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Biomedical subjects

A Mazar

Publications and source records attributed to A Mazar.

At least 37 records · Page 2Linked to original sources
PubMed1993

Dental extractions in patients with bleeding disorders. The use of fibrin glue.

Eighty patients with various bleeding disorders underwent 135 extractions without preventive replacement hematologic therapy. The local hemostatic control involved the use of fibrin glue Beriplast. Secondary bleeding occurred in 9 of 12 patients with severe hemophilia when the concentration of the aprotinin in the fibrin glue was 1,000 KIU/ml. When it was increased to 10,000 KIU/ml and swish and swallow rinses of tranexamic acid before and after the dental extractions were added, only 3 of 25 hemophilia patients suffered from secondary bleeding. Local use of fibrin glue is a safe and cost-effective tool to treat patients with severe bleeding disorders. None of the 43 patients with coagulopathies other than severe hemophilia suffered bleeding after extractions.

Adolescent↗
PubMed1992

Expression of urokinase and its receptor in invasive and non-invasive prostate cancer cell lines.

We previously reported that extracellular matrix invasion by the prostate cancer cell lines, PC-3 and DU-145 was contingent on endogenous urokinase being bound to a specific cell surface receptor. The present study was undertaken to characterize the expression of both urokinase and its receptor in the non-invasive LNCaP and the invasive PC-3 and DU-145 prostate cells. Northern blotting indicated that the invasive PC-3 cells, which secreted 10 times more urokinase (680 ng/ml per 10(6) cells per 48 h) than DU-145 cells (63 ng/ml per 10(6) cells per 48 h), had the most abundant transcript for the plasminogen activator. This, at least, partly reflected a 3 fold amplification of the urokinase gene in the PC-3 cells. In contrast, urokinase-specific transcript could not be detected in the non-invasive LNCaP cells previously characterized as being negative for urokinase protein. Southern blotting indicated that this was not a consequence of deletion of the urokinase gene. Crosslinking of radiolabelled aminoterminal fragment of urokinase to the cell surface indicated the presence of a 51 kDa receptor in extracts of the invasive PC-3 and DU-145 cells but not in extracts of the non-invasive LNCaP cells. The amount of binding protein correlated well with binding capacities calculated by Scatchard analysis. In contrast, the steady state level of urokinase receptor transcript was a poor predictor of receptor display. PC-3 cells, which were equipped with 25,000 receptors per cell had 2.5 fold more steady state transcript than DU-145 cells which displayed 93,000 binding sites per cell.

Blotting, Northern↗
PubMed1992

Decreased urokinase receptor expression by overexpression of the plasminogen activator in a colon cancer cell line.

There is now ample evidence that the proteolytic action of urokinase (UK) is potentiated by a specific cell surface receptor. The present study was undertaken to determine the role of UK as a modulator of its binding site. GEO colonic cells, which secrete low levels of UK (approximately 2.5 ng/ml per 72 h per 10(6) cells) and display approx. 10(4) receptors per cell, the majority of which are vacant, were transfected with an exogenous UK gene driven by the RSV long terminal repeat (LTR) promoter (pRSVUK). Several UK-overexpressing pRSVUK clones were identified by an e.l.i.s.a., Northern blotting and Southern blotting, and analysed for receptor numbers after an acid pretreatment which dissociates receptor-bound UK. pRSVUK GEO clones, expressing high levels of UK, consistently bound 50-75% less radioactive di-isopropylfluorophosphate (DFP)-UK than clones harbouring the selectable marker gene neo only or control GEO cells. Cross-linking experiments with a radioactive N-terminal fragment of UK which binds to the receptor showed a decreased amount of a binding protein of approx. 51 kDa in representative pRSVUK-transfected cells. Saturation and Scatchard analysis indicated that this reduction in radioligand binding reflected a 40-70% decrease in the number of UK receptors, rather than a change in the dissociation constant. The reduction in receptor display could be accounted for by a decrease in the amount of steady-state mRNA encoding the receptor. Radioactive DFP-UK binding to pRSVUK GEO clones, which display two-thirds less receptors than their neo counterparts, could be restored to control levels (untreated cells harbouring neo) by cultivating them in the presence of an antibody which inhibits the interaction of UK with its receptor. These data suggest that for one colonic cell line at least, UK reduces the expression of its own binding site via an autocrine stimulation of its cell surface receptor.

