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Biomedical subjects

N Plant

Publications and source records attributed to N Plant.

15 recordsLinked to original sources
PubMed2006

Biological monitoring for trimethylbenzene exposure: a human volunteer study and a practical example in the workplace.

This paper presents data from both a human volunteer study looking at exposure to 1,3,5-trimethylbenzene (TMB) and an occupational hygiene study of a printing firm using screen wash containing technical grade TMB. The biomarkers measured were TMB in blood and breath, and urinary dimethylbenzoic acids (DMBAs). The volunteer (N = 4) study showed that TMB was rapidly absorbed into the bloodstream reaching a mean level of 0.85 micromol l(-1) during a 4 h exposure to 25 p.p.m. TMB. There was little decline 1 h post-exposure possibly indicating storage of TMB in adipose tissue. Breath TMB levels peaked within an hour of exposure commencing and averaged 137 nmol l(-1) during exposure. Elimination of TMB in breath was biphasic with an initial half-life of 60 min. Peak excretion of urinary DMBA occurred 4-8 h after the end of exposure and averaged 40 mmol mol(-1) creatinine. Elimination of DMBA in urine was biphasic with half-lives of 13 and 60 h indicating that accumulation of body burden throughout the working week is likely if exposure is repeated. The occupational hygiene study demonstrated an excellent correlation between personal air TMB levels and post-shift urinary DMBA levels (r = 0.997) collected on the third working day. The regression equation from this study indicates that 8 h exposure to 25 p.p.m. TMB would result in a urinary DMBA level of 206 mmol mol(-1) creatinine. All workers showed pre-shift levels of DMBA from exposure to TMB on previous days. Both urinary DMBA and breath TMB levels can be used as biomarkers of TMB exposure. Urine samples should be taken post-shift towards the end of the working week as significant body burden accumulation throughout the working week can be expected. Breath sampling is more suited to task or single-shift monitoring.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2003

Relative receptor expression is a determinant in xenobiotic-mediated CYP3A induction in rat and human cells.

1. Species differences in xenobiotic-mediated transcriptional activation of CYP3A genes are known to exist. These differences are proposed to be due, in part, to host cell differences. 2. Host cell effects were investigated by trans-species transient transfection of reporter genes containing either the rat CYP3A23 or human CYP3A4 proximal promoters into human HepG2 and rat FaO and H4IIEC3 hepatoma cells. HepG2 and FaO cells supported activation of both CYP3A constructs by xenobiotics in a species-specific manner, whereas H4IIEC3 cells were non-permissive. 3. The mRNA complement of the cell lines was then quantified by semiquantitative RT-PCR for adult CYP3As (CYP3A23, CYP3A4/5), steroid hormone receptors (constitutive androstane receptor, glucocorticoid receptor-alpha, pregnane X receptor) and transcription factors (Hepatic nuclear factor 4alpha, retinoid X receptor). 4. Principal component analysis of absolute receptor levels demonstrated a wide scattering, with no coherent pattern. In contrast, PCA of relative receptor ratios segregated H4IIEC3 cells from all other samples. 5. The observation is confirmed that species differences in response to xenobiotics are a result of host cell environment. In addition, new evidence is provided to support the hypothesis that in addition to individual receptor activation profiles, the relative abundance of steroid hormone receptors that control CYP3A gene expression play an important role in this observed species difference.

Animals↗
PubMed2003

Transcriptional regulation of cytochrome P4503A4 gene expression: effects of inherited mutations in the 5'-flanking region.

1. Understanding the genetic basis of interindividual variability in drug disposition and response is a fundamental focus for rational and individualized drug treatment. Cytochrome P4503A4 (CYP3A4) has a central role in human drug metabolism and polymorphic variation has been reported in this gene. 2. This study reports the in vitro functional analysis of inherited mutations in the 5' flanking region of the CYP3A4 gene using reporter constructs in which the 1141 bp proximal promoter region from the mutant alleles was inserted between a single copy of the CYP3A4 300 bp core distal enhancer (XREM) sequence and the cDNA for human secretory alkaline phosphatase. 3. Reporter constructs were co-transfected with an hPXR expression vector into human liver and intestinal cells in culture and xenobiotic modulation of CYP3A4 promoter activity determined by chemiluminescent secretory alkaline phosphatase assay. DNA-protein interactions were next examined using electrophoretic mobility shift assays. 4. The results demonstrated that inherited mutations in the CYP3A4 gene proximal promoter region could cause significant up-regulation of in vitro transcriptional activation by CYP3A4 xenobiotic inducers. In addition, the magnitude of the effect appeared to be dependent on the cell type used in the functional assays, possibly due to the differing availability of specific intracellular transcription factors or their activating ligands.

