Biomedical subjects
Publications and source records attributed to J Price.
The authors describe the staff development and expansion of a preadmission clinic in one Canadian teaching hospital. The nurses' shift in focus from technical skills to assessment, education, and counseling skills is described. The benefits observed from an increasing preadmission service are also high lighted.
A cysteine to serine substitution at amino acid 23 in the 5-HT2C receptor gene alters the pharmacological properties of the protein. We investigated this polymorphism in subjects with schizophrenia resistant to conventional neuroleptic drugs, and analysed our data for allelic association between the disease state or clinical response to the atypical antipsychotic drug, clozapine. Ninety percent of subjects who had one or more 5-HT2Cser alleles (19/21) were classified as clozapine responders compared with 59% (84/141) without this allele (chi 2 = 7.7, p = 0.005), suggesting that this mutation is a predictor of good response to clozapine. There was no association between schizophrenia and the 5-HT2Cser allele, but our results indicate that the 5-HT2C receptor may contain the major site of action through which clozapine mediates its antipsychotic effects.
Various point mutations of lysyl residues in yeast mitochondrial porin (283 residues) were tested for their ability to assemble in vitro into the outer membranes of intact yeast mitochondria. Assembly was evaluated by protection from proteinases. The extent of assembly of two of the mutants, K234E and K236E porins, was much less than for wild-type in either post-translational or co-translational assembly assays. Lysine to glutamate mutants at other positions and K234R porin assembled as well as wild-type, but K234Q porin was poorly inserted. When both Lys-234 and Lys-236 were mutated, K234R/K236R porin was inserted better than K234Q/K236Q porin, which was inserted better than K234E/K236E; however, none of these mutants assembled as well as wild-type porin. It was concluded that optimal assembly of yeast porin depended on the presence of positively charged residues at both positions 234 and 236 and a lysine at one of these positions. After undergoing the assembly reaction, mutants that were vulnerable to proteinase K (i.e. K234E, K234Q, and K236E porins) seemed to be incompletely digested and were, to varying degrees, resistant to extraction by Na2CO3 (pH 11.5). These experiments suggested that these mutants were incompletely inserted into the outer membrane. Both Lys-234 and Lys-236 are included in an internal pentapeptide, VKAKV, that is conserved in porins from protists, plants, and animals, and it is possible that, at least, the lysines in this tract are one of the signals for the membrane assembly of these proteins.
This paper reports on the mechanism of substrate activation by the enzyme 4-chlorobenzoyl coenzyme A dehalogenase. This enzyme catalyzes the hydrolytic dehalogenation of 4-chlorobenzoyl coenzyme A (4-CBA-CoA) to form 4-hydroxybenzoyl coenzyme A (4-HBA-CoA). The mechanism of this reaction is known to involve attack of an active site carboxylate (Asp or Glu side chain) at C(4) of the substrate benzoyl ring to form a Meisenheimer complex. Loss of chloride ion from this intermediate results in the formation of an arylated enzyme intermediate. The arylated enzyme is hydrolyzed to free enzyme plus 4-HBA-CoA by the addition of water at the acyl carbon [Yang, G., Liang, P.-H., & Dunaway-Mariano, D. (1994) Biochemistry 33, 8527]. The present studies have focused on the activation of the 4-CBA-CoA for nucleophilic attack by the active site carboxylate group. UV-visible, 13C-NMR, and Raman spectroscopic techniques were used to monitor changes in the distribution of the pi electrons of the benzoyl moiety of benzoyl-CoA adducts [substituted at C(4) with methyl (4-MeBA-CoA), methoxy (4-MeOBA-CoA), or hydroxyl (4-HBA-CoA) groups or at C(2) or C(3) with a hydroxyl group (2-HBA-CoA and 3-HBA-CoA)] resulting from the binding of these ligands to the dehalogenase active site. The UV-visible spectra measured for 4-HBA-CoA in aqueous buffer at pH 7.5 and in the dehalogenase active site revealed that a large red shift (from 292 to 373 nm) in the lambda max of the benzoyl moiety occurs upon binding.(ABSTRACT TRUNCATED AT 250 WORDS)
We report allelic association between a polymorphism (T102C) within the coding region of the 5-HT2A gene (HTR2A, 13q14-21) and response to clozapine in schizophrenic patients. Homozygosity for the C102 allele was more frequent (30/57, 53%) among patients who did not respond to clozapine than in those who responded (23/92, 25%). This finding is evidence that allelic variation of genes which encode neurotransmitter receptors can influence clinical response to antipsychotic drugs.
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Neurotransmitter choice is a crucial step in neural development. In the cerebral cortex, pyramidal neurons use the excitatory neurotransmitter glutamate, whereas non-pyramidal cells use the inhibitory neurotransmitter GABA. We are interested in how these two neuronal types are generated. We labelled precursor cells from embryonic rat cerebral cortex with a retroviral vector in dissociated cell cultures, and examined the neurotransmitter phenotype of their progeny immunohistochemically after 2 weeks in vitro. We discovered, first, that precursor cells in culture generate glutamatergic and GABAergic neurons in proportions similar to those in vivo. Second, we found that neuronal precursor cells gave rise to both GABAergic and glutamatergic neurons. These results suggest that neuronal precursor cells in the cerebral cortex have the potential to generate both neuronal subtypes. Moreover, these data are consistent with a stochastic model of neurotransmitter specification.
