Biomedical subjects
B Wright
Publications and source records attributed to B Wright.
A feasibility study comparing two treatment approaches for chronic fatigue syndrome in adolescents.
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Experimental limb transplantation, part II: excellent return of function and indefinite survival after withdrawal of immunosuppression.
In this study the three components of an immunosuppressive combination therapy were gradually withdrawn in a rat limb transplantation model to evaluate the effects on long-term survival of the grafted limbs, rejection rate, and functional recovery. The procedure was performed in 16 rats across a strong Brown Norway to Fischer 344 histocompatibility barrier. Eight animals served as a control group that was not given any antirejection therapy and rejected their limb within a few days. The remaining eight animals were administered a 2-week course of immunosuppressive therapy including tacrolimus (TRL; 2 mg/kg/d), mycophenolate mofetil (MMF; 15 mg/kg/d), and prednisolone (Pred; 0.5 mg/kg/d). At 2 weeks, Pred and MMF were simultaneously tapered by 20% of the dosage every week; by week 7 the animals were on TRL only. TRL was then tapered at the same rate (20% every week) to a maintenance dose of 0.6 mg/kg/d at week 12. After 6 months the immunosuppression was stopped. Four of 8 animals did not reject throughout the study up, to the 1-year endpoint. At this stage they show excellent functional outcomes, evaluated by clinical tests and walking tract analysis. The remaining four rats developed a rejection at an average of 267 days postoperatively (range 224 to 302 days), corresponding to an average of 87 days (range 44 to 122 days) without any immunosuppression. They were sacrificed as soon as rejection was confirmed for histological examination of the various tissues. This study showed that a triple combination therapy provides excellent long-term functional outcomes of the transplanted limbs, with no rejection episodes, no side effects, or complications, even 6 months after withdrawal of all immunosuppressive components, suggesting the possible emergence of tolerance.
Experimental limb transplantation, part III: induction of tolerance in the rigorous strain combination of Brown Norway donor to Lewis recipient.
The complete withdrawal of immunosuppressive therapy after hind-limb transplantation across a strong histocompatibility barrier (Brown-Norway to Lewis) included a low-dose combination of FK506, mycophenolate mofetil (MMF), and prednisone. MMF and prednisone were tapered and withdrawn between weeks 2 and 7. From weeks 8 to 24, Group 1 animals (n=23) had FK506 tapered; for those in Group 2 (n=11) the dose of FK506 was not changed. At week 24, FK506 was stopped. The six limb grafts in Group 1 (26%) that achieved the 1-year end-point uneventfully showed chimerism by bone marrow and skin grafting supporting the presence of donor-specific tolerance. Rejection, which was common during tapering of FK506, was reversed by salvage therapy. All limbs were rejected postwithdrawal in Group 2. This study showed that tapering of FK506 combined with salvage therapy may allow long-term survival of some transplanted limbs after complete withdrawal of immunosuppressive therapy despite a complete MHC barrier.
The emerging role of the emergency care practitioner.
OBJECTIVES: To examine the emerging role of the emergency care practitioner (ECP) with comparisons to paramedic practice. Key activities were identified of newly appointed ECPs using qualitative methodology and a qualitative and quantitative comparison of patient treatment was made. METHOD: A constructivist methodology taking account of stakeholder input and drawing upon the constant comparisons of different group's construction of reality. Four practitioners completed reflective patient case studies and adapted patient report forms, which were compared with a second case group of 11 paramedics. In addition individual and focus groups interviews were performed with key stakeholders. RESULTS: In the comparison between ECP and paramedic roles, 331 paramedic incidents were compared with 170 ECP reports. ECPs treated 28% of patients on scene compared with 18% by paramedics (p = 0.007). Fifty per cent of ECPs patients were conveyed compared with 64% of paramedics (p = 0.000). Analysis of the 269 reflective reports and 14 stakeholder interviews revealed four key themes. Firstly, ECPs had a beneficial impact on the deployment of resources, especially relating to non-conveyance. Secondly, their training and education improved their decision making repertoire and developed their confidence for a leadership role. Thirdly, inter-agency collaboration and cooperation was improved, and finally, care benefits were increased especially relating to immediacy of treatment and referral mechanisms. CONCLUSIONS: The results indicate that an investment in the ECP role could be beneficial, however, more work is required to evaluate the development of practice, the quality of care, and cost benefits.
A comparison of quantitative NMR and radiolabelling studies of the metabolism and excretion of Statil (3-(4-bromo-2-fluorobenzyl)-4-oxo-3H-phthalazin-1-ylacetic acid) in the rat.
