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Biomedical subjects

C Ward

Publications and source records attributed to C Ward.

At least 19 recordsLinked to original sources
PubMed1992

Myeloma affects both the growth and function of human osteoblast-like cells.

Myeloma behaves differently to other osteolytic tumours which metastasize to bone, in that the latter usually provoke reactive bone formation in the host bone. A previous study showed that a myeloma cell line (GM1500) secreted an osteoblast-inhibiting factor(s). The present study was undertaken to determine whether other myeloma cells also secreted a factor(s) which inhibited both cell proliferation and DNA synthesis of osteoblast-like cells and whether the myeloma also affected the function of osteoblasts. The results showed that a second cell line (Karpas 707) as well as myeloma tissue taken from two patients had a similar effect. The myeloma cells did not affect total collagen or protein synthesis, and did not affect the overall degree of mineralization. A biphasic effect was seen on alkaline phosphatase activity. Thus, although the proliferation of the pre-osteoblast was affected, the synthetic functions of the osteoblasts were not.

Alkaline Phosphatase↗
PubMed1992

The origin of water and urea sampled at bronchoalveolar lavage in asthmatic and control subjects.

Bronchoalveolar lavage (BAL) urea has been advocated as a denominator that might allow for the dilution of the pulmonary epithelial lining fluid sampled at BAL, and so provide a meaningful method of expressing BAL data. We investigated the origin of water and urea sampled at BAL in five asthmatic and five control subjects using radiolabeled urea injected intravenously 5 min before BAL. Labeled BAL urea was found to be fully equilibrated with that in the bloodstream. A strong relationship was found between influx of radiolabeled water and radiolabeled urea from blood to BAL fluid, suggesting that urea sampled at BAL may be derived predominantly from an acute movement from the bloodstream into the BAL aspirate. We conclude that urea is an inappropriate denominator for the expression of BAL results, and that the fluid and solute dynamics that occur during BAL are both complex and variable.

Adult↗
PubMed1991

High incidence of vancomycin-associated leucopenia and neutropenia in a cardiothoracic surgical unit.

A retrospective case record review was undertaken to determine the incidence of vancomycin-associated leucopenia in a cardiothoracic surgical unit. Forty-nine patients received 50 courses of vancomycin therapy. Nine patients (18%) developed reversible leucopenia (white cell count less than 4000 x 10(6)/l) or neutropenia (polymorphonuclear leucocyte count less than 1500 x 10(6)/l). Four patients (8%) had severe neutropenia (less than 1000 x 10(6)/l). The median total dosage associated with leucopenia and neutropenia was 30 g, range 22-56 g. The median duration of treatment in leucopenic and neutropenic patients was 22 days, range 6-28 days. The median recovery time to a normal white cell count was 4 days, range 1-11 days. Patients who developed leucopenia on vancomycin therapy did not differ from those who did not with respect to age, total vancomycin dose, length of therapy, underlying illness, incidence of cardiac surgery or use of concomitant medications. Vancomycin-associated leucopenia and neutropenia is common in patients with cardiothoracic infections, many of whom are on several other medications. White cell counts should be estimated regularly in such patients.

Adult↗
PubMed1991

Which vasodilator drug in patients with chronic heart failure? A randomised comparison of captopril and hydralazine.

