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Biomedical subjects

J S Clark

Publications and source records attributed to J S Clark.

At least 37 records · Page 2Linked to original sources
PubMed1997

Left ventricular hypertrophy and arterial blood pressure in experimental models of hypertension.

Cardiac hypertrophy in essential and experimental (genetic) hypertension have been initially attributed to increased pressure load. However, the level of blood pressure does not parallel the degree of cardiac hypertrophy, i.e., a complex relationship rather than a simple dose-response effect has to be suggested. Several non-haemodynamic factors which influence LV mass have been identified with genetic and neuro-hormonal influences playing a major role. The experimental strategies which have been used to highlight one or more of these influences include pharmacological studies of regression or prevention of LVH and studies designed to produce LVH de-novo in normotensive strains. All these studies while confirming an important role of haemodynamic factors also stress the major influence of the renin-angiotensin system and the inter-relationship between angiotensin II and nitric oxide. In contrast, genetic strategies, from simple co-segregation analysis to most complex genome scan studies, suggest the existence of "susceptibility genes" for LV hypertrophy, a finding which deserves further study in large collections of siblings and family groups with essential hypertension.

Animals↗
PubMed1997

Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Animals↗
PubMed1997

Frequent users of the emergency department: can we intervene?

OBJECTIVE: To determine whether the use of individualized patient care plans and multidisciplinary case management would decrease ED utilization by frequent ED users. METHODS: The authors performed a prospective, randomized clinical trial of the impact of a care plan on ED use by adults with frequent ED visits. Patients with > 10 ED visits to a university hospital in 1993 were identified. Patients were matched for age, sex, and number of visits and then randomized into 2 groups. The control group received standard emergency care. The treatment group was managed by a multidisciplinary team and treated in the ED according to individualized care plans. ED use was tracked at the university hospital and at the other 5 community hospitals in the city. RESULTS: Of the 70 enrolled patients, 25 of 37 control patients and 27 of 33 treatment patients made visits to the university hospital during the 1-year study period. Only those patients with follow-up visits were included in the data analysis. Patients remaining in the control group made 247 total visits (range 1-65) to the university hospital and 179 total visits (range 0-38) to the community hospitals during the study period. Patients in the treatment group made 320 total visits (range 1-72) to the university hospital and 254 total visits (range 0-135) to the community hospitals during the study period. There was no significant difference in the median number of visits made to either the university hospital or the community hospitals by the patients in the control group and those in the treatment group. CONCLUSIONS: The use of individualized care plans and case management did not significantly decrease ED utilization by frequent ED users. However, the impact of individualized care plans and case management on other quality-of-care measures (e.g., patient satisfaction, ED length of stay, hospitalizations, primary care visits, and health care costs) remains to be determined.

Adult↗
PubMed1997

Cardiac output and mixed venous oxygen content measurements by a tracer bolus method: theory.

We present a bolus method of inert-gas delivery to the lungs that facilitates application of multiple inert gases and the multiple inert-gas-exchange technique (MIGET) model to noninvasive measurements of cardiac output (CO) and central mixed venous oxygen content Reduction in recirculation error is made possible by 1) replacement of sinusoidal input functions with impulse inputs and 2) replacement of steady-state analyses with transient analyses. Recirculation error reduction increases the inert-gas selection to include common gases without unusually high (and difficult to find) tissue-to-blood partition coefficients for maximizing the systemic filtering efficiency. This paper also presents a practical method for determining the recirculation contributions to inert expired profiles in animals and determining their specific contributions to errors in the calculations of CO and from simulations applied to published ventilation-perfusion ratio (V/Q) profiles. Recirculation errors from common gases were found to be reducible to the order of 5% or less for both CO and whereas simulation studies indicate that measurement bias contributions from recirculation, V/Q mismatch, and the V/Q extraction process can be limited to 15% for subjects with severe V/Q mismatch and high inspired oxygen fraction levels. These studies demonstrate a decreasing influence of V/Q mismatch on parameter extraction bias as the number of inert gases are increased. However, the influence of measurement uncertainty on parameter extraction error limits improvement to six gases.

