this technique, the deuterium abundance in the water vapour present in single exhalations of breath can be determined. Thus, from the temporal variations of breath deuterium following the ingestion of a known quantity of D(2)O, we show that total body water can be determined non-invasively and the kinetics of water flow around the body can be tracked.
Body Water↗
The peri-implant breast capsule: an immunophenotypic study of capsules taken at explantation surgery.
Silicone-based breast implants continue to be the focus of many studies attempting to correlate implant failure to clinical and pathological factors. Routine pathology of peri-implant capsule is extensively described in the literature. The actual significance of the cellular events remains unconfirmed, particularly with reference to clinical outcome. This study reviews our experience with explanted capsules. The study makes specific reference to the immunohistochemistry of the cells participating in the capsule and the significance of the immunophenotypic characterization of these cells to clinical outcome. The use of a wide selection of immunomarkers for T and B lymphocytes and histiocytes provided no supporting evidence for local cell participation in the capsule, which may indicate the presence of an immunological reaction present in the capsule at the time of explantation. One was only able to confirm the presence of a low grade inflammatory process and progression to fibrosis and calcification over time. Statistical correlation was obtained only between Baker grade of capsular contracture and CD3/CD68 immunomarker positivity. CD45RO did show correlation with pain. No correlation was demonstrated with calcification. The results obtained in this study highlighted the need for further investigations into the mechanism of histiocyte and fibrocyte recruitment and activation in the capsule, a possible source of pain and contracture, which is a serious long-term clinical finding leading to the necessity for explantation.
Adult↗
Discounting for health effects in cost-benefit and cost-effectiveness analysis.
When health effects can be valued in monetary terms, as in cost-benefit analysis, they should be discounted at the same rate as costs. If health effects are measured in quantities (e.g. quality adjusted life years) as in cost-effectiveness analysis (CEA) and the value of health effects is increasing over time, discounting the volume of health effects at a lower rate than costs is a valid method of taking account of the increase in the future value of health effects. We show that the Keeler-Cretin paradox, often used as an argument against discounting health effects at a lower rate than costs, has no relevance for the choice of discount rate in CEA. We present individualistic and welfare models to argue that the rate of growth of the value of health effects is positive. The welfare model suggests that the value of health grows at a rate dependent on the rate of growth of the value of the direct effect of health on utility, the growth rate of income, the elasticity of the marginal utility of income and the extent to which individuals are insured against the income risks of ill health.
Cost-Benefit Analysis↗
On-line measurement of the absolute humidity of air, breath and liquid headspace samples by selected ion flow tube mass spectrometry.
We describe how selected ion flow tube mass spectrometry (SIFT-MS) can be used to determine the absolute humidity of air, breath and liquid headspace samples. This involves the determination of the relative count rates of the H3O+ ions and those H3O+.(H2O)(1,2,3) hydrate ions that inevitably form in the helium carrier gas when humid samples are being analysed by SIFT-MS using H3O+ precursor ions. This requires an understanding of the kinetics of hydrated hydronium ion formation, the involvement of mass discrimination in the analytical quadrupole mass spectrometer and the decreased diffusive loss of the heavier hydrates along the flow tube. Thus, we show that the humidity of breath and liquid headspace samples, typically at the few percent level, can be directly obtained on-line to the SIFT-MS instrument along with the concentrations of trace gases, which are present at much lower levels. We emphasise the value of parallel humidity measurements in ensuring good real-time sampling of breath and liquid headspace and the value of such measurements to trace gas analysis using SIFT-MS.
Journal Article↗
Accuracy and precision of flowing afterglow mass spectrometry for the determination of the deuterium abundance in the headspace of aqueous liquids and exhaled breath water.
We have assessed the accuracy and precision of our flowing afterglow mass spectrometric method (FA-MS) for absolute measurements of deuterium abundance in water using standardised tap water/D(2)O mixtures within the D/H range from 155 ppm (local tap water) to 1104 ppm, prepared by the gravimetric method. The results of this study show that a precision and accuracy of 1% can be achieved for the deuterium abundance in water samples. This is quite adequate for the main application, which is the rapid, non-invasive measurement of total body water by deuterium analysis of breath water vapour using the D(2)O dilution method.
Body Water↗
Acute neuroleptic stimulates DOPA decarboxylase in porcine brain in vivo.
The activity of DOPA decarboxylase measured in homogenates from rat striatum, or calculated from the rate of tracer decarboxylation measured ex vivo, is stimulated following acute treatment with antagonists of dopamine D2-like receptors. We used compartmental kinetics to test the hypothesis that utilization of the DOPA decarboxylase substrate [(18)F]fluorodopa is potentiated in living striatum following acute treatment with a typical neuroleptic. The kinetics of the tracer uptake were determined in eight anesthetized female pigs (40 kg) and in three animals receiving an infusion of haloperidol (75 microg kg(-1) h(-1)) for 1 h prior to tracer administration and throughout the 2-h positron emission recording. The relative activity of DOPA decarboxylase in striatum was increased threefold by the treatment. This potentiation of DOPA decarboxylation after pharmacological blockade of dopamine D2-like receptors may be used to optimize the utilization of exogenous DOPA in the treatment of Parkinson's disease.
Animals↗
Bimanual coordination in chronic schizophrenia.
Anomalies of movement are observed both clinically and experimentally in schizophrenia. While the basal ganglia have been implicated in its pathogenesis, the nature of such involvement is equivocal. The basal ganglia may be involved in bimanual coordination through their input to the supplementary motor area (SMA). While a neglected area of study in schizophrenia, a bimanual movement task may provide a means of assessing the functional integrity of the motor circuit. Twelve patients with chronic schizophrenia and 12 matched control participants performed a bimanual movement task on a set of vertically mounted cranks at different speeds (1 and 2 Hz) and phase relationships. Participants performed in-phase movements (hands separated by 0 degrees ) and out-of-phase movements (hands separated by 180 degrees ) at both speeds with an external cue on or off. All participants performed the in-phase movements well, irrespective of speed or cueing conditions. Patients with schizophrenia were unable to perform the out-of-phase movements, particularly at the faster speed, reverting instead to the in-phase movement. There was no effect of external cueing on any of the movement conditions. These results suggest a specific problem of bimanual coordination indicative of SMA dysfunction per se and/or faulty callosal integration. A disturbance in the ability to switch attention during the out-of-phase task may also be involved.
Adult↗