1. Fifty patients with symptoms due to chronic heart failure despite diuretic therapy were randomised to receive additional treatment with either hydralazine or captopril. The dose was titrated; 24 received hydralazine and 26 captopril up to a maximum daily dosage of 225 mg and 75 mg respectively. Forty-three patients had coronary heart disease and seven dilated cardiomyopathy. 2. Dyspnoea and tiredness were assessed using a visual analogue scale (0-100) before and during 12 weeks' treatment. Captopril produced a significantly greater reduction in breathlessness (F = 31.6, P less than 0.001) and tiredness (F = 65.8, P less than 0.001) compared with hydralazine. 3. There was an increase in treadmill exercise time during treatment with both hydralazine (from 5.5 (3.47-7.53) min to 6.9 (4.87-8.93) min), and captopril (from 5.0 (3.05-6.95) min to 7.8 (5.85-9.75) min), but the degree of improvement was significantly greater in the patients treated with captopril (F = 7.4, P less than 0.001). 4. There was no significant change in right ventricular ejection fraction (from 27.9 (19.3-36.5)% to 28.7 (20.1-37.3)%) or left ventricular ejection fraction (from 22.2 (14.2-30.2)% to 23.9 (15.9-31.9)%) during treatment with hydralazine. However, both right and left ventricular ejection fraction increased significantly during treatment with captopril (from 27.1 (18.9-35.3)% to 32.0 (23.8-40.2)%, P less than 0.05; and from 25.0 (17.2-32.8)% to 29.6 (21.8-37.4)%, P less than 0.05 respectively). 5. These results suggest that in patients with symptoms due to chronic heart failure despite diuretic therapy, treatment with captopril produces a greater symptomatic and haemodynamic improvement than treatment with hydralazine.

Adult↗
PubMed1991

Effects of human neutrophil elastase and Pseudomonas aeruginosa proteinases on human respiratory epithelium.

It has been suggested that proteinase enzymes could play an important role in the pathogenesis of chronic bronchial infections including bronchiectasis and cystic fibrosis (CF). Because Pseudomonas aeruginosa frequently colonizes the respiratory tract in bronchiectasis and CF, we examined the in vitro effects of human neutrophil elastase (HNE) and proteinase enzymes produced by P. aeruginosa (elastase: PE; alkaline proteinase: PAP) on the ciliary beat frequency (CBF) and ultrastructure of human nasal ciliated respiratory epithelium. HNE (500 micrograms/ml) progressively reduced CBF and caused marked epithelial disruption; lower concentrations (100 and 20 micrograms/ml) also caused epithelial disruption but without slowing CBF. The effects of HNE (500 micrograms/ml) were completely abolished by adding alpha 1-antitrypsin (5 mg/ml). There was no synergy between HNE and pyocyanin, a product of P. aeruginosa which slows CBF. PE in phosphate-buffered saline also caused epithelial disruption without slowing CBF; however, PE in medium containing divalent metal ions caused CBF slowing as well as epithelial disruption at 100 micrograms/ml. PAP (500 micrograms/ml) had almost no effect on ciliated epithelium. The effects of HNE and PE on nasal and bronchial epithelium obtained from the same patient were similar. Light and transmission electron microscopy revealed that HNE and PE were cytotoxic and caused detachment of epithelial cells from neighboring cells and the basement membrane. There was cytoplasmic blebbing of the cell surface and mitochondrial damage; however, no increase of abnormalities in the ultrastructure of cilia on living cells was seen. These results support the hypothesis that HNE and PE contribute to the delayed mucociliary clearance and epithelial damage that is observed in patients with chronic bronchial infection.

Bronchi↗
PubMed1991

Breast carcinomas synthesize factors which influence osteoblast-like cells independently of osteoclasts in vitro.

Bone metastases in breast cancer may be osteolytic, osteosclerotic, or a mixture of the two. Although stimulation of bone resorption by breast cancer cells has attracted some interest, the formation of osteosclerotic secondary tumours and the influence of human mammary carcinoma cells on osteoblasts (bone forming cells), both important in understanding breast cancer--bone interactions, have been largely neglected. We therefore examined the effects of conditioned medium (CM) from two cultured human breast cancer cell lines (MCF7 and ZR-75) and from primary cultures of breast carcinomas from two patients, on osteoblasts and recruitment of bone-resorbing cells (osteoclasts) in vitro. Osteoblast-like cells (BDC) were cultured from human trabecular bone explants. Osteoclast maturation was studied in fetal rat calvaria cultured on collagen gels. CM from the MCF-7 line and cells derived from one patient each inhibited BDC DNA synthesis, but stimulated osteoclast recruitment. In contrast, CM from the second patient's cells or ZR-75 enhanced DNA synthesis in BDC, but blocked osteoclast maturation. This suggests that human breast carcinomas secrete soluble factors which influence both osteoclasts and osteoblasts. A further unexpected implication is that mammary carcinoma cells may cause local osteosclerosis by directly stimulating osteoblasts, rather than through raised bone turnover in metastases.