Blotting, Northern↗
PubMed1992

Characterization of urokinase receptor expression by human placental trophoblasts.

The processes of implantation and placentation are both dependent on the invasion and remodeling of the uterine endometrium and vasculature by trophoblasts. Because the secretion and autocrine binding of urokinase (uPA) appears to be a common mechanism used by cells to facilitate plasmin-dependent tissue invasion, we measured the production of uPA and expression of uPA receptors by trophoblasts. Prourokinase bound specifically, reversibly, and with high affinity to cultured trophoblasts, via the uPA epidermal growth factor-like domain. Trophoblasts derived from two first-trimester placentae bound more prourokinase than cells isolated from term placentae. Furthermore, in vitro differentiation of cultured cytotrophoblasts into syncytiotrophoblasts was associated with diminished expression of urokinase receptors and a parallel decrease in the cellular content of uPA receptor mRNA. Trophoblasts also secreted prourokinase and plasminogen activator inhibitors types 1 and 2 (PAI-1 and PAI-2). Although prourokinase was secreted in amounts sufficient to endogenously saturate trophoblast uPA receptors, trophoblasts secreted greater amounts of PAI-1 and PAI-2 than uPA, and no net plasminogen activator activity was detected in trophoblast conditioned medium. In contrast, plasminogen added directly to cultured trophoblasts was readily converted to plasmin. Although the invasion and remodeling of uterine tissues by trophoblasts is a complex process dependent on several proteases of varying specificity, our findings suggest that the expression and modulation of urokinase receptors on the trophoblast cell surface may play an important role in this process.

Cells, Cultured↗
PubMed1992

Domain structure and interactions of recombinant urokinase-type plasminogen activator.

Urokinase-type plasminogen activator (uPA) is a mosaic glycoprotein composed of an epidermal growth factor-like (EGF), a kringle and a serine protease (SP) module. It exists in single and two-chain forms designated HMW pro-uPA and HMW uPA, respectively. A low molecular weight form, LMW uPA, lacks the EGF and kringle modules and is composed of the SP module alone. Recombinant-expressed proteins representing both HMW forms exhibit four reversible unfolding transitions that are resolved by deconvolution of melting curves obtained by differential scanning calorimetry at pH 4.5; no differences in the melting properties of the single and two-chain forms were found. The proteolytic fragment Ser1-Lys135 (EGF-kringle) exhibits two transitions, while the isolated EGF and kringle modules each exhibit a single two-state transition. Thus, both of these modules retain an independently folded compact structure when isolated. The isolated SP module (LMW uPA) exhibits two closely spaced transitions at low pH indicating the melting of two domains of similar stability. Fluorescence-detected melting curves of LMW uPA reveal increasing cooperativity with increasing pH, suggesting an increase in the interaction between the two SP domains. Treatment of both HMW and LMW uPA with the tripeptide inhibitor Glu-Gly-Arg-chloromethylketone dramatically increased the stability of both domains of the SP module which now melt together in a single two-state transition, even at low pH, with no effect on the EGF and kringle modules. From these data one concludes that UK consists of four independently folded domains. Two are formed by the EGF and kringle modules which do not interact with each other or with the SP module. The SP module contains two domains that are independent at low pH but exhibit a tendency to merge into a single cooperative unit at neutral pH or after treatment with the tripeptide inhibitor.

Amino Acid Chloromethyl Ketones↗
PubMed1991

Involvement of urokinase and its receptor in the invasiveness of human prostatic carcinoma cell lines.