Animals↗
PubMed1996

Quantitative trait loci in genetically hypertensive rats. Possible sex specificity.

We performed a total genome screen in an F2 cross derived from the stroke-prone spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat. Blood pressure at baseline and after 1% NaCl was measured by radiotelemetry; other phenotypes included heart rate, motor activity, left ventricle weight to body weight ratio, and vascular smooth muscle cell polyploidy, a measure of vascular hypertrophy. Quantitative trait loci affecting a given phenotype were mapped relative to microsatellite markers by using the MAPMAKER/QTL 1.1 computer package. We identified three blood pressure quantitative trait loci, two on rat chromosome 2 and one on rat chromosome 3. The quantitative trait loci close to genetic markers D2Mgh12 ("suggestive" linkage, with a maximal logarithm of the odds [LOD] score of 3.1) and D3Mgh16 (significant linkage, with a maximal LOD score of 5.6) showed possible sex specificity in the male F2 cohort only. This was confirmed by the likelihood ratio test for the difference in locus effects between the sexes. We also identified a new quantitative trait locus for LV hypertrophy on rat chromosome 14 ("suggestive" linkage, with a maximal LOD score of 3.1). The sex specificity of blood pressure quantitative trait loci will be important in designing congenic strains and substrains for fine genetic mapping and for identifying genes that regulate blood pressure.

Animals↗
PubMed1995

Expression and loss of heterozygosity of c-met proto-oncogene in primary breast cancer.

The c-met proto-oncogene encodes the receptor to hepatocyte growth factor-scatter factor (HGF-SF), a mesenchyme-derived cytokine with cell-dissociating, invasion, and angiogenic properties. The expression of c-met in breast cancer is the subject of controversy; 111 primary breast cancers were examined for LOH of c-met by Southern blot electrophoresis. c-met expression was measured in a further 40 patients with breast cancer and in 8 patients with benign breast disease by flow cytometry. LOH of c-met was detected in only 4% of informative breast cancers. Expression of c-met was significantly greater in patients with breast cancer than in those with benign breast disease (P < 0.01, Mann-Whitney). There was no correlation however between increased c-met expression and clinicopathological prognostic variables. These results do not support the role of c-met as a tumour suppressor gene in breast cancer but suggest increased receptor expression in malignant breast disease. The significance of this increased expression in breast cancer is the subject of further investigation.

Blotting, Southern↗
PubMed1995

The effects of perindopril on vascular smooth muscle polyploidy in stroke-prone spontaneously hypertensive rats.

OBJECTIVE: To quantify vascular smooth muscle polyploidy and growth kinetics in aortic cells from stroke-prone spontaneously hypertensive rats (SHRSP) and from normotensive Wistar-Kyoto (WKY) rats, and to examine the effects of treatment with the angiotensin converting enzyme (ACE) inhibitor perindopril on these parameters. DESIGN: The following experimental groups were used: young (age < 20 weeks) and old (age > 20 weeks) untreated WKY rats and untreated SHRSP; SHRSP treated with perindopril, and age- and sex-matched control SHRSP; and SHRSP treated with hydralazine and hydrochlorothiazide and age- and sex-matched control SHRSP. The effects of treatment of the SHRSP with perindopril for 30 days on vascular smooth muscle polyploidy and growth kinetics were measured and compared with the effects of equivalent antihypertensive doses of hydralazine and hydrochlorothiazide. METHODS: Vascular smooth muscle polyploidy was measured using flow-cytometry DNA analysis of freshly harvested cells. Growth curves were performed on cultured aortic cells. Plasma renin activity was measured by an antibody-trapping method, plasma angiotensin II (Ang II) by radioimmunoassay and plasma ACE activity by a colorimetric method. Cardiac hypertrophy was evaluated by measuring the heart weight:body weight and left ventricle + septum weight:body weight ratios. RESULTS: The SHRSP had markedly and significantly elevated G2 + M phase of the cell cycle. Treatment with perindopril resulted in a significant reduction in polyploidy in the SHRSP, whereas treatment with hydralazine and hydrochlorothiazide had no effect on the percentage of cells in the G2 + M phase of the cell cycle. The regression of polyploidy after treatment with perindopril was associated with a significant reduction in the concentration of Ang II and ACE activity, and with a significant regression of cardiac hypertrophy. Increased mitogenesis of cultured vascular smooth muscle cells from the SHRSP was not altered by treatment with perindopril. CONCLUSIONS: ACE inhibition reduces vascular smooth muscle polyploidy in large conduit arteries. This type of vascular protection is mediated by the reduced Ang II and possibly by increased kinins level, rather than by the hypotensive effect alone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

