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Biomedical subjects

J D Pearson

Publications and source records attributed to J D Pearson.

At least 91 records · Page 5Linked to original sources
PubMed1995

Nitric oxide synthase activities in placental tissue from normotensive, pre-eclamptic and growth retarded pregnancies.

OBJECTIVE: To measure nitric oxide synthase activity in tissues from the placenta, placental bed and umbilical cord at delivery in normal and complicated pregnancies. DESIGN: A prospective blinded study. SETTING: The obstetric departments of three London teaching hospitals. SUBJECTS: Samples of whole placenta, dissected stem villous arteries, umbilical cord vessels and the placental bed of the uterus were collected at delivery and assayed for nitric oxide synthase activity. Samples of placenta were taken from ten normotensive, six pre-eclamptic and eight growth retarded pregnancies, and stem villous arteries from a further seven normotensive pregnancies. RESULTS: There was minimal placental bed nitric oxide synthase activity in each group. Placental villous homogenates from pregnancies complicated by pre-eclampsia and fetal growth retardation had significantly lower activities of nitric oxide synthase than those from normotensive women with appropriately grown babies. There were no significant differences in calcium dependent or calcium independent nitric oxide synthase activities in the umbilical vein and artery in the normal or in the pre-eclamptic groups. However, there was significantly more calcium dependent than calcium independent nitric oxide synthase in the umbilical veins in all groups. CONCLUSIONS: Local nitric oxide production in the placental bed of the uterus is unlikely to contribute substantially to the low resting vascular tone in the uteroplacental circulation. However, a relative deficiency of placental nitric oxide in pregnancies complicated by fetal growth retardation and pre-eclampsia may contribute to the development of the high impedance fetoplacental circulation found in these conditions.

Female↗
PubMed1995

Gender differences in a longitudinal study of age-associated hearing loss.

Current studies are inconclusive regarding specific patterns of gender differences in age-associated hearing loss. This paper presents results from the largest and longest longitudinal study reported to date of changes in pure-tone hearing thresholds in men and women screened for otological disorders and noise-induced hearing loss. Since 1965, the Baltimore Longitudinal Study of Aging has collected hearing thresholds from 500 to 8000 Hz using a pulsed-tone tracking procedure. Mixed-effects regression models were used to estimate longitudinal patterns of change in hearing thresholds in 681 men and 416 women with no evidence of otological disease, unilateral hearing loss, or noise-induced hearing loss. The results show (1) hearing sensitivity declines more than twice as fast in men as in women at most ages and frequencies, (2) longitudinal declines in hearing sensitivity are detectable at all frequencies among men by age 30, but the age of onset of decline is later in women at most frequencies and varies by frequency in women, (3) women have more sensitive hearing than men at frequencies above 1000 Hz but men have more sensitive hearing than women at lower frequencies, (4) learning effects bias cross-sectional and short-term longitudinal studies, and (5) hearing levels and longitudinal patterns of change are highly variable, even in this highly selected group. These longitudinal findings document gender differences in hearing levels and show that age-associated hearing loss occurs even in a group with relatively low-noise occupations and with no evidence of noise-induced hearing loss.

Adult↗
PubMed1995

Rapid decline in FEV1. A new risk factor for coronary heart disease mortality.

Coronary heart disease (CHD) is the leading cause of mortality in the United States. The present cohort study was conducted to determine whether rate of FEV1 loss independently predicts CHD mortality in apparently healthy men. White male Baltimore Longitudinal Study of Aging (BLSA) participants without CHD underwent clinical evaluation at 2-yr intervals; 883 had satisfactory pulmonary and lipid studies and returned for a least one visit. Cases were BLSA subjects without CHD on entry who died a "coronary death" (death from acute myocardial infarction, sudden death, or congestive heart failure in the presence of coronary artery disease). Forced expiratory maneuvers followed American Thoracic Society guidelines. Serum cholesterol, blood pressure, cigarette smoking, and body mass index were obtained from the BLSA database. There were 79 CHD deaths and 804 survivors during an average follow-up of 17.4 yr. After adjustment for age, initial FEV1% predicted, smoking status, hypertension, and cholesterol, a time-dependent proportional hazards model showed that cardiac mortality, but not all causes of mortality, generally increased with increasing quintile of FEV1 decline for the entire cohort (relative risk [RR] 2.92-5.13) and separately for the subset of never-smokers. Thus, excess CHD mortality follows a large decline in FEV1, independent of the initial FEV1% predicted, cigarette smoking, and other common CHD risk factors.