We have investigated the role of urokinase (UK) and its cell-surface receptor in determining the invasiveness of prostate cancer cells. Three human cell lines, DU-145, PC-3 and LNCaP, that differ in androgen-responsiveness and growth characteristics, were tested. Analysis of the conditioned medium by an enzyme-linked immunosorbent assay showed secretion of UK by DU-145 (63 ng/mL/10(6) cells/48 hr) and PC-3 (682 ng/mL/10(6) cells/48 hr), but absence of secretion by LNCaP cells. Western blot analysis and enzyme activity assay of the conditioned medium confirmed these results. Scatchard analysis of radioligand binding with acid pretreated cells showed the presence of a single population of high affinity UK receptors on DU-145 cells (93,000 sites/cell, Kd = 0.9 nM) and PC-3 cells (25,000 sites/cell, Kd = 1.0 nM) but not on LNCaP cells. DU-145 and PC-3 cells were found to be highly invasive in in vitro invasion assays: 4.5 +/- 0.5% and 6.5 +/- 0.5%, respectively, of total tumor cells (approximately 2 x 10(5)) had penetrated reconstituted basement membrane (Matrigel) in a 72 hr incubation in serum-free growth medium. Under similar conditions, less than 0.25% LNCaP cells invaded Matrigel. The data indicate that androgen unresponsive, aggressive prostate tumor cells of high metastatic potential, DU-145 and PC-3, secrete UK and display cell-surface UK receptors, fully charged with the protease. Conversely, relatively indolent LNCaP cells of low metastatic potential do not secrete UK nor do they possess its binding sites. UK receptor antagonists, UK 12-32 and UK 6-135, which compete with labeled UK for binding to prostatic cells but do not inhibit cellular proliferation or UK secretion, markedly reduced DU-145 and PC-3 cell invasion (80-85% inhibition), thereby suggesting an important role of receptor-bound UK in prostate tumor cell invasion.

Basement Membrane↗
PubMed1990

An amino-terminal fragment of urokinase isolated from a prostate cancer cell line (PC-3) is mitogenic for osteoblast-like cells.

A peptide mitogen for cultured osteoblast-like cells was purified from serum-free conditioned culture medium of a human prostatic cancer cell line, PC-3. Based on amino acid sequencing and estimated molecular weight, this peptide was identified as an NH2-terminal fragment of urokinase-type plasminogen activator (uPA). Recombinant high molecular weight (HMW) uPA and the NH2-terminal growth factor domain (GFD) of uPA, but not low molecular weight (LMW) uPA (lacking the NH2-terminal region) stimulated [3H] thymidine incorporation and proliferation in osteoblast-like cells, and specific, competitive binding sites for HMW, but not LMW, uPA were demonstrable. These studies demonstrate the production of a mitogenic NH2-terminal fragment of uPA by a human prostatic cancer cell line which may be of importance in the pathogenesis of osteoblastic metastases.

Adenocarcinoma↗
PubMed1990

Sarcoidosis with oral involvement.

A case of sarcoidosis with bilateral hilar lymphadenopathy and multiple submucosal papular oral mucosa lesions is presented. The clinical signs and symptoms described in this case are not uncommon, and their distinguishing features may expedite accurate diagnosis. Early incisional biopsy of the oral mucosa appears useful for histopathologic proof of the diagnosis.

Acute Disease↗
PubMed1989

Increased theophylline clearance in asthmatic patients due to terbutaline.

The pharmacokinetic mechanism of the theophylline-terbutaline interaction has been studied. Sustained release theophylline 200-400 mg b.d. was given with placebo or terbutaline 2.5 mg t.d.s. to six adult asthmatic patients. Terbutaline decreased the serum trough theophylline levels from 8.1 to 7.3 micrograms/ml, improved daily the clinical score from 1.51 to 1.26 and increased the peak expiratory flow rate from 316 to 370 l/min. In a single dose study following the chronic therapy, it was shown that there was no change in the peak theophylline concentration or in the timing of the peak, but the t1/2 was reduced from 9.0 to 7.5 h, and the systemic clearance was increased from 20.2 to 24.8 ml.h-1.kg-1. Thus, terbutaline reduced the serum theophylline concentration by increasing its systemic clearance.

Adult↗
PubMed1986

Effect of nifedipine and theophylline in asthma.