The role of a phosphatidylcholine-specific phospholipase C in the production of diacylglycerol for nitric oxide synthesis in macrophages activated by IFN-gamma and LPS.

Murine macrophages activated by interferon (IFN)-gamma and bacterial lipopolysaccharide (LPS) produce large amounts of nitric oxide (NO), which is a critical mediator for a variety of biological functions. The expression of this inducible NO synthase (iNOS) involves a protein kinase C (PKC)-dependent pathway, but the mechanism for the PKC activation in this system is unclear. Through analysis of diacylglycerol (DAG) synthesis and choline metabolism in activated macrophages, direct evidence is provided that NO synthesis involves the activation of an unusual phosphatidylcholine-specific phospholipase C (PC-PLC) and not a phosphatidylinositol-specific phospholipase C (PI-PLC) or phospholipase D (PLD).

Amino Acid Oxidoreductases↗
PubMed1993

Altered lymphocyte populations in tumour invaded nodes of breast cancer patients.

Lymphocytes from matched pairs of tumour-invaded and tumour-free lymph nodes from 22 stage II breast cancer patients have been analysed for expression of phenotypic and activation markers by flow cytometry. Although the relative proportions of T and B lymphocytes were similar in the two nodes, significant differences in the distribution of T cell subsets were observed between nodes that were invaded and those that were not. The CD4/CD8 ratio was markedly depressed in tumour invaded nodes (P < 0.001). This was due to an increase in the number of CD8+ T cells (P < 0.001) and a decrease in the CD4+ T cell population (P = 0.008) in invaded nodes in comparison with tumour-free nodes. The percentage of CD8+ T cells expressing HLA DR (P = 0.023) and IL-2 receptors (Tac) (P = 0.029) was significantly higher in invaded nodes and, while CD4+ T cells expressing HLA DR (P = 0.036) were also in a higher proportion of Tac expressing CD4+ T cells failed to reach significance. Although invaded nodes in a few patients were found to have a higher percentage of IgG-expressing B cells, no significant differences were observed between the two groups of nodes. These results suggest that the presence of metastatic tumour cells in a lymph node is associated with specific alterations in the T cell population.

B-Lymphocytes↗
PubMed1992

Dual colour flow cytometry of p53 and c-erbB-2 expression related to DNA aneuploidy in primary and metastatic breast cancer.

DNA aneuploidy and p53 or c-erbB-2 expression were simultaneously measured in 29 breast tumours by two-colour flow cytometry. (i) The majority of tumours had some cells expressing either p53 (5-68%) or c-erbB-2 (1-56%). (ii) Expression of p53 and c-erbB-2 was observed mainly in the aneuploid population of mixed aneuploid and diploid tumours but there was no significant correlation with a specific DNA index. Aneuploid tumours contained higher percentages of c-erbB-2 positive cells (average 25%) than purely diploid tumours (average 15%) but this just failed to reach significance (P = 0.074). No relevant trends were noted for p53 expression. (iii) Significantly increased c-erbB-2 expression was observed in stage 2 tumours (26%) compared to stage 1 tumours (12%) (P = 0.001) with no trend evident for p53 expression. (iv) The metastatic tumour in the axillary node contained similar or slightly higher percentages of positive cells than the matched primary tumour.

Aneuploidy↗
PubMed1992

T cell receptor gamma/delta expression on lymphocyte populations of breast cancer patients.