Adolescent↗
PubMed1994

Serum immunoglobulin G reactive with endothelial cells in inflammatory bowel disease.

Evidence of a humoral immune response to endothelium was sought in the sera of patients with inflammatory bowel disease. In an ELISA, IgG binding to human umbilical vein endothelial cells was found in 21% of Crohn's disease sera, 10% of ulcerative colitis sera, 6% of sera from patients with acute infective diarrhea, and 8% of normal control sera. The increased prevalence in Crohn's disease sera was significant (P < 0.05). IgG-endothelial cell binding was cell specific, was not Fc-mediated, and did not mediate complement-dependent cell lysis. It was not increased by pretreatment of cells with interleukin-1 or tumor necrosis factor. Endothelial cell binding was retained by IgG F(ab')2 fragments from one of three reactive Crohn's sera, but none of three nonreactive sera. The low prevalence of this interaction, even in patients with immunohistochemically confirmed vasculitis, makes it unlikely that Crohn's disease is determined by a humoral autoimmune response to endothelium.

Adult↗
PubMed1994

Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases.

OBJECTIVE: Serum prostate-specific antigen (PSA) values are most useful for prediction of disease recurrence after surgery. It is unknown whether a detectable PSA level after surgery indicates a local recurrence potentially benefiting from pelvic irradiation or distant metastases requiring hormonal treatment. METHODS: We analyzed postoperative rate of change of serum PSA levels as a predictor of local versus distant disease recurrence after radical prostatectomy. Between 1982 and 1991, 1,058 men underwent radical prostatectomy for localized prostate cancer and follow-up consisted of determining serum PSA levels and digital rectal examinations. Clinical follow-up of 542 men for four or more years and 78 men for eight or more years yielded ten-year actuarial disease recurrence rates of 4 percent for local recurrence, 8 percent for distant metastases, and 23 percent for an isolated elevation of serum PSA level only. Fifty-one patients with isolated elevations of PSA levels only were followed expectantly until they were diagnosed with either local or distant metastases. RESULTS: A linear mixed effects regression analysis was used to model these data. Using these models, the time to a serum PSA level of 0.5 ng/mL, the PSA level one year following surgery, pathologic stage, Gleason sum, and the rate of change of PSA (PSA velocity [PSAV]) were tested as predictors of local versus distant metastases. A combination of PSAV, pathologic stage, and Gleason grade best distinguished local from distant metastases. CONCLUSIONS: These data suggest that PSAV in men with an isolated elevation of PSA levels following radical prostatectomy might aid in clinical decision making.

Actuarial Analysis↗
PubMed1994

Natural history of changes in prostate specific antigen in early stage prostate cancer.

Until recently, the only information on the growth rate of prostate tumors has been derived from cross-sectional histological labeling studies, autopsy data and clinical studies of patients managed expectantly. However, serial measurements of prostate specific antigen (PSA) may now allow studies of the natural history of the earliest stages of prostate cancer. Frozen sera samples from the Baltimore Longitudinal Study of Aging have been used to compare the patterns of change in PSA levels in men with and without prostate cancer up to 25 years before the diagnosis of cancer. Men with no prostatic disease exhibited a slow linear increase in PSA levels, whereas benign prostatic hyperplasia cases showed a gradual acceleration in the rate of change in PSA. In contrast, cancer cases exhibited an early linear phase followed by an exponential phase of increase in PSA levels before diagnosis. On average, the exponential phase of PSA increases began 7 to 9 years before the tumors were detected clinically. Thus, there is a significant window of opportunity for early detection of prostate cancer. The changes in PSA observed in men with and without prostate cancer are consistent with available information on prostatic growth and the long natural history of prostate cancer. A better understanding of the various factors that affect serum PSA levels may allow more effective use of PSA measurements to detect early stage tumors and predict the biological potential of a tumor.

