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Biomedical subjects

M J West

Publications and source records attributed to M J West.

At least 55 records · Page 3Linked to original sources
PubMed1997

Feasibility of conducting cardiovascular outcome research in Australian general practice: results from the ANBP2 pilot study. Australian National Blood Pressure Study.

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was > or = 160 mmHg systolic or > or = 90 mmHg diastolic if systolic BP was > or = 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82,000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP > or = 160/90 mmHg. Forty-seven per cent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.

Aged↗
PubMed1997

Association of the brain natriuretic peptide gene with blood pressure and heart weight in the rat.

1. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are important in the control of body fluid homeostasis, blood pressure (BP) regulation and vascular remodelling. The genes for these peptides may, therefore, be involved in the pathogenesis of genetic hypertension. We have previously described a quantitative trait locus (QTL) for BP in the ANP gene region on rat chromosome 5. We have now assessed the possibility that this QTL lies at the closely linked BNP locus. 2. Intra-arterial BP and heart weight were measured in 12-week-old (n = 207) and 24-week-old (n = 88) F2 rats derived from crosses between Wistar-Kyoto normotensive rats and spontaneously hypertensive rats. We designed polymerase chain reaction primers to amplify a microsatellite in the BNP gene from genomic DNA. Analysis of variance was used for cosegregation analysis. Linkage mapping and localization of QTL was performed using the Mapmaker computer package. 3. A significant correlation was found between genotype for the BNP gene and systolic BP (P < 0.001) in 12-week-old rats. The ANP gene, but not the BNP gene, was associated with systolic BP in 24 week rats. There was no segregation of heart weight with BNP genotype at 12 or 24 weeks of age. The BNP gene mapped approximately 20 cM from the ANP gene in our rat hybrids, away from the previously described QTL. There was evidence for a second BP locus near to but distinct from the BNP gene. 4. These results suggest that BP QTL are present in the natriuretic peptide gene region but that the ANP and BNP genes themselves have no major effect on BP in this cross.

Animals↗
PubMed1997

Association analysis of six candidate genes in a sample of Australian hypertensive patients.

1. Essential hypertension is characterized by increased vascular resistance due to narrowing of the small arterioles. This may be influenced by vasoactive substances, cell growth and vascular remodelling. 2. A sample of Australian hypertensive and normotensive subjects was investigated for association with genetic markers which are candidates for a role in blood pressure (BP) regulation due to potential effects on vascular diameter. 3. The six markers used were for genes encoding vasoconstrictors, growth factors and a structural protein of the extracellular matrix. 4. No significant association of any of the markers used was found with BP status in this sample of patients.

Aged↗
PubMed1997

Spinal cord excitatory amino acid receptors and plasma catecholamine autonomic responses in the conscious rabbit.

Intrathecal administration of the specific glutamate subtype receptor agonist NMDA (N-methyl-D-aspartate), or the non-NMDA receptor agonist AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid), at the level of the lower thoracic spinal cord in the conscious rabbit, produces increased levels of plasma norepinephrine and a rise in blood pressure. These responses are specifically inhibited with prior intrathecal administration of the NMDA receptor antagonist AP-5 (2-amino-5-phosphonovaleric acid) or non-NMDA receptor antagonist DNQX (6, 7-dinitroquinoxaline-2, 3-dione), respectively. In contrast, arterial baroreflex activation induced by transient hypotension following intravenous sodium nitroprusside increases levels of plasma norepinephrine which are inhibited with intrathecal AP-5, but not DNQX. The experiments are consistent with glutamate acting as a neurotransmitter in the spinal cord influencing control of sympathetic nerve function via activation of spinal cord NMDA and non-NMDA subtype receptors. The results support previous work suggesting that baroreflex function is predominantly mediated by spinal NMDA receptors and that spinal glutamate receptors are important in baroreflex control of the circulation.

Animals↗
PubMed1996

Aberrant translational control of the c-myc gene in multiple myeloma.