The discovery of stem cells in adult nerve tissue makes the repair of brain damage a realistic possibility.
We have used retroviral vectors to study cell lineage in the embryonic rat cerebral cortex both in vivo and in dissociated cell culture. We provide evidence that during the late phase of corticogenesis, most precursor cells of the ventricular zone are specified for the production of a single cell type, either neurons or one of the glial cell types. Although specified, the precursor cells that generate neurons can apparently generate both pyramidal and non-pyramidal cells. Earlier stages of development are dominated by a different type of precursor cell with a number of properties that lead us to believe that it is the founding, multipotential precursor cell of the cerebral cortex. We discuss a possible model of cell lineage which unifies these various observations.
An increase in the expression of the glial fibrillary acidic protein (GFAP) gene by astrocytes appears to constitute a crucial component of the brain's response to injury because it is seen in many different species and features prominently in diverse neurological diseases. Previously, we have used a modified GFAP gene (C-339) to target the expression of beta-galactosidase (beta-gal) to astrocytes in transgenic mice (Mucke et al.; New Biol 3:465-474 1991). To determine to what extent the in vivo expression of GFAP-driven fusion genes is influenced by intragenic GFAP sequences, the E. coli lacZ reporter gene was either placed downstream of approximately 2 kb of murine GFAP 5' flanking region (C-259) or ligated into exon 1 of the entire murine GFAP gene (C-445). Transgenic mice expressing C-259 versus C-445 showed similar levels and distributions of beta-gal activity in their brains. Exclusion of intragenic GFAP sequences from the GFAP-lacZ fusion gene did not diminish injury-induced upmodulation of astroglial beta-gal expression or increase beta-gal expression in non-astrocytic brain cells. These results demonstrate that 2 kb of murine GFAP 5' flanking region is sufficient to restrict transgene expression primarily to astrocytes and to mediate injury-responsiveness in vivo. This sequence therefore constitutes a critical target for mediators of reactive astrocytosis. While acute penetrating brain injuries induced focal increases in beta-gal expression around the lesion sites in C-259, C-445, and C-339 transgenic mice, infection of C-339 transgenic mice with scrapie led to a widespread upmodulation of astroglial beta-gal expression. Hence, GFAP-lacZ transgenic mice can be used to monitor differential patterns of astroglial activation in vivo. These and related models should facilitate the assessment of strategies aimed at the in vivo manipulation of GFAP expression and astroglial activation.
Cell lineage studies of the rat cerebral cortex suggest that by midneurogenesis, most precursor cells of the ventricular zone are specified to produce a single cell type. Yet there is also evidence for multipotential precursor cells. We used a retroviral vector to follow the developmental potential of cortical precursor cells by labeling cortical cells in cultures from embryos between 12 and 18 days of gestation. We found specified precursor cells as early as embryonic day 12, in addition to bipotential cells that generate neurons and astrocytes. Most importantly, we discovered a type of neural precursor cell, a neuroepithelial cell, that predominates earlier in development, differs distinctly from the specified precursor cells, and as a population, appears to be multipotential. These data suggest that corticogenesis progresses from an early phase dominated by neuroepithelial cells to a later phase characterized by multiple populations of specified precursor cells.
With so many neurotrophins and receptors now known, how is our picture of neurotrophism changing? Recent studies on knockout mice have confirmed our expectations of neurotrophin action in neuronal development. A notable exception is the activation of TrkB, on motor neurons, by an unknown ligand. It is also clear that some neurotrophins have diverse activities and influence early developmental stages. There are interesting new data concerning the role of p75, the low affinity neurotrophin receptor, as a modulator of neurotrophin activity. Even more exciting are new studies on glia-derived neurotrophic factor (GDNF) which demonstrate that this growth factor acts as a potential protector of motor neurons and striatal dopaminergic neurons.
A sensitive and highly specific method for the determination of methylmalonic acid (MMA) in bovine plasma is described. Following solvent extraction and butylation, samples are analysed by gas chromatography and detected using high-resolution mass spectrometry. The limit of detection for the assay was 0.025 mumol l-1 MMA and the recovery of added MMA ranged from 98 to 103%. The application of the method is demonstrated for the analysis of MMA in plasma taken from cattle that had been maintained on a cobalt-deficient diet for 64 weeks.
The social ranking (or social competition) theory of depression suggests that the capacity for episodes of depressed mood evolved as a mechanism for inhibiting challenge. Depressed mood induces the sufferer to accommodate to low social rank, or to losing in social competition, or to adopting the one-down position in a complementary relationship (Price, 1991; Price, Sloman, Gardner, Gilbert & Rohde, 1994; Sloman, Price, Gilbert & Gardner, 1994). Thus depressed patients should be observed to forego the privileges of high rank and of winning, such as exercising social power and getting their own way. However, several commentators have noted that depressed patients often seem to be very powerful, and even appear to use their depression to manipulate others. This paper attempts to reconcile the theory to such observations.