The identification and quantitation of the metabolites of Statil in rat bile and urine were investigated by 1H- and 19F-NMR spectroscopy and liquid scintillation counting. Male Wistar rats received a single oral dose of 100 mg/kg of radiolabelled Statil. Statil is known to produce glucuronide conjugates which are predominantly excreted into the bile in male rats. The complex multiphasic matrix of bile has been shown to make identification of the resonances by 1H-NMR spectroscopy very difficult as Statil appeared to be micellar bound giving rise to very broad signals. This not only impaired unambiguous signal characterisation but also quantification. The partial separation by SPEC-(1)H-NMR spectroscopy enabled the disruption of the micellar matrices and hence enabled the identification of Statil predominantly as aglycone, and to a lesser extent as glucuronide conjugate. In addition, minor acyl migration products of Statil glucuronide could also be detected as they were separated during the SPEC-process. 19F-NMR spectroscopic measurements on whole bile confirmed their presence as a number of overlapped signals could be observed. The selectivity, simplicity and signal dispersion characteristic of 19F-NMR spectroscopy also enabled the calculation of dose related recoveries of Statil related material in the bile and urine samples without the need for a radiolabel. The aim of this work was to investigate the usefulness and limitations of NMR spectroscopy of intact bile and urine as a means of quantifying levels of drug metabolites. The results obtained from NMR spectroscopy are compared with those obtained using scintillation techniques. Scintillation counting yields unequivocal quantification results, provided the label is preserved in metabolites as has been the case here. In general, quantification by 19F-NMR results similar to those obtained by scintillation counting (in agreement within about 20%). However, discrepancies have been observed with very small and broad 19F-NMR signals in bile. Nevertheless, 19F-NMR spectroscopy of bile is a rapid and facile method for assessing metabolite levels of fluorinated drugs.
Identification of the urinary metabolites of 4-bromoaniline and 4-bromo-[carbonyl-13C]-acetanilide in rat.
1. The urinary excretion of 4-bromoaniline and its [carbonyl-(13)C]-labelled N-acetanilide, together with their corresponding metabolites, have been investigated in the rat following i.p. administration at 50 mg kg(-1). 2. Metabolite profiling was performed by reversed-phase HPLC with UV detection, whilst identification was performed using a combination of enzymic hydrolysis and directly coupled HPLC-NMR-MS analysis. The urinary metabolite profile was quantitatively and qualitatively similar for both compounds with little of either excreted unchanged. 3. The major metabolite present in urine was 2-amino-5-bromophenylsulphate, but, in addition, a number of metabolites with modification of the N-acetyl moiety were identified (from both the [(13)C]-acetanilide or produced following acetylation of the free bromoaniline). 4. For 4-bromoacetanilide, N-deacetylation was a major route of metabolism, but despite the detection of the acetanilide following the administration of the free aniline, there was no evidence of reacetylation (futile deacetylation). 5. Metabolites resulting from the oxidation of the acetyl group included a novel glucuronide of an N-glycolanilide, an unusual N-oxanilic acid and a novel N-acetyl cysteine conjugate.
Directly coupled high-performance liquid chromatography and nuclear magnetic resonance spectroscopic with chemometric studies on metabolic variation in Sprague--Dawley rats.
We report here the first combined use of NMR-PR (pattern recognition) analysis and directly coupled HPLC--NMR analysis to identify metabolic subpopulations in normal laboratory animals and their discriminating endogenous urinary biomarkers. Urine samples obtained from control Sprague-Dawley rats (n = 68) were analyzed using (1)H NMR spectroscopy and principal components (PC) analysis to investigate physiological variability. Two distinct subpopulations of animals were classified based on metabolite excretion profiles. Analysis of the PC loadings established the spectral regions that were responsible for classification of the subpopulations and was used to direct the identification of biomarkers using a directly coupled HPLC--NMR analysis. One population had low urinary hippurate levels together with an increased concentration of 3-(3-hydroxyphenyl)propionic acid (3-HPPA)and 3-hydroxycinnamic acid (3-HCA). The other subpopulation excreted high levels of hippurate. Thus, we report the bimodal occurrence of hippuric acid and chlorogenic acid metabolites in a genetically homogeneous population of rats maintained under identical conditions, which may have significance in relation to the understanding of the consequences of biochemical variation in animals used for drug toxicity testing.
Veterinary ethics: filling a gap in undergraduate education.
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Who is to blame?
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Changes that impact upon health care: what do you know?
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Clinical information systems. If you build it, will they come?
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Humanitarian aspects of health support in operations other than war.