We demonstrate a 10- to 25-fold increase in the amount of c-myc protein in several independent cell lines derived from patients with multiple myeloma (MM). This is not accompanied by a corresponding increase in the overall level of the c-myc mRNA. There is, however, a 3.4-fold increase in the amount of c-myc mRNA associated with the polysomes in these cell lines without any detectable change in either the polysome size or the rate of translation elongation, thus suggesting that there is an increase in the extent of mobilisation of c-myc mRNA to the polysomes in MM. Analysis of the 5' untranslated region of c-myc has revealed the presence of a mutation, in all of the MM cell lines examined, in a region which has been implicated previously in the translational control of this mRNA species. These data suggest aberrant translational control of the c-myc gene in cell lines derived from patients with MM, which may contribute towards pathogenesis of the disease.

Exons↗
PubMed1996

Estimation of the number of somatostatin neurons in the striatum: an in situ hybridization study using the optical fractionator method.

Somatostatin-containing neurons of the striatum constitute fewer than 5% of the total neuronal population. Their involvement in the feedforward inhibition of the spiny projection neurons, the modulation of other interneurons, and the regulation of regional blood flow indicates that this small population of neurons plays an important role in the processing of information in the striatum. As a first step in developing a quantitative structural framework within which a more rigorous analysis can be made of the functional circuitry of the striatum, we used modern unbiased stereological techniques to make estimates of the total number of neurons expressing mRNA for somatostatin in the striatum of rats. The strategy developed involved the application of the optical fractionator technique to relatively thick tissue sections that were hybridized in situ with a relatively short oligonucleotide probe conjugated to a nonradioactive reporter molecule. The approach is generally applicable to other subpopulations of in situ hybridized cells in other parts of the brain and can provide a link between molecular neurobiology and stereology. The mean total number of neurons on one side of the striatum was estimated to be 21,300. An analysis of the sampling scheme indicated that counting no more than 200 neurons in a systematic sample of not more than 15 sections per individual results in an estimate with a precision that is more than sufficient for comparative and experimental studies. The issues that must be considered when analyzing in situ hybridized tissue with modern stereological methods, the interpretive caveats inherent in the resulting data, and the unique perspectives provided by data like that presented here for striatal somatostatin neurons are discussed.

Animals↗
PubMed1996

Unbiased stereological estimation of the total number of synapses in a brain region.

Modern stereological methods have been used to make unbiased estimates of the total number of synapses in the striatum radiatum of the hippocampal CA1 region of five rabbits. The approach used involved a two stage analysis and is generally applicable to all parts of the nervous system. During the first stage of the analysis, the reference volume was estimated by point counting, at the light microscope level, according to the Cavalieri principle. During the second stage, the numerical density of synapses was estimated with dissectors at the electron microscopic level. The total number of synapses was calculated as the product of the numerical density and the volume of the region. The sampling with points and dissectors was carried out in all three dimensions of the entire CA1 region in a manner that ensured that all parts of the region and all synapses within it had equal probabilities of being sampled. An analysis of the precision of the estimate of total synapse number has been performed in terms of the variances of volume and synaptic numerical density at different levels of sampling, i.e. at the level of points, sections, individual animals and group of animals. Detailed descriptions of the procedures used to estimate the total number of synapses, evaluate the precision of the estimates, and optimize the sampling scheme are provided.

Analysis of Variance↗
PubMed1996

Social malleability in cowbirds: new measures reveal new evidence of plasticity in the eastern subspecies (Molothrus ater ater).

The social experiences of young Molothrus ater ater cowbirds were manipulated in a 2-year study. In the 1st year, males were housed with pairs of canaries. The males were tested in 3 social contexts. Also, vocal repertoires were recorded and played back to females. In contrast to a previous study of the M. a. artemisiae subspecies, the males did not vocalize to the canaries in courtship tests (T. M. Freeberg, A. P. King, & M. J. West, 1995) but showed incompetent courtship of female cowbirds. In their 2nd year, half of the males were housed with older males and female cowbirds, and half were housed with only females. Those exposed to older males courted much more successfully than did those deprived of such experience. All males developed new repertoires, and song potencies did not correlate across years. The data reveal intraspecific variation in the ontogeny of mate recognition but intraspecific dependence on social learning to acquire courtship skills.

Animals↗
PubMed1996

Cosegregation of genes on chromosome 5 with heart weight and blood pressure in genetic hypertension.