Adult↗
PubMed1994

Endothelial cell function and thrombosis.

Healthy endothelium is a metabolically active interface between the blood and extravascular tissues. Its intimal surface is anticoagulant and antithrombotic, and it secretes a variety of molecules involved in regulating platelet function and blood coagulation. The rapid interactions between platelets, their secreted components, or thrombin and endothelial cells at sites of vessel damage ensure the local secretion of mediators such as prostacyclin and nitric oxide that limit the intravascular growth of the haemostatic plug. There is considerable evidence that a decreased ability of endothelial cells to synthesize NO contributes to the pathogenesis of arterial disease. Local deficiency of PGI2 synthesis has also been implicated in the thrombotic problems in haemolytic uraemic syndrome. Endothelium is also the source of circulating von Willebrand factor, important for efficient platelet adhesion. Chronically elevated plasma levels of vWF in a series of diseases where there is vascular pathology apparently reflect endothelial cell damage or activation, and may contribute to the prothrombotic tendency they exhibit. They may be compounded by decreased levels of the surface anticoagulant thrombomodulin, if the increased concentrations of the soluble forms of thrombomodulin detected in the circulation under similar conditions are a reflection of loss from the endothelium. Further alterations of function in a procoagulant/prothrombotic direction take place when endothelial cells are exposed to certain cytokines or lipopolysaccharide. Tissue factor synthesis is induced, thrombomodulin expression is decreased, and there is enhanced sensitivity of vWF secretion. In addition, the balance of tissue-type plasminogen activator and plasminogen activator inhibitor type I secretion is changed in favour of the latter. These processes are each likely to contribute to the occurrence of disseminated intravascular coagulation which can accompany septic shock.

Animals↗
PubMed1994

Vessel wall interactions regulating thrombosis.

Endothelial cells are responsible for the secretion or surface expression of a wide variety of mediators involved in the control of thrombosis. These include von Willebrand factor, prostacyclin, nitric oxide, thrombomodulin, tissue-type plasminogen activator and its inhibitor, tissue factor and the tissue factor pathway inhibitor. The production of each of these can be modulated; in some cases very rapidly in response to external stimuli, in other cases more slowly. Thrombin is a key stimulus, which affects the production of almost all of these mediators. In addition, several cytokines and bacterial endotoxins shift the balance of endothelial mediator secretion from the basal anticoagulant profile towards a procoagulant profile.

Blood Coagulation↗
PubMed1994

Antiendothelial cell antibodies can be cytotoxic to endothelial cells without cytokine pre-stimulation and correlate with ELISA antibody measurement in Kawasaki disease.

To confirm the presence of antiendothelial cell antibodies (AECA) and study the clinical value of their measurement in Kawasaki disease (KD), sera from patients with KD were assessed for binding to human umbilical vein endothelial cells (HUVEC) using a cellular based ELISA, and for complement-mediated cytotoxicity using 111In-labelled HUVEC. In the ELISA assay, IgM AECA were detected in 16/22 sera, whereas IgG AECA were only present in one out of 19 sera. There was a significant difference in IgM AECA titres when comparing patients with controls. Eight out of 16 sera showed cytotoxicity against HUVEC, and this was significantly enhanced when HUVEC were pretreated with tumour necrosis factor (TNF). IgM AECA titres measured by ELISA were positively correlated with their cytotoxicity. The findings suggest that IgM class AECA in sera from patients with KD are detectable by ELISA method, and that some of these antibodies, 50% in this study, can mediate complement-dependent cytotoxicity against endothelial cells.

Adolescent↗
PubMed1994

Discrimination between citrulline and arginine transport in activated murine macrophages: inefficient synthesis of NO from recycling of citrulline to arginine.