Animals↗
PubMed1990

Genomic sequencing of the 5'-flanking region of the mouse beta-globin major gene in expressing and nonexpressing mouse cells.

Genomic sequencing of two CG sites located in the 5'-flanking promoter region of the mouse beta-globin major gene shows these sites to be heavily methylated in the DNA from L929 mouse fibroblasts, a cell line that does not express the beta-globin gene. By contrast, the same CG sites in the DNA obtained from murine erythroleukemia cells, which can express the beta-globin gene, are unmethylated. The results suggest that either differentiation of progenitor cells to form the erythroid precursor murine erythroleukemia cell and/or transformation by the Friend virus group leads to demethylation of these CG sites. Final activation of the transcription process for the mouse beta-globin gene does not require demethylation in the 5'-promoter region of the DNA.

5-Methylcytosine↗
PubMed1990

Effect of donor age on the growth in vitro of cells obtained from human trabecular bone.

The proliferation of human bone-derived cells (BDCs) was assessed in vitro, using [3H]thymidine incorporation and cell counting in a haemacytometer. The cells were cultured from human trabecular bone from 87 patients aged 2-88 years. The in vitro growth of these cells was unaffected by the chronological age of the donor. However, the cell number at confluence was shown to decrease with increasing donor age, this trend being most marked after 60 years of age. Other assays of the metabolic efficiency of the BDCs, namely, total protein, osteocalcin, and alkaline phosphatase synthesis, did not show any change with increasing donor age. These results suggest that while the ability of individual cells to divide and to perform specific synthetic activities is unimpaired with increasing age, other subtler changes may occur, leading to a decrease in the bone's osteogenic capacity.

Adolescent↗
PubMed1990

Immunoscintigraphy of colorectal cancer with an antibody to epithelial membrane antigen (EMA).

Immunoperoxidase staining of LICR-LON M8, a mouse monoclonal antibody reactive with epithelial membrane antigen, showed a strong reaction with colorectal cancer. This finding prompted an immunoscintigraphic study of colorectal cancer patients using this antibody. Sixteen patients had external gamma scintigraphy after intravenous injection of indium 111-labeled M8. Positive scans were obtained in 11 of the 13 patients with primary colorectal cancers, and 2 of the 3 patients with recurrent tumors. The high indium 111 background in the liver prevented the detection of hepatic metastases in 5 patients. Twelve patients had samples taken of tumor, normal colon, and venous blood at the time of surgery. The ratio of labeled antibody uptake in tumor to that of blood was 5.1 (+/- 3.6 S.D.), which was significantly different (P = 0.001) to that of the similar ratio for normal colon (2.0 +/- 1.6 S.D.). The tumor to normal colon uptake ratio was 2.6 (+/- 1.3 S.D.). These results suggest a specific uptake of indium 111-labeled M8 by colorectal cancer.

Aged↗
PubMed1990

Genotoxicity and cell cycle effects of platinum-based imaging agents in cisplatin-resistant human tumour cells.