The effect of nifedipine, 10 mg po q.i.d. for 2 weeks, was studied in a randomized, double-blind, crossover trial in nine patients with asthma receiving theophylline. Nifedipine did not significantly affect the mean (+/- SD) morning peak expiratory flow rate (PEFR; 336 +/- 130 L/min for drug vs. 349 +/- 92 L/min for placebo), evening PEFR (393 +/- 69 L/min for drug vs. 367 +/- 66 L/min for placebo), symptom score (27.4% +/- 22.9% for drug vs. 33.8% +/- 26.4% for placebo), or the number of albuterol inhalations per day (5.8 +/- 3.5 for drug vs. 6.2 +/- 4.1 for placebo). Furthermore, there was no change in PEFR 30, 60, or 120 minutes after nifedipine dosing. Nifedipine did not significantly affect the steady-state serum theophylline trough levels (9.1 +/- 2.2 mg/ml for drug vs. 10.2 +/- 1.9 micrograms/ml for placebo) or the theophylline pharmacokinetic parameters, such as the elimination t1/2, peak serum concentration, time to peak, and AUC(0-24). We conclude that nifedipine has little, if any, effect on the clinical status, PEFR, or theophylline serum levels in patients with asthma who receive theophylline.

Adult↗
PubMed1986

Effect of oral colchicine on T cell subsets, monocytes and concanavalin A-induced suppressor cell function in asthmatic patients.

Asthmatic patients have a deficiency of concanavalin A-(Con A) induced suppressor cell function. We tested whether oral colchicine 0.5 mg twice daily for 7 days could correct this immunoregulatory abnormality. Peripheral blood mononuclear cells were incubated with Con A and then suppression of proliferation was measured by coculture of these cells with healthy volunteers' mononuclear cells and phytohaemagglutinin. Sixteen asthmatic patients had significantly (P less than 0.002) decreased Con A-induced suppressor cell function (17.0 +/- 17.2%, mean +/- s.d.) as compared to 13 healthy volunteers (37.9 +/- 14.9%). Oral colchicine significantly (P less than 0.05) increased, though only partially corrected, these 16 asthmatic patients' Con A-induced suppressor cell function (28.1 +/- 14.3%). Asthmatic patients had an increased number of monocytes (691 +/- 289 vs 388 +/- 271/mm3 for normals, P less than 0.01) and a normal number of lymphocytes, Leu 4+ total T cells, Leu 3+ helper/inducer T cells, and Leu 2+ suppressor/cytotoxic T cells as well as a normal Leu 3/Leu 2 ratio. Oral colchicine significantly (P less than 0.005) decreased the number of monocytes (451 +/- 255/mm3) without significantly affecting the number of lymphocytes, Leu 4+, Leu 3+, or Leu 2+ T cells, or the Leu 3/Leu 2 ratio. These results are consistent with the hypothesis that the deficiency of Con A-induced suppressor cell function in asthmatic patients may be due, in part, to an increased number and/or abnormal activity of monocytes. If so, then oral colchicine may have partially corrected the deficiency of Con A-induced suppressor cell function by decreasing the number and/or modulating the activity of monocytes.

Adult↗
PubMed1986

Respiratory disease in animal house workers.

A cross-sectional survey was made to determine the prevalence of respiratory disorders, and the association between symptoms and workplace exposure, in 90 animal-house workers (AHW) and 100 controls (C) without occupational exposure to laboratory animals. Each subject provided a detailed history and serum for radioimmunoassays, and underwent: physical examination, skin testing with common inhalant and animal-derived antigens, and pulmonary function studies. Both groups were comparable with respect to age, sex, smoking habits, and atopy. Rhinitis occurred with similar frequency in each group. However, a more frequent occurrence of asthma (p less than 0.05, non-specific infectious respiratory disease (p less than 0.005), and impaired pulmonary functions (p less than 0.001) was found among AHW. An atopic background was a predisposing factor for the development of laboratory-animal-related respiratory symptoms. These findings imply an increased vulnerability to respiratory disease related to workplace exposure to laboratory animals in atopic individuals.

Adult↗
PubMed1985

Changes in diaphragmatic EMG spectra during hyperpneic loads.