Genetic factors may be involved in both essential hypertension and cardiac hypertrophy. To identify genes contributing to elevated for blood pressure and cardiac hypertrophy in the spontaneously hypertensive rat (SHR), we performed a cosegregation analysis between blood pressure and heart weight and microsatellite markers for the candidate gene ANF on chromosome 5 in F2 animals obtained by mating SHR with Wistar-Kyoto (WKY) rats. We found evidence for a quantitative trait locus (QTL) determining mean blood pressure on chromosome 5 between atrial natriuretic factor (ANF) and MITR-3893 loci. No evidence for a QTL influencing heart weight was found. We propose that in SHR, blood pressure and heart weight may be independently controlled by different genetic mechanisms and that a gene close to ANF locus on chromosome 5 contributes towards hypertension in these animals.

Analysis of Variance↗
PubMed1996

Angiotensin I converting enzyme gene cosegregates with blood pressure and heart weight in F2 progeny derived from spontaneously hypertensive and normotensive Wistar-Kyoto rats.

The present investigation examines the association of angiotesin I converting enzyme (ACE) genotypes with blood pressure and heart weight in an F2 population of rats derived from a cross between spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. ACE genotype of rats in the F2 population was determined using a microsatellite polymorphism. Our investigation revealed that cardiac mass was not correlated with blood pressure at 12 weeks of age within the SHR, WKY, F1 or F2 groups of rats. In male rats, ACE genotype accounted for approximately 20% of the difference in mean blood pressure between SHR and WKY rats. There was no effect in females. It was also responsible for 21%-29% of the difference in heart weight both in female and male animals. The allele derived from the SHR parent appeared recessive to the allele from WKY parent for both heart weight and blood pressure. These results suggest that a gene in the region of the ACE locus is one of the genetic factor influencing blood pressure and heart weight in SHR.

Animals↗
PubMed1996

Neuronal loss in hippocampus in rats exposed to toluene.

Both clinical and epidemiological studies of the effects of exposure to toluene have shown that long-term exposure may result in chronic toxic encephalopathy, where one of the major symptoms is memory deficits. We have attempted to identify the structural basis of the toxic effects of toluene in the hippocampus, a region of the brain known to be involved in learning and memory processes and well suited for stereological analysis. Rats were exposed to 1500 ppm of toluene, six hours per day, five days per week for six months. This was followed by a four-month-period without exposure prior to sacrifice. The total number of neurons in each of the five subdivisions of hippocampus of six exposed and six control rats was estimated with the optical fractionator. A statistically significant neuron loss of 16% was found in regio inferior (CA3 and CA2) of the exposed rats.

Animals↗
PubMed1995

Translational upregulation of the c-myc oncogene in Bloom's syndrome cell lines.

Previous studies have shown a constitutive increase in the levels of c-myc protein in cell lines derived from patients with the cancer-prone disorder Bloom's Syndrome (BS). We report here that this overexpression results from a specific increase in the translation of the c-myc mRNA and is not the result of either a chromosomal translocation involving the c-myc locus or an amplification of this gene. We also did not detect any increase in the stability of the c-myc protein or any significant increases in the levels of c-myc mRNA expressed in BS cells compared to control cell lines. Overall, there is a 39-80% increase in the association of the c-myc mRNA with polysomes in BS cell lines. Since, in some cases, overexpression of the c-myc protein has been shown to increase levels of the translation initiation factors eIF-4E and eIF-2 alpha, which may themselves play a role in malignant conversion, we have also examined the levels of these proteins in BS cells and found them to be either comparable or lower than those in control cell lines. These data suggest that if c-myc does contribute to the cancer predisposition phenotype in BS then it does not appear to act via an eIF-4E and eIF-2 alpha mediated pathway.

Bloom Syndrome↗
PubMed1995

[Differential neuronal loss in the hippocampus in normal aging and in patients with Alzheimer disease].