1. The kinetics, specificity, pH- and Na(+)-dependency of L-citrulline transport were examined in unstimulated and lipopolysaccharide (LPS)-activated murine macrophage J774 cells. The dependency of nitric oxide production on extracellular arginine or citrulline was investigated in cells activated with LPS (1 microgram ml-1) for 24 h. 2. In unstimulated J774 cells, transport of citrulline was saturable (Kt = 0.16 mM and Vmax = 32 pmol micrograms-1 protein min-1), pH-insensitive and partially Na(+)-dependent. In contrast to arginine, transport of citrulline was unchanged in LPS-activated (1 microgram ml-1, 24 h) cells. 3. Kinetic inhibition experiments revealed that arginine was a relatively poor inhibitor of citrulline transport, whilst citrulline was a more potent inhibitor (Ki = 3.4 mM) of arginine transport but only in the presence of extracellular Na+. Neutral amino acids inhibited citrulline transport (Ki = 0.2-0.3 mM), but were poor inhibitors of arginine transport. 4. Activated J774 cells did not release nitrite in the absence of exogenous arginine. Addition of citrulline (0.01-10 mM), in the absence of exogenous arginine, could only partially restore the ability of cells to synthesize nitrite, which was abolished by 100 microM NG-nitro-L-arginine methyl ester or NG-iminoethyl-L-ornithine. 5. Intracellular metabolism of L-[14C]-citrulline to L-[14C]-arginine was detected in unstimulated J774 cells and was increased further in cells activated with LPS and interferon-gamma. 6. We conclude that J774 macrophage cells transport citrulline via a saturable but nonselective neutral carrier which is insensitive to induction by LPS. In contrast, transport of arginine via the cationic amino acid system y+ is induced in J774 cells activated with LPS.7. Our findings also confirm that citrulline can be recycled to arginine in activated J774 macrophage cells. Although this pathway provides a mechanism for enhanced arginine generation required for NO production under conditions of limited arginine availability, it cannot sustain maximal rates of NO synthesis.

Animals↗
PubMed1994

Endothelial polyamine uptake: selective stimulation by L-arginine deprivation or polyamine depletion.

Uptake of putrescine and spermidine by cultured porcine aortic endothelial cells was time dependent and linear for 60 min. Transport, against a 5- to 10-fold concentration gradient, demonstrated both saturable and non-saturable components. Apparent concentration giving one-half maximal transport (Kt) values for putrescine and spermidine were 9 and 0.6 microM, respectively. Transport was reduced at 0 degrees C, suggesting that the process is energy requiring; inhibition by N-ethylmaleimide or p-chloromercuribenzoate suggested a requirement for sulfydryl groups. Transport of putrescine, but not spermidine, was partially activated by Na+. Spermidine and spermine did not inhibit putrescine uptake, and putrescine and spermine did not inhibit spermidine uptake, suggesting the presence of a separate transporter for each polyamine. Pretreatment with DL-2-difluoromethy-lornithine increased the uptake of putrescine but not spermidine. The endothelial cell putrescine transporter is thus sensitive to polyamine depletion, suggesting that transport from the extracellular space may be an important source of polyamines. L-Ornithine or L-arginine were not inhibitory, indicating that polyamine and cationic amino acid transport is mediated by independent systems. The sensitivity of putrescine transport to L-arginine but not to L-ornithine deprivation suggests that intracellular levels of arginine rather than ornithine regulate polyamine metabolism and transport in these cells. Thus factors that affect arginine utilization may also influence polyamine metabolism.

Animals↗
PubMed1993

Effect of 5'-deoxy-5'-isobutylthioadenosine on formation and release of adenosine from neonatal and adult rat ventricular myocytes.

