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Biomedical subjects

J D Pearson

Publications and source records attributed to J D Pearson.

At least 109 records · Page 6Linked to original sources
PubMed1993

The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer.

Clinical stage, Gleason score and serum prostate specific antigen (PSA) levels are used separately to predict pathological stage in patients with localized prostate cancer. Because the degree of tumor differentiation has a profound influence on the expression of serum PSA, serum PSA levels alone do not reflect tumor burden accurately. To overcome this obstacle we tested these 3 variables alone and in combinations as predictors of final pathological stage in 703 men with clinically localized prostate cancer at our institution. All patients were assigned a clinical stage by 1 urologist. The Gleason score was determined from preoperative needle biopsy and serum PSA levels were measured on an ambulatory basis. Final pathological stage was determined to be either organ confined, established capsular penetration, seminal vesicle involvement or lymph node involvement. Logistic regression analysis with the likelihood ratio chi-square test determined that serum PSA, Gleason score and clinical stage all predicted final pathological stage well. The results were improved with combinations of the 3 variables (serum PSA, Gleason score and clinical stage) and the combination provided the best separation. From these analyses probability plots and nomograms have been constructed to assist urologists in the preoperative prediction of final pathological stage for patients with clinically localized prostate cancer.

Biomarkers, Tumor↗
PubMed1993

The control of production and release of haemostatic factors in the endothelial cell.

Endothelial cell products contribute to many aspects of the regulation of haemostasis. They include potent inhibitors of platelet aggregation (prostacyclin and nitric oxide) rapidly released in response to agonists such as thrombin. Similar agonists also induce the formation of platelet-activating factor by endothelium. Endothelial cell surface ectonucleotidase enzymes control the catabolism of platelet-active adenine nucleotides. The main source of the circulating coagulant cofactor von Willebrand factor is the endothelium, where it is stored in granules for agonist-triggered exocytosis and also secreted constitutively. Surface anticoagulant activities are due to the presence of antithrombin and thrombomodulin. Endothelial cells also secrete plasminogen activator and its inhibitor. Many of these reactions are significantly modulated by exposure of endothelium to cytokines or bacterial endotoxin, the most striking example being the new synthesis and surface expression of the procoagulant tissue factor (thromboplastin).

Adenine Nucleotides↗
PubMed1993

Propofol stimulates nitric oxide release from cultured porcine aortic endothelial cells.

Propofol, an intravenous anaesthetic agent, causes marked vasodilatation in vivo. In the present study the effects of propofol on the release of nitric oxide (NO) from vascular endothelial cells was determined in vitro. Application of propofol to co-cultures of porcine aortic endothelial and smooth muscle cells resulted in a rapid increase in cyclic GMP formation. This increase was significantly inhibited following pretreatment of the cells with either NG-nitro-L-arginine (L-NOARG) or in the presence of haemoglobin. When applied to smooth muscle cells alone, propofol did not result in an increase in cyclic GMP levels. These results demonstrate that propofol stimulates the production and release of NO from cultured endothelial cells and suggest that the vasodilatation and hypotension observed when propofol is given in vivo may be due to NO release.

Animals↗
PubMed1993

Selective inhibition by dexamethasone of induction of NO synthase, but not of induction of L-arginine transport, in activated murine macrophage J774 cells.

1. Effects of dexamethasone on induction of nitric oxide (NO) synthase and L-arginine transport by lipopolysaccharide (LPS) were examined in a murine cultured macrophage cell line J774. Metabolism of L-arginine to L-citrulline and subsequent changes in intracellular amino acids pools were correlated with changes in nitrite production. 2. Despite a high intracellular concentration of arginine in activated J774 cells, LPS (1 microgram ml-1, 8 h) induced a 2.4 fold increase in arginine transport. Treatment of cells with cycloheximide (1 microgram ml-1) inhibited the time-dependent (1-8 h) induction of NO synthase and arginine transport mediated by LPS. 3. Induction of NO synthase by LPS (1 microgram ml-1, 24 h) alone was accompanied by a marked increase in arginine utilisation leading to decreased intracellular arginine levels and elevated intracellular and extracellular L-citrulline levels. These changes were further enhanced in the presence of interferon-gamma (IFN-gamma, 100 units ml-1, 24 h). 4. Dexamethasone (1 microM) abolished the increases in both nitrite and citrulline production induced by LPS alone but only partially reversed the combined effects of LPS and IFN-gamma. In contrast, treatment of cells with dexamethasone (10 microM) had no effect on the LPS-mediated induction of arginine transport or the decrease in intracellular arginine concentration. 5. We conclude that induction of arginine transporter activity in LPS-stimulated J774 cells involves de novo synthesis of carrier proteins, which increases transport of exogenous arginine during enhanced NO production. Moreover, the intracellular signalling pathways mediating induction of arginine transport and of NO synthase by LPS in activated macrophages diverge, since only the latter is sensitive to dexamethasone.