The causal relationship between the neurodegenerative changes that accompany normal ageing and those that characterize Alzheimer's disease is unclear. The high incidence of Alzheimer's disease associated with old age and the presence of its neuropathological signs in non-demented older individuals suggest that these two phenomena involve the same neurodegenerative processes and mechanisms and that Alzheimer's disease is an extension of normal ageing. On the other hand, the identification of environmental and genetic risk factors associated with Alzheimer's disease suggests the involvement of a specific disease process that is not related to normal ageing. The resolution of this fundamental issue is of importance in the design of investigative and therapeutic strategies. In this report, we describe differences in the regional patterns of neuronal loss, in the hippocampal region of the brains of Alzheimer's patients and normal ageing subjects, that indicate that Alzheimer's disease is not the manifestation of accelerated ageing, but the expression of a distinct pathological process.

Aged↗
PubMed1995

Quantification of neutrophil chemotaxis: a comparison of stereological and 51Cr-labelling methods.

A stereological method has been used to estimate the number of migrated polymorphonuclear leukocytes in a multipore filter assay. The estimates have been compared to those obtained with conventional 51Cr-labelling methods. The precision of the estimates in individual subjects with the two methods was similar, and in both cases the contribution to the interindividual variance made by the methods was small compared to the biological variance. However, the 51Cr-labelling method resulted in a significant reduction in the fraction of neutrophils that migrated as well as a delay in the chemotactic response. Optimal assay conditions with regard to sample size, cell concentration, incubation time and chemoattractant fMLP concentration have been established for the stereological method and the virtues of the two techniques discussed.

Chemotaxis, Leukocyte↗
PubMed1994

Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease.

The distinction between the neurodegenerative changes that accompany normal ageing and those that characterise Alzheimer's disease is not clear. The resolution of this issue has important implications for the design of therapeutic and investigative strategies. To this end we have used modern stereological techniques to compare the regional pattern of neuronal cell loss in the hippocampus related to normal ageing to that associated with Alzheimer's disease. The loss related to normal ageing was evaluated from estimates of the total number of neurons in each of the major hippocampal subdivisions of 45 normal ageing subjects who ranged in age from 13 to 101 years. The Alzheimer's disease related losses were evaluated from similar data obtained from 7 cases of Alzheimer's disease and 14 age matched controls. Qualitative differences were observed in the regional patterns of neuronal loss related to normal ageing and Alzheimer's disease. The most distinctive Alzheimer's disease related neuron loss was seen in the CA1 region of the hippocampus. In the normal ageing group there was almost no neuron loss in this region (final neuron count in the CA1 region: 4.40 x 10(6) neurons for the Alzheimer's disease group vs 14.08 x 10(6) neurons in the normal ageing group). It is concluded that the neurodegenerative processes associated with normal ageing and with Alzheimer's disease are qualitatively different and that Alzheimer's disease is not accelerated by ageing but is a distinct pathological process.

Adolescent↗
PubMed1994

Inhibition of human vascular smooth muscle cell growth by heparin.

We examined the inhibitory effect of heparin on vascular smooth muscle cell (VSMC) outgrowth from cultured coronary artery explants of primary atherosclerotic lesions and of undiseased regions from the same patients, compared with explant outgrowth from control patients (idiopathic cardiomyopathy) with no evidence of atherosclerosis. For undiseased tissue regardless of origin, heparin significantly delayed half-maximum percentage explant outgrowth time (mean difference from control treatment 2.1 [SE 0.8] days for atherosclerosis patients and 2.3 [1.0] days for control patients). For plaque tissue, heparin had no such effect. Thus the proliferative state of the cells involved in outgrowth may influence the activity of heparin.

Cell Division↗
PubMed1994

Hippocampus of the domestic pig: a stereological study of subdivisional volumes and neuron numbers.

With the aim of establishing a quantitative structural basis for comparative and experimental studies, the volumes of the hippocampal subdivisions and the total number of neurons in each subdivision were estimated in domestic pig brains using modern stereological techniques. In addition to a detailed description of the stereological methods used in the analysis, comprehensive descriptions of the architectonic boundaries of the subdivisions are included. The absolute and relative volumes of the subdivisions were compared to those of a number of other species and the relationship between the number of neurons and the volume of the subdivisions was compared to that in homologous subdivisions of laboratory rats and humans. The methodology used to estimate the volumes and the total number of neurons in the individual subdivisions were evaluated with regard to the sensitivity that they can provide in experimental studies.

Animals↗