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Biomedical subjects

J F Costello

Publications and source records attributed to J F Costello.

At least 55 records · Page 3Linked to original sources
PubMed1991

Bombesin immunoreactive neurons in the hypothalamic paraventricular nucleus innervate the dorsal vagal complex in the rat.

Bombesin-like immunoreactivity has been localized within neuronal cell bodies of the hypothalamus and nerve terminals within the dorsal vagal complex. The possibility that the hypothalamus is a source for bombesin-like immunoreactive terminals within the dorsal vagal complex was examined using the combined retrograde tracing and immunohistochemical technique. After injections of retrograde tracer were made into the dorsal vagal complex, cells in the hypothalamus labeled with both retrograde tracer and bombesin immunoreactivity were localized in the parvocellular part of the paraventricular nucleus. In the paraventricular nucleus most of the vagal projecting bombesin immunoreactive neurons were located within the medial parvocellular subdivision. Approximately 30% of the bombesin immunoreactive neurons in this subnucleus projected to the dorsal vagal complex. The results suggest that the paraventricular hypothalamic nucleus is a major source of bombesin terminals within the dorsal vagal complex. This pathway may mediate some of the autonomic nervous system changes that are observed when bombesin is injected within the central nervous system. Additionally, this data adds to a growing amount of evidence supporting the role of bombesin as a peptide neurotransmitter.

Amidines↗
PubMed1991

Participation of the cysteinyl leukotrienes in the acute bronchoconstrictor response to inhaled platelet activating factor in man.

To determine whether the effects of platelet activating factor on the airways may be due to the production of leukotrienes we studied the effects of pretreatment with the selective cysteinyl leukotriene antagonist SK&F 104353-Z2 on the airway and cellular responses to inhaled platelet activating factor. Eight healthy men were studied in a randomised, double blind placebo controlled cross-over study. A single dose of platelet activating factor that caused a fall of at least 35% in specific airways conductance (sGaw) was determined initially for each subject. Challenge with this dose of platelet activating factor was then carried out on two further occasions after pretreatment with a single nebulised dose of SK&F 104353-Z2 or placebo. The % reductions in specific airways conductance and of partial flow at 30% of vital capacity (PVmax30) were less after SK&F 104353-Z2 than after placebo (22 versus 34 for sGaw, 19 versus 31 for PVmax30). The mean (95% confidence limits (CL] differences in the maximum % fall from control values for SK&F 104353-Z2 and placebo were -12.6 (-23.8, -1.4) for sGaw and -12.5, (-20.8 -4.2) for PVmax30. The mean % fall in neutrophil count was similar after SK&F 104353-Z2 (46%) and after placebo (50%) (95% CL of difference 13.6, 6.6). Bronchial responsiveness to methacholine did not increase above baseline values in any subject when measured two weeks after challenge by platelet activating factor. This study suggests that leukotrienes play a part in the response to platelet activating factor in man.

Adult↗
PubMed1991

Plasma oxalate levels rise in hemodialysis patients despite increased oxalate removal.

The cause of secondary hyperoxalemia and oxalosis in patients on maintenance dialysis is unknown. The oxalate removal rate was determined in 26 patients on maintenance hemodialysis and 6 on continuous ambulatory peritoneal dialysis by measuring oxalate removed by dialysis and urinary excretion. The role of vitamin B6 deficiency and ascorbate in the raised plasma oxalate concentrations of these patients was evaluated. Plasma oxalate in hemodialysis patients, 442 +/- 41 micrograms/100 mL (mean +/- SE), and peritoneal patients, 394 +/- 115 micrograms/100 mL, were significantly higher than that in normal subjects, 11 +/- 1 microgram/100 mL (P less than 0.001). Average daily oxalate removal in subjects on hemodialysis, based on dialysis losses and urinary excretion, 35 +/- 3 mg/24 h, was significantly greater than urinary excretion of normal subjects, 26 +/- 1 (P less than 0.01). Oxalate removal from peritoneal dialysis patients, 28 +/- 2 mg/24 h, was not significantly different from that of hemodialysis patients or urinary excretion of normal subjects. Plasma ascorbate and B6 status were not correlated with plasma oxalate. A positive