Amino Acid Oxidoreductases↗
PubMed1993

PSA velocity for the diagnosis of early prostate cancer. A new concept.

An evaluation of longitudinal changes in PSA in men with and without prostate disease revealed that with age, the development of prostate disease is the most important factor influencing changes in PSA. Furthermore, the PSA changes with age are significantly different in men with and without prostate disease. The PSA velocity is greater in men with prostate cancer than in men with BPH and greater in men with prostate cancer and BPH than in men without any prostate disease. Thus, evaluation of PSA changes may help distinguish between men with prostate cancer and those without the disease. This idea will need to be confirmed prospectively. Finally, estimation of PSA doubling time from changes in PSA suggests that changes reflect prostatic growth. Therefore, PSA velocity could be of benefit in identifying men with prostate cancer that is destined to progress.

Adult↗
PubMed1992

The roles of protein kinase C and intracellular Ca2+ in the secretion of von Willebrand factor from human vascular endothelial cells.

Secretion of von Willebrand factor (vWf) glycoprotein from storage granules in human umbilical-vein endothelial cells was studied in vitro. Either elevation of intracellular Ca2+ concentration ([Ca2+]i) with a Ca2+ ionophore or activation of protein kinase (PK) C by phorbol 12-myristate 13-acetate caused vWf secretion, and together the agents acted synergistically. However, when vWf release was stimulated by receptor-mediated agonists, selective inhibition of PKC had no effect on histamine-induced secretion and significantly elevated thrombin-induced secretion. Furthermore, ATP, which efficiently elevates [Ca2+]i in these cells, was a very poor effector of vWf release. We conclude that elevation of [Ca2+]i by physiological agonists is necessary for vWf release, but other signalling mechanisms, as yet uncharacterized, but not due to PKC activation, are required for full induction of the secretory pathway.

Adenosine Triphosphate↗
PubMed1992

Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease.

Prostate growth curves were estimated from serial prostate-specific antigen (PSA) measurements on frozen sera in three groups of men: (a) 16 men with no prostatic disease by urological history and examination; (b) 20 men with a histological diagnosis of benign prostatic hyperplasia (BPH) who had undergone simple prostatectomy; and (c) 18 men with a histological diagnosis of prostate cancer. The median number of repeated PSA measurements over an 8- to 26-yr period prior to histological diagnosis or exclusion of prostate disease was eight and 11 for noncancer and cancer subjects, respectively. Predicted rates of change in PSA (PSA velocity) were linear and curvilinear for control and BPH subjects, respectively. Subjects with cancer demonstrated both a linear and an exponential phase of PSA velocity. Based on time to double PSA, we estimated the epithelial doubling time for men without prostate disease to range from 54 +/- 13 yr at age 40 to 84 +/- 13 yr at age 70. For men with BPH, doubling times ranged from 2 +/- 13 yr at age 40 to 17 +/- 5 yr at age 85. Subjects with local/regional and advanced/metastatic cancer had similar PSA doubling times of 2.4 +/- 0.6 yr and 1.8 +/- 0.2 yr, respectively. These data are consistent with what is known about prostatic growth with age in men without prostate disease and BPH, and the kinetics of prostate cancer growth. Estimates of prostatic growth rate from changes in PSA may be useful clinically in management of men with prostate disease.

Aged↗
PubMed1992

L-arginine transport is increased in macrophages generating nitric oxide.

Transport of L-arginine and nitrite production were examined in the murine macrophage cell line J774. Bacterial lipopolysaccharide (LPS) induced a dose- and time-dependent stimulation of nitrite production, which was further increased in the presence of interferon-gamma. Nitrite synthesis was absolutely dependent on extracellular L-arginine and inhibited in the presence of L-lysine or L-ornithine. In unactivated J774 cells L-arginine transport was saturable, with an apparent Km of 0.14 +/- 0.04 mM and Vmax. of 15 +/- 2 nmol/h per 10(6) cells. LPS (1 microgram/ml) induced a time-dependent stimulation of L-arginine transport, and after 24 h the Vmax. increased to 34 +/- 2 nmol/h per 10(6) cells. These findings indicate that activation of J774 cells with LPS produces an increase in both L-arginine transport and nitrite synthesis. The elevated rate of L-arginine transport in activated J774 cells may provide a mechanism for sustained substrate supply during enhanced utilization of L-arginine for the generation of NO.