Changes in electromyographic (EMG) activity of the diaphragm were examined in human subjects during different levels of voluntary hyperpnea. Diaphragmatic EMG was recorded using both surface and esophageal electrodes. The power spectra density (PSD) of the EMG signal was calculated and characterized by the high frequency to low frequency (H/L) ratio and by the centroid frequency (Fc). During high levels of voluntary hyperpnea, a significant decrease in both the H/L ratio and Fc occurred, which was similar in diaphragmatic EMG recorded by either surface or esophageal electrodes. This similarity in EMG spectral changes suggested that when diaphragmatic EMG was recorded using surface electrodes, there was only minimal contamination from the activity of other chest wall muscles. Changes in EMG Fc were detected during levels of hyperpnea which could be readily sustained. Thus, diaphragmatic EMG spectral changes were not characteristic of imminent ventilatory failure (i.e., an inability to sustain a target level of ventilation). In contrast, significant changes in EMG H/L ratio were observed only during hyperpneic loads which could not be sustained. This difference in sensitivity between the Fc and H/L ratio was due to the increased variability of H/L ratio and suggests that the H/L ratio may fail to detect small but significant shifts in EMG spectra. The relationship between the rate of decrease in EMG Fc and the level of hyperpnea was not statistically significant. We conclude that diaphragmatic EMG spectral changes do occur during hyperpneic loads, but we question the specificity of using diaphragmatic EMG spectral changes in predicting ventilatory failure.

Adult↗
PubMed1985

Aminophylline and its influence on ventilatory endurance in humans.

The purpose of this study was to evaluate whether the previously demonstrated improvement in contractile tension of diaphragmatic muscle with aminophylline results in improved ventilatory endurance. We measured the maximal sustained ventilatory levels during prolonged isocapnic hyperpnea as an index of ventilatory muscle function. This measurement was made in 7 normal subjects and 7 patients with chronic obstructive pulmonary disease during the intravenous administration of saline and aminophylline on 2 separate days. The order of administration of the infusions was randomized. Although both groups showed slightly higher sustained ventilatory levels during aminophylline infusion, the magnitude of change was small and unlikely to have a significant clinical benefit in the setting of respiratory muscle fatigue.

Adult↗
PubMed1985

Occupational respiratory disease in veterinarians.

In order to determine the effect of occupational animal exposure on the occurrence of respiratory disease, we studied 257 active veterinarians and 100 control subjects who had not had occupational animal contact. All participants provided a detailed medical history and underwent spirometry, skin tests, and determination of total serum IgE levels. Asthma was significantly more prevalent in veterinarians (16.3%) than in controls (6%), (P less than .05), as was infectious/obstructive respiratory disease, 10.5% in veterinarians, 3% in controls (P less than .025). Only 13 of 257 veterinarians had respiratory symptoms related to animal contact; of these, seven experienced only allergic rhinitis while six reported both asthma and rhinitis. Animal-related allergic rhinitis was found more frequently in laboratory animal veterinarians than among veterinarians in farm, pet, or poultry practice. No symptoms typical of hypersensitivity pneumonitis were reported in veterinarians, nor were precipitins to animal antigens demonstrable.

Humans↗
PubMed1982

Components of variability in serum theophylline concentrations during maintenance therapy with a sustained release formulation.

Fifteen adult chronic asthmatic patients were studied on 6 consecutive days of the second week of treatment with a new sustained release theophylline formulation, and 8 were again studied after three months on the same dosing regimen (375 mg b.i.d.). Serum theophylline concentrations were maintained in the therapeutic range (peak - 19.7 +/- 5.0 micrograms/ml; trough - 13.0 +/- 3.2 micrograms/ml) throughout the 12 hour dosing interval, and were greater than 75% of the peak concentration over 8.6 +/- 2.9 h. A degree of drug accumulation was evident in that the 1-h and 5-h levels rose from 12.2 +/- 4.1 and 4.5 +/- 4.8 micrograms/ml during the second week to 16.9 +/- 4.6 and 18.4 +/- 4.5 micrograms/ml, respectively, at three months. Between-patient differences accounted for 61%-71% of the total variation in steady state theophylline concentrations. After accounting for differences due to sampling time and assay error, unexplained random, within-individual variability amounted to 11%-18% of the total. Quantitative estimation of these components of variability may be incorporated into dosage forecasting methods based on single determinations of serum concentration.

Administration, Oral↗