A series of cis-dichloroplatinum(II) 2,3-diaminopropionamide complexes synthesised as potential imaging agents was tested for activity against a human ovarian tumour cell line (CI-80-13S) with high natural resistance to cisplatin and carboplatin as compared with other human cells. The most potent compound, the dimethyl ester of dichloro-[4-(methyleneiminodiacetic acid)phenyl (2',3'-diamino-propionamide)]platinum(II) (complex III), exhibited toxicity towards CI-80-13S cells similar to that observed in other cell lines, an effect that was not shown by the ligand alone or by cis-dichloroplatinum(II) 2,3-diaminopropionamide. However, complex III ester reproduced the genotoxic effects of cisplatin as judged by differential inactivation of two strains of adenovirus and by inhibition of cellular DNA and RNA synthesis; no major differences in these properties were observed between CI-80-13S and cisplatin-sensitive cells. Substantial inhibition of DNA and RNA synthesis was found within 2 h of treatment, much earlier than the effect of cisplatin. Complex III ester, which was 30- to 100-fold less potent than cisplatin, inhibited cell cycle progression in a similar way to equitoxic cisplatin, with cells accumulating in G2 at a dose of low toxicity and being arrested in all stages at higher levels. The latter in combination with colcemid caused extensive fragmentation of CI-80-13S cells. These results suggest that the mechanism of toxicity of such complexes involves factors, in addition to DNA damage, which rapidly inhibit nucleic acid synthesis and overcome natural resistance to cisplatin in the CI-80-13S cell line.

Adenoviridae↗
PubMed1990

The actions of GR32191B, a thromboxane receptor antagonist, on the effects of inhaled PAF on human airways.

We investigated acute bronchoconstriction and changes in airway responsiveness to methacholine following the inhalation of platelet activating factor (PAF) in an open study of 12 non-asthmatic subjects. Ventilatory function was monitored using a flow rate at 30% of vital capacity (V30) and airway responsiveness was measured as PD40V30, i.e. the dose of metacholine causing a 40% fall in V30. PAF (3-422 micrograms) resulted in dose-related acute bronchoconstriction in 10 of the 12 subjects. There was no association between the airway responsiveness to PAF and to methacholine. Ten subjects showed some increase in airway responsiveness to methacholine 1 or 3 days following PAF. Overall, these changes were statistically significant (P less than 0.05) but were of small magnitude (geometric mean PD40V30pre-PAF = 457 micrograms; 24 hr after PAF = 259 micrograms; 72 hr after PAF = 258 micrograms) and variable: only seven subjects showing increased airway responsiveness on both day 1 and day 3 after PAF. Six subjects who appeared to show increases in airway responsiveness following PAF were re-studied with the inhaled PAF pre-medicated by either placebo or a specific thromboxane receptor antagonist (GR32191B) in a double-blind fashion. GR32191B did not reduce the acute bronchoconstriction due to PAF. In this part of the study, these six subjects did not show significant increases in airway responsiveness following the placebo pre-medicated PAF challenge and so no effect of the drug on airway responsiveness could be shown.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1990

The pharmacokinetics of the antidepressant tianeptine and its main metabolite in healthy humans--influence of alcohol co-administration.

A balanced 3 way cross-over study involving 12 young healthy volunteers (6 men and 6 women) was used to determine the pharmacokinetic parameters of the antidepressant tianeptine following a single dose administered by oral and intravenous route. The influence of alcohol on the pharmacokinetics of tianeptine when given per os was also investigated. Kinetic parameters of metabolite MC5, the C5 side chain beta-oxidation product of tianeptine, were simultaneously determined. Following intravenous administration total clearance and volume of distribution of tianeptine were 230 +/- 59 ml.min-1 and 0.47 +/- 0.14 l.kg-1 respectively. When given orally, tianeptine was absorbed rapidly (tmax = 0.94 +/- 0.47 h). The mean systemic availability was estimated to be 99 +/- 29%. Tianeptine was eliminated from plasma with a half-life of 2.5 +/- 1.1 h, mainly via extrarenal route since its renal clearance averaged 0.38 +/- 0.47 ml.min-1. Plasma levels of metabolite MC5 were lower than those of the parent drug but decreased with a longer half-life (7.2 +/- 5.7 h). Alcohol co-administration decreased tianeptine absorption rate and lowered tianeptine plasma levels by about 30% but did not affect those of the MC5 metabolite.

Administration, Oral↗
PubMed1990

The reversible effect of lignocaine on the stimulated metabolic activity of bronchoalveolar lavage cells.