The quantitative distribution and phenotype of gamma/delta lymphocytes in the peripheral blood (PBL), tumour draining lymph node (LNL) and tumour infiltrating lymphocytes (TIL) from breast carcinoma patients were determined by one- and two-colour flow cytometry. The TCR-gamma/delta + cells generally expressed the T cell lineage antigen CD3. The proportions of such cells were variable but generally small from all the three sources. Phenotypic analysis revealed that the CD8 marker was consistently and predominantly observed on gamma/delta + CD3+ cells in the tumour infiltrate, whereas CD4 expression, while generally low, was noted on a significant percentage (median 10%) of LNL gamma/delta + lymphocytes. In both PBL and LNL the predominant gamma/delta cell population was CD4-8-.

Antibodies, Monoclonal↗
PubMed1991

An assessment of the radiological module of NEONATE as an aid in interpreting chest X-ray findings by nonradiologists.

NEONATE is a prototype of an expert system for the Newborn Intensive Care Unit developed at the Primary Children's Medical Center in Salt Lake City, Utah. A pilot study was undertaken to see if the addition of radiological frames to the NEONATE software could aid attending Neonatologists to interpret chest X-ray films. A set of radiological frames was created from rules generated by a radiologist. The performance of these radiological frames was compared to the performance of other radiologists using the Kappa statistic to measure agreement. There is a good agreement between the computer's decisions and the radiologists' decisions. The radiological frames were also tested to see if they help physicians who are not trained in radiology. A system that compares the residents' interpretation and the computer's interpretation to a gold standard interpretation was developed. It shows that the computer helps the first and second year residents, but not the third year residents. This article suggests that NEONATE's interpretation of chest X-ray findings are close to the radiologists' interpretations. While NEONATE's radiological frames help novice physicians in reaching better chest X-ray interpretation, the current study suggests that they are not likely to help a Neonatologist.

Evaluation Studies as Topic↗
PubMed1990

"NEONATE"--an expert application for the "HELP" system: comparison of the computer's and the physician's problem list.

NEONATE is a prototype of an expert application for the HELP Hospital Information System. Its goal is to improve documentation in the Newborn Intensive Care Unit. The decision module of NEONATE is designed to produce an admission problem list. In this paper, the admission problem list that NEONATE generates was compared to the admission problem list of the current CETUS system for 30 patients. These were compared to a retrospectively constructed gold standard problem list. Of 101 problems in the gold standard list, 56 were on the current admission reports; 82 were found by NEONATE. NEONATE found 31 problems missed on the current admission reports; the current admission reports contained 5 problems missed by NEONATE. The current admission reports contained 9 false positives; whereas NEONATE's reports contained 27. Of the 27, 16 were caused by a single rule in NEONATE. We conclude that an expert system has great potential for improving the documentation of the patient problem list.

Expert Systems↗
PubMed1990

Post-mortem changes of neurotransmitter concentrations in the rat brain regions.

Using High Performance Liquid Chromatography coupled with electrochemical detection the post-mortem stability of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxy indole acetic acid (5-HIAA) were examined in the rat hypothalamus, amygdala, cerebral cortex, cerebellum and corpus striatum over an 8 hour time period. Changes in concentrations of the different neurotransmitters were less than it might be expected. The significant changes were: a. A fall in NA levels in the cerebral cortex by 4 hours and in the hypothalamus at 8 hours. b. A reduction in DA concentrations in the corpus striatum at 8 hours but a two fold rise of levels in the hypothalamus at 1 and 2 hours. c. A four-fold increase in 5-HT concentrations in the amygdala throughout the 8 hours studied. The results indicate that for comparative studies on post-mortem brain tissue correction factors should be employed to take into account differential changes in the concentrations of the various neurotransmitters.

Animals↗
PubMed1985

Heart rate and laying behavior in two strains of domestic chicken.

The heart rates of caged hens, from two strains of domestic chicken (Gallus gallus domesticus), during the 20 min before and after oviposition were studied. Heart rates were measured using subcutaneously implanted radiotelemetry devices. In one strain, heart rate was low and relatively constant before laying, increased sharply at the moment of laying, and then decreased gradually during the post-laying period. Hens from this strain exhibited sitting behavior before laying. In contrast, in the other strain, heart rates increased steadily during the pre-laying period, peaked sharply at the moment of laying, and then declined during the post-laying period. Hens from this strain exhibited restless pacing behavior before laying.

Animals↗