Animals↗
PubMed1992

Aprotinin does not inhibit the release of PGI2 or vWF from cultured human endothelial cells.

The release of prostacyclin (PGI2) and von Willebrand factor (vWF) from human umbilical vein endothelial cells (HUVEC) was examined to determine if aprotinin had any effects on these endothelial cell reactions. These end-points were chosen to indicate if this serine protease inhibitor caused alterations in the control of haemostatic function by endothelium, in the light of the improvement in haemostasis seen in patients given aprotinin therapy at the time of open heart surgery. Stimuli used to promote secretion of prostacyclin and vWF were human alpha-thrombin, histamine, protamine sulphate, poly-L-lysine and phorbol myristate acetate. Aprotinin (30 microMs) had no significant effect on the basal or stimulated release of PGI2 or vWF from HUVEC.

Aprotinin↗
PubMed1992

Nitric oxide is not involved in the initiation of insulin secretion from rat islets of Langerhans.

The involvement of nitric oxide as an intracellular messenger in the control of insulin secretion from pancreatic Beta cells was studied in rat islets of Langerhans by measuring: (i) nitric oxide generation in response to physiological insulin secretagogues; (ii) the effects of inhibitors of nitric oxide synthesis on insulin secretory responses to physiological secretagogues, and on insulin synthesis; (iii) changes in islet cyclic guanosine monophosphate in response to secretagogues; (iv) the effects of exogenous cyclic guanosine monophosphate and dibutyryl cyclic guanosine monophosphate on insulin secretion from electrically permeabilised islets and from intact, respectively. These studies produced no evidence that nitric oxide generation is required for the initiation of insulin secretion by common secretagogues. However, the results of our experiments suggest that the generation of nitric oxide may be involved in long-term, glucose-dependent increases in cyclic guanosine monophosphate content of islet cells, although the physiological relevance of these changes requires further investigation.

Amino Acid Oxidoreductases↗
PubMed1992

A longitudinal approach to modeling outcomes in a nursing home study.

Recent developments in longitudinal statistical methodology have improved our ability to model dynamic processes such as adaptation to nursing homes. Longitudinal observations provide information on individual patterns of change and factors affecting them. However, longitudinal analyses are often complicated by unequal periods of observation and individual variability in patterns of change. This paper demonstrates the use of a linear mixed-effects model to study adaptation in a longitudinal nursing home study with different numbers of repeated measurements for each individual because of discharges, transfers, and mortality.

Adaptation, Psychological↗
PubMed1992

Aprotinin inhibits platelet adhesion to endothelial cells.

Studies were conducted to assess the effect of the serine protease inhibitor aprotinin on platelet adherence to both thrombin-stimulated and unstimulated human umbilical vein endothelial cells. Aprotinin treatment reduced significantly the adherence of platelets to endothelium pretreated or not with thrombin. In addition, aprotinin similarly reduced the adherence of platelets to plastic or collagen-coated tissue culture wells suggesting that the main site of action of the drug in this system is on the platelets. The role of endothelium-derived relaxing factor (EDRF; nitric oxide) in these platelet-endothelium reactions was investigated by prior incubation of both platelets and endothelial cells with NG-monomethyl-L-arginine (L-NMMA) which prevents the production of nitric oxide. The results demonstrated that nitric oxide was a significant inhibitor of the thrombin-induced platelet adherence in this assay system. Treatment with aprotinin in the presence or absence of L-NMMA reduced adherence of platelets to equivalent levels suggesting that aprotinin acts directly on the platelets via a mechanism that is EDRF-independent, to inhibit adherence.

Aprotinin↗
PubMed1992

Identification of inhibitors of nitric oxide synthase that do not interact with the endothelial cell L-arginine transporter.

The effects of inhibitors of nitric oxide (NO) synthase and other cationic amino acids on unidirectional L-arginine transport were studied in porcine aortic endothelial cells cultured in microwell plates or perfused in microcarrier columns. L-Homoarginine, L-lysine and L-ornithine inhibited transport of L-arginine. The NO synthase inhibitors NG-monomethyl-L-arginine and NG-iminoethyl-L-ornithine also reduced L-arginine uptake, whereas NG-nitro-L-arginine and its methyl-ester had no inhibitory effect. The ability to modulate selectively endothelial cell L-arginine transport or NO synthase activity will allow further characterization of the arginine transporter and its role in regulating NO biosynthesis.