Lignocaine concentrations were measured in the aspirate from a low volume (100 ml) bronchoalveolar lavage (BAL) in twenty patients who had received topical 4% lignocaine as required, and compared to those found in the aspirate from a 180 ml BAL in ten patients who had received 1.5% isotonic lignocaine. The median BAL supernatant lignocaine concentration was significantly lower at 0.14 mM (range 0.07-0.44 mM) in the group who received 1.5% lignocaine, compared to 1.08 mM (range 0.03-7.05 mM) in those given 4% lignocaine (p less than 0.01). The effect of increasing concentrations of lignocaine on BAL neutrophil and pulmonary macrophage metabolic activity, as assessed by latex-stimulated luminol- and lucigenin-amplified chemiluminescence (CL), respectively, in mixed BAL cell populations, were measured following preincubation of "washed" harvested BAL cells with 0.4-8.0 mM lignocaine. There was no demonstrable decline in either cell activity with lignocaine concentrations of up to 2 mM, with dose-dependent inhibition of both above this threshold. Cell viability was unaffected. In a further experiment, the inhibition induced by 8 mM lignocaine on both pulmonary macrophage (lucigenin-amplified CL of harvested BAL cells) and isolated peripheral blood neutrophil metabolic activity was completely reversed by a single "wash", following both 30 and 60 min incubations at 4 degrees C, which was equivalent to resuspending harvested BAL cells in fresh medium after separation from BAL supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

The relative contribution of bronchoalveolar macrophages and neutrophils to lucigenin- and luminol-amplified chemiluminescence.

The relationship between differential cell counts and latex-stimulated luminol and lucigenin-amplified chemiluminescence (CL) was investigated by mixing alveolar macrophages (AM) obtained at bronchoalveolar lavage (BAL) with allogeneic peripheral blood neutrophils (PMN) in varying proportions. In 5 non-asthmatic subjects, the mean luminol-amplified CL increased linearly from 2.1 (0.9 SEM) x 10(5) counts per second (cps) with less than 2% PMN, greater than 96% AM to 47.3 (11.1 SEM) x 10(5) cps with greater than 94% PMN, 0% AM (r = 0.996, p less than 0.001). The regression had a y-intercept indistinguishable from 0 cps, suggesting that luminol-amplified CL exclusively reflected PMN activity. Using the same technique, the mean lucigenin-amplified CL showed a fall from 35 (2.3 SEM) x 10(5) cps with a cell population of greater than 96% AM, less than 2% PMN to 20 (2.3 SEM) x 10(5) cps with 0% AM, greater than 94% PMN. Both PMN and AM appeared to contribute to lucigenin-amplified CL, with AM contributing approximately 1.7 times as much activity per cell as PMN. Lucigenin-amplified CL appeared to be an appropriate technique for measuring AM activity when the proportion of PMN in mixed cell populations was small. A linear relationship was found between percent PMN count and luminol-amplified CL measured in a mixed BAL cell population from asthmatic subjects (p less than 0.01) and non-asthmatic controls (p less than 0.01). The slope of this regression line was significantly greater for subjects with asthma than for control subjects (p less than 0.01), suggesting a uniform increase in PMN activity in cells obtained from asthmatic airways.

Acridines↗
PubMed1990

Platelet-activating factor in bronchoalveolar lavage fluid from asthmatic subjects.

Bronchoalveolar lavage (BAL) was performed on 28 asthma patients, 7 patients with emphysema and 11 control subjects. Total and differential cell counts were performed and cellular metabolic activity was assessed using luminol and lucigenin amplified chemiluminescence. BAL supernatants were assayed for platelet-activating factor (PAF) and lyso-PAF using a sensitive guinea-pig bioassay. Eight of the asthma patients but none of the emphysema patients or control subjects had PAF in their BAL fluid. Lyso-PAF was measurable in BAL fluid in most subjects and no differences were detected between groups. Among the asthma patients, the presence of PAF in BAL supernatant was significantly associated with a combination of low neutrophil and high lymphocyte counts (p less than 0.05) and with macrophage metabolic activity as assessed by lucigenin chemiluminescence (p less than 0.05).

Adolescent↗