5' Flanking Region↗
PubMed2003

Nocturnal enuresis is a common complication following cardiac transplantation.

AIMS: To investigate the incidence of nocturnal enuresis post-cardiac transplantation. METHODS: Seventy two cardiac transplantations have been performed in children under 16 years of age. All recipients who were alive and over 4 years of age at the time of the study received a questionnaire about urinary symptoms; 54 of the 57 eligible children participated. RESULTS: Twenty five children had persistent nocturnal enuresis post-transplantation. Thirteen of them had previously attained reliable night-time dryness but developed secondary nocturnal enuresis following transplantation, with three subsequently regaining dryness at ages 8, 12, and 17 years; 10 were still wetting mean age 12.3. Twelve children had not achieved night-time dryness when transplanted (all were under 4 years of age at the time) and continued to wet. Only one of these children achieved dryness (at age 12 using oxybutynin); the other 11 remained wet at night at a mean age of 9.3 years. Twenty nine children were dry at night post-transplantation, but 21 of them had nocturia at least three times a week. There is a significant difference in age at transplantation between the primary nocturnal enuretic children (mean age 2.0) and the secondary nocturnal enuretic children (mean age 7.4) as well as between the primary nocturnal enuretic children and the non-enuretic children (mean age 9.0). CONCLUSIONS: Transplanting young children frequently delays the normal attainment of night-time continence or causes them to start wetting again. It should not be dismissed as a minor problem as it causes low self-esteem and is socially limiting. It is important families are aware it is a direct result of the transplantation process.

Adolescent↗
PubMed2002

Differential gene expression in rats following subacute exposure to the anticonvulsant sodium valproate.

Sodium valproate (VPA) is clinically employed as an anticonvulsant and, to a lesser extent, as a mood stabilizer. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage of these rare adverse effects, with fatalities occurring mainly in children receiving polypharmacy. Previous studies have highlighted the different pharmacological effects of acute valproate exposure, a combination of which are likely to underpin its observed broad-spectrum anticonvulsant efficacy. However, limited studies have been undertaken to investigate the subacute effects of this compound and how genomic effects may underlie the observed hepatotoxic effects. Investigation into the mild hepatoxicity observed in rats exposed to high doses of VPA may provide important information on the human situation. Male Sprague-Dawley rats were dosed with 500 mg/kg/day sodium valproate: after necropsy, mRNA was subjected to suppression PCR subtractive hybridization, identifying 8 up-regulated and 14 down-regulated mRNA species. The down-regulation of several mRNA species coding for enzymes involved in cellular energetics (e.g., succinate dehydrogenase, aldolase B) was of particular interest, as mitochondrial dysfunction is a key feature of valproate hepatotoxicity. In vitro studies were then undertaken to examine the dose and time dependence of these changes and also their effect on the overall energy levels within the cell. We demonstrate that, both in vivo and in vitro, valproate exposure in rats results in a significant decrease in pathways involved in cellular energy homeostasis. These changes may provide insight into the rare human hepatoxicity associated with this compound.

Animals↗
PubMed2001

Maternal uniparental heterodisomy for chromosome 2: detection through 'atypical' maternal AFP/hCG levels, with an update on a previous case.

We report a case of maternal uniparental disomy 2, detected through routine screening of placental karyotypes following the finding of 'atypical' AFP/hCG levels in the second trimester, with intrauterine growth retardation (IUGR) but otherwise normal outcome at term. Although the child remained small, subsequent early physical and mental development has also been normal. Additionally, we report long-term follow-up of an earlier case, again with relatively normal physical and mental development. The significance of atypical AFP/hCG results and the predictive value of prenatal testing for UPD2 in trisomy 2 confined placental mosaicism (CPM) cases are discussed.

Adult↗
PubMed2001

Use of a reporter gene assay to predict and rank the potency and efficacy of CYP3A4 inducers.

Regulation of the CYP3A4 gene has been studied using an in vitro reporter gene assay. The effect of 17 xenobiotics on approximately 1 kilobase of the CYP3A4 proximal promoter, upstream of a secretory placental alkaline phosphatase reporter gene was investigated following transfection into the HepG2 cell line. Transfections were carried out either in the basal system or with cotransfection of expression plasmids for the human pregnane X receptor (hPXR) and the human glucocorticoid receptor (hGR), two important receptors in the regulation of CYP3A4 gene expression. Compounds were tested at four concentrations, and the resulting data were used to calculate maximal induction (I(max)) and EC(50) values. An "overall inductive ability" (IA) was derived by dividing I(max) by EC(50). Of the compounds tested seven were established transcriptional inducers, all of which were positive in the in vitro assay. The remaining 10 compounds represented a group with preliminary evidence for CYP3A transcriptional activation. Nine of these compounds produced statistically significant inductions in vitro, with only pravastatin failing to activate the reporter gene. This is of potential interest in light of the high IA values observed with the other structurally and functionally similar statins tested. We conclude that a four-concentration-point, in vitro model is capable of identifying CYP3A4 transcriptional inducers and yields an IA value allowing the ranking of compounds for their overall ability to induce CYP3A4 transcription. In addition, the majority of the compounds tested showed increased IA values in the hPXR/hGR cotransfected system, underpinning the importance of these receptors in CYP3A4 gene transcriptional regulation.