Amino Acid Oxidoreductases↗
PubMed1992

Regulation of extracellular adenosine production by ectonucleotidases of adult rat ventricular myocytes.

We have investigated the kinetic properties of the extracellular reaction sequence ATP----ADP----AMP----adenosine catalyzed by ectonucleotidases at the surface of adult rat cardiac myocytes. Analysis of progress of reaction curves indicates that depletion of substrate at cell surfaces dominates the regulation of the rate of hydrolysis of ATP or of ADP when it is the initial substrate. Preferential delivery of intermediate products to be substrates at cell surfaces makes a significant contribution to the regulation of adenosine production from ATP or ADP. Preferential delivery has more impact on the delivery of ADP from adenosinetriphosphatase (ATPase) to adenosinediphosphatase (ADPase) than on delivery of AMP from ADPase to 5'-nucleotidase. At high initial ATP concentrations, feed-forward inhibition of AMP hydrolysis also modulates the rate of adenosine production. Taken together, the properties of the ectonucleotidases on the myocyte provide a milieu at the cell surface that tends to be poor in nucleotides, especially ATP and ADP (P2 purinoceptor agonists), and rich in adenosine (a P1 purinoceptor agonist) during periods of supply of extracellular nucleotides.

5'-Nucleotidase↗
PubMed1992

Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells.

The ability of vasculitis-associated anti-neutrophil cytoplasm antibodies (ANCA) to activate neutrophils and mediate release of radiolabel from 111Indium-labeled cultured human umbilical vein endothelial cells (HUVEC) was determined as a measure of the potential cytotoxicity of ANCA-activated neutrophils against vascular endothelium. Priming of neutrophils with low doses of phorbol 12-myristate 13-acetate (PMA) (1 ng/ml) and ionomycin (0.1 mumol/1) was required, together with pretreatment of endothelial cells with BCNU (1,3-bis-[2-chloroethyl]-1-nitrosourea; 0.26 mmol/l). Under these conditions and using a 4-hour serum-free assay system, mouse monoclonal antibodies (MAb) to the target autoantigens proteinase-3 (Pr-3) and myeloperoxidase (MPO) mediated enhanced release of 111Indium from HUVEC compared with control MAb. Human IgG Fab2 C-ANCA (recognizing Pr-3) and P-ANCA (recognizing MPO) did likewise. Preactivation of HUVEC with TNF (50 U/ml, 4 hr) enhanced the release of 111Indium from HUVEC generated by neutrophils activated with anti-Pr-3 and anti-MPO MAb. These data support the suggestion that activation of neutrophils by ANCA within the vascular lumen may contribute to endothelial cell injury.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1992

Measurement of body surface topography using an automated imaging system.

An automatic computer imaging system for recording body surface topography has been developed on a microcomputer-based image processing system. The computer processes fringe patterns generated on the surface of the trunk and reconstructs the complete 3-dimensional form of the surface. From the topographic reconstruction, clinical parameters of scoliotic deformity such as Angle of Trunk Inclination are calculated at a number of levels from the upper thoracic to the sacral region. These multiple level measurements illustrate the change in deformity over the trunk and correspond to measurements obtained using conventional tactile devices on patients.

Biometry↗
PubMed1991

Bradykinin and ATP stimulate L-arginine uptake and nitric oxide release in vascular endothelial cells.

The effects of bradykinin and ATP on L-arginine transport and nitric oxide (NO) production were studied in porcine aortic endothelial cells cultured and perfused on microcarriers and deprived of L-arginine for 24 h. Stimulation of cells with bradykinin (100 nM) or ATP (100 microM) resulted in a rapid increase in L-arginine uptake and NO release. In the presence of nitro-L-arginine (100 microM), an inhibitor of NO synthase, the stimulatory effect of bradykinin on L-arginine uptake was partially inhibited while NO release was completely abolished. Nitro-L-arginine alone was not an inhibitor of basal L-arginine transport, suggesting that its inhibitory action was not directly on the L-arginine transporter but a result of the inhibition of NO generation. These data indicate that during agonist-stimulated NO production there is a concomitant increase in the transport of L-arginine into endothelial cells providing a mechanism for the continual generation of NO.

Adenosine Triphosphate↗