The decade of the 1990s proved to be very busy for health personnel serving in the Australian Defence Force (ADF). During this time, they deployed to areas as far away as Africa, after the genocide in 1994, and areas closer to home. There have been missions in Indonesia, Bouganville, and Papua New Guinea. In more current times, the most significant deployment has been to East Timor where health personnel remain today. Furthermore, there have been a number of deployments on short missions to various areas within Australia's strategic area of interest. Every mission has a mission statement. In all cases involving health personnel, the statement outlines their primary tasking, which will be the provision of health support to the troops in force. The secondary tasking, which inevitably follows, is the provision of health support to the local community from within any spare capacity. It is this spare capacity that this article will discuss. The primary focuses of this article are what care should be provided and the limitation of such care, how health care should be provided, what training is required for health personnel who will provide this care, and the policies that are required to be in place to monitor this care.
Selective deuterium exchange during superheated heavy water chromatography-nuclear magnetic resonance spectroscopy-mass spectrometry of sulfonamides.
Superheated deuterium oxide has been investigated as an eluent for reversed-phase HPLC on a polystyrene-divinylbenzene column with UV, 1H NMR and MS detection using a series of sulfonamides as model compounds. In the course of these studies, a selective, specific and efficient deuteration of the methyl groups on a pyrimidine ring was observed during chromatography of certain of the sulfonamides. The potential of this methodology for producing deuterium-labelled compounds from substances bearing suitable substituents is considered. The utility of HPLC-NMR-MS as a means for studying on-column reactions is discussed.
Cell specificity of the transcription-factor repertoire used by a lentivirus: motifs important for expression of equine infectious anemia virus in nonmonocytic cells.
The equine infectious anemia virus (EIAV) long-terminal repeat (LTR) has been identified as highly variable, both in infected horses and in cell culture. This nucleotide hypervariation is localized to the LTR enhancer region. The EIAV LTR has been implicated in controlling both the cell tropism and virulence of the virus and it is postulated that the enhancer-region hypervariation may be responsible for the LTR effects. Our previous studies have demonstrated that the presence of DNA motifs bound by the ets transcription-factor family member PU.1 are critically important for EIAV expression in equine macrophages. Here we identify and characterize the EIAV LTR enhancer motifs PEA-2, Lvb, Oct, and CRE, that bind to fibroblast nuclear extracts. Three of these four motifs, PEA-2, Oct, and CRE, were determined to be important for expression of the LTR in a fibroblast cell line that supports productive infection of EIAV. These motifs that are important for expression of the LTR in fibroblasts were found to be interdigitated between the PU.1 sites. We hypothesize that the combination of motif interdigitation and cell-specific usage of these motifs may be responsible for the observed EIAV LTR enhancer-region hypervariation.
Have the Cross-Informant Syndromes of the CBCL any practical value in identifying grouped ICD10 diagnoses?
120 children referred to a child and adolescent psychiatric service in a university clinic were studied with the aim of deriving predictors for grouped ICD10 diagnoses using the CBCL Cross-Informant-Syndromes (CISs). CIS7 (Delinquent Behaviour) and CIS8 (Aggressive Behaviour) were shown to significantly separate Disruptive Behaviour Disorders from all other disorders. As cross-validation, a separate clinical sample of 118 children from a similar service in another part of the country was used to see to what extent the CIS predictors from the first sample held up in the second sample. Positive and Negative Predictive Powers, all corrected for chance, confirmed that the Disruptive Behaviour Disorder group could be usefully separated from all other disorders using the Delinquent Behaviour and the Aggressive Behaviour Cross-Informant Syndrome scores. There was no good evidence that Emotional (Anxiety-Mood) Disturbance could be usefully separated in the same way using the Anxious-Depressed Syndrome (CIS3) or any other syndrome. Discriminant Function Analysis showed that there was no significant improvement in prediction when more elaborate linear combinations of the syndromes were used.
Application of directly coupled HPLC-NMR-MS/MS to the identification of metabolites of 5-trifluoromethylpyridone (2-hydroxy-5-trifluoromethylpyridine) in hydroponically grown plants.
Directly coupled HPLC-NMR-MS was used to characterize two major metabolites of 5-trifluoromethylpyridone (2-hydroxy-5-trifluoromethylpyridine), a model compound for herbicides, after it had been dosed into hydroponically grown maize plants. The combination of NMR and MS data allowed the identification of both of these metabolites, namely, the N-glucoside and O-malonylglucoside conjugates of the parent pyridone. This work demonstrates the efficiency and the potential application of HPLC-NMR-MS to the investigation of the metabolism of agrochemicals. The work also indicates that combination of the use of hydroponically grown plants and directly coupled HPLC-NMR-MS allows rapid identification of metabolites with little sample preparation.