1. Studies in rat polymorphonuclear leucocytes have suggested that 5'-deoxy-5'-isobutylthioadenosine (IBTA), an inhibitor of the IMP-selective cytosolic 5'-nucleotidase, may be used to test its role in adenosine formation in intact cells. We investigated adenosine formation in neonatal and adult rat cardiomyocytes. 2. 2-Deoxyglucose (30 mM) with oligomycin (2 micrograms/ml) induced a 90-100% fall in ATP concentration in 10 min in neonatal and 60 min in adult heart cells. Adenosine accumulation was substantially increased, accounting for 13% of the fall in ATP concentration in neonatal cells and 56% in adult cells. 3. Anti-(rat liver ecto-5'-nucleotidase) serum did not inhibit adenosine accumulation. Furthermore, dipyridamole (10 microM), a nucleoside-transport blocker, inhibited by 80% the appearance of the newly formed adenosine in the medium, showing that adenosine is produced intracellularly by both adult and neonatal-rat myocytes in response to inhibition of oxidative metabolism. 4. IBTA (3 mM) inhibited by 80% the appearance of adenosine in the medium, but did not inhibit total adenosine accumulation by neonatal-rat myocytes and only modestly inhibited total adenosine accumulation by adult myocytes. 5. IBTA, like dipyridamole, inhibited incorporation of extracellular adenosine (10 microM) into neonatal and adult ventricular myocyte nucleotides by 60-70%. Transport of IBTA (100 microM) into the cells did not appear to be inhibited by dipyridamole (30 microM). 6. We conclude that IBTA acted primarily to inhibit adenosine release from myocytes. The small effect on adenosine formation rates implies that the IMP-selective cytosolic 5'-nucleotidase plays a minor role in this tissue.

5'-Nucleotidase↗
PubMed1993

Myeloperoxidase binds to vascular endothelial cells, is recognized by ANCA and can enhance complement dependent cytotoxicity.

Myeloperoxidase (MPO) and proteinase-3 (Pr-3) can bind to vascular endothelial cells (EC) and are available for recognition by autoantibodies present in P-ANCA or C-ANCA containing sera, respectively. The bound MPO also retains its enzymic functions and effectively interacts with hydrogen peroxide to mediate detachment of endothelial cells from their substratum. EC bound MPO-anti-MPO complexes can contribute to the complement-dependent EC injury demonstrated by some P-ANCA sera.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Arginine uptake and metabolism in cultured murine macrophages.

Transport of L-arginine and nitrite production were examined in the murine macrophage cell line J774. Lipopolysaccharide (LPS) induced a dose- and time-dependent stimulation of nitrite production which was further increased in the presence of interferon-gamma (IFN-gamma). Nitrite synthesis was dependent on extracellular arginine and inhibited in the presence of L-lysine. Treatment of cells with LPS and IFN-gamma caused a reduction in intracellular L-arginine concentration which was accompanied by increases in the levels of L-citrulline in both the cells and culture medium. 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 nitric oxide.

Animals↗
PubMed1993

Relationship between changes in prostate-specific antigen and prognosis of prostate cancer.

Changes in prostate-specific antigen (PSA), used to estimate PSA doubling times, may reflect prostate cancer growth. To determine if PSA doubling time prior to diagnosis predicted outcome in men with prostate cancer, we evaluated 16 men with prostate cancer who had (1) serial PSA determinations (mean 9.9) on frozen sera from twelve to twenty-six years before diagnosis; (2) at least five years of follow-up in those subjects without metastatic disease (range 5.5-12.3 years); and (3) archival material from diagnosis available for pathologic evaluation. PSA doubling time prior to diagnosis was investigated with relation to patient outcome (regardless of treatment) and the known predictors of tumor behavior, Gleason score and nuclear morphometry. In 5 of 16 men who had evidence of metastatic disease at diagnosis, metastasis developed or they died of prostate cancer during follow-up (group 1). Eleven of 16 had no evidence of metastatic disease during follow-up (group 2). Both Gleason score and variance of nuclear roundness (VNR) were significantly greater for group 1 (p < 0.05). There was no significant difference between the two groups with respect to PSA doubling time, and the PSA level at diagnosis did not correlate with the development of metastatic disease. One of 5 men with no PSA level greater than 4.0 ng/mL prior to diagnosis died within two years of diagnosis. These data suggest that (1) a normal PSA at diagnosis does not exclude an aggressive cancer, and (2) changes in PSA that occur before the diagnosis of prostate cancer may not always predict outcome. Since PSA level is influenced by tumor grade, an inability to correct PSA for tumor grade could have influenced the results.

Aged↗