8 research outputs found
Mitochondrial inhibitors may act as promoters of differentiation in the serum free HL60 cell line [Abstract]
Enzymes of drug metabolism during delirium
Background: delirium is common in ill medical patients. Several drugs and polypharmacy are recognised risk factors, yet
little is known about drug metabolism in people with delirium.
Objective: the aim of this study was to investigate the activities of plasma esterases (drug metabolising enzymes) in delirium.
Design: this was a prospective study of delirium present at time of hospital admission (community acquired) or developing
later (hospital acquired) in patients admitted as a medical emergency and aged 75 years or over.
Methods: following informed consent or assent cognitive screening was completed on all patients on admission and every
48 hours subsequently. Delirium was diagnosed by Confusion Assessment Method and DSM IV criteria. Blood samples
were taken on admission and at onset of delirium if this was later. Four plasma esterase assays were performed spectrophotometrically:
acetylcholinesterase, aspirin esterase, benzoylcholinesterase, butyrylcholinesterase.
Results: 283 patients (71% of eligible) were recruited, with mean age 82.4 years and 59% female. 27% had community
acquired delirium, 10% developed hospital acquired delirium, 63% never developed delirium. On admission the mean activities
of all four esterase assays were statistically significantly lower in delirious than non delirious patients. There were no significant
differences on admission in any plasma esterase activity between patients with hospital and community acquired
delirium. In-hospital mortality was associated with low plasma esterase activities on admission.
Conclusion: plasma esterase activities are suppressed during delirium. These data reinforce the need for extreme caution with drugs in this vulnerable population
Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region
The proximal promoter region of the human pituitary expressed growth hormone (GH1) gene is highly polymorphic, containing at least 15 single nucleotide polymorphisms (SNPs). This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Functional analysis showed that 12 haplotypes were associated with a significantly reduced level of reporter gene expression whereas 10 haplotypes were associated with a significantly increased level. The former tend to be more prevalent in the general population than the latter (p<0.01), possibly as a consequence of selection. Although individual SNPs contributed to promoter strength in a highly interactive and non-additive fashion, haplotype partitioning was successful in identifying six SNPs as major determinants of GH1 gene expression. The prediction and functional testing of hitherto unobserved super-maximal and sub-minimal promoter haplotypes was then used to test the efficacy of the haplotype partitioning approach. Electrophoretic mobility shift assays demonstrated that five SNP sites exhibit allele-specific protein binding. An association was noted between adult height and the mean in vitro expression value corresponding to an individual's GH1 promoter haplotype combination (p=0.028) although only 3.3% of the variance of adult height was found to be explicable by reference to this parameter. Three additional SNPs, identified within sites I and II of the upstream locus control region (LCR), were ascribed to three distinct LCR haplotypes. A series of LCR-GH1 proximal promoter constructs were used to demonstrate that 1) the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that 2) the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of inter-individual differences in GH1 gene expression thus appears to be extremely complex
Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke
A novel dysfunctional growth hormone variant (Ile179Met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway
The pituitary-expressed GH1 gene was screened for mutation in a group of 74 children with familial short stature. Two novel mutations were identified: an Ile179Met substitution and a -360AG promoter variant. The Ile179Met variant was shown to exhibit a similar degree of resistance to proteolysis as wild-type GH, indicating that the introduction of Met does not cause significant misfolding. Secretion of Ile179Met GH from rat pituitary cells was also similar to that of wild type. Although receptor binding studies failed to show any difference in binding characteristics, molecular modeling studies suggested that the Ile179Met substitution might nevertheless perturb interactions between GH and the GH receptor loop containing the hotspot residue Trp169, thereby affecting signal transduction. The ability of the Ile179Met variant to activate a signal transducer and activator of transcription (STAT) 5-responsive luciferase reporter gene and induce phosphorylation of STAT 5 and ERK was therefore studied. In contrast to its ability to activate STAT 5 normally, activation of ERK by the Ile179Met variant was reduced to half that observed with wild type. Although differential effects on the activation of distinct signaling pathways by a mutant receptor agonist are unprecedented, these findings also suggest that the ERK pathway could play a role in mediating the action of GH