Cytochrome P-450 CYP3A↗
PubMedDate not supplied

Developmental modulation of cysteine conjugate beta-lyase/glutamine transaminase K/kynurenine aminotransferase mRNA in rat brain.

Cysteine conjugate beta-lyase/glutamine transaminase K/kynurenine aminotransferase (CS-lyase/GTK/KAT) is a tri-functional enzyme found in several organs, including the brain. Kynurenine aminotransferase is important in tryptophan metabolism in the CNS, producing kynurenic acid, a NMDA receptor antagonist and neuroprotective. Tryptophan not metabolised via kynurenine aminotransferase may form quinolinic acid, a NMDA receptor agonist and neurotoxin. Kynurenic acid co-treatment blocks quinolinic acid induced lesions in the CNS in rat. In many conditions exhibiting neurodegeneration (i.e. Huntington's, Parkinsonism, Down's syndrome) quinolinic acid and/or kynurenic acid concentrations are altered, suggesting the ratio of these chemicals may be important in neurodegeneration. We have investigated the developmental modulation of CS-lyase/GTK/KAT mRNA in rat brain. CS-lyase/GTK/KAT mRNA was measured in 14, 21, 28, 35, 42 day post-natal and adult rats. While many regions demonstrated a steady increase to adult levels, two other profiles were seen. Five regions rapidly reached adult levels of the mRNA, while two peaked above the adult level before falling back. This provides evidence that expression of the CS-lyase/GTK/KAT gene is physiologically modulated, and provides the basis for further investigation into the mechanism of control. Artificial modulation could possibly be used to alter levels of the neuroprotectant kynurenic acid in neurodegeneration.

Animals↗
PubMedDate not supplied

Expressed sequence tags (ESTs) and single nucleotide polymorphisms (SNPs): what large-scale sequencing projects can tell us about ADME.

To date over 800 complete genomes have been sequenced, with many more partially complete. Coupled with the large amount of mRNA transcript sequence data being produced from expression studies, there is now a daunting amount of information available to the research scientist. This review examines how this information may be best used, focusing on examples from sequences encoding absorption, distribution, metabolism and excretion (ADME)-related proteins in particular. Through the use of phylogenetic, splice variant and single nucleotide polymorphism (SNP) analysis, the review examines not only how insights into species-specific responses to drug exposure may be gained, but also how best to utilize this information to predict both individual human responses and the impact of population variance in response.

Alternative Splicing↗
PubMedDate not supplied

Ethical dilemmas in clinical supervision. 1: Need for guidelines.

In this article, the first of two parts, the authors focus on ethical dilemmas in clinical supervision. Given that there may be several factors that contribute to the limited uptake of clinical supervision, the authors suggest that one reason might be the clinician's concern and confusion regarding the potential ethical dilemmas that could arise when providing clinical supervision. Most issues do not produce ethical dilemmas, but some do. Therefore, this article offers a brief description of the purpose and alleged benefits of supervision, and examines the current position of the law in regard to ethical dilemmas within supervision. It then provides six vignettes where supervisors are faced with ethical dilemmas. These will be discussed in the second part of this article.

Conflict, Psychological↗
PubMedDate not supplied

Ethical dilemmas in clinical supervision. 2: Need for guidelines.

In this, the second half of this two-part article, the authors focus on ethical dilemmas in clinical supervision. Referring to the case vignettes included in the first part of this article (Vol 7(15): 920-3), the authors highlight how ethical dilemmas can arise and then provide some discussion on how they might be handled. As a result of the discussion, the authors conclude that there is a clear need for a specific set of guidelines to be produced that would help safeguard best practice within clinical supervision and ensure it remains an opportunity to help and support nurses in reflecting on their dilemmas, difficulties and successes (Cutcliffe and Proctor, 1998a). This would prevent supervision from becoming another form of management monitoring which might inadvertently prevent the resolution of intra- and interpersonal issues affecting the care of clients.

Community Health Nursing↗
PubMedDate not supplied

Up in the air.

Explore the source record for details and available documents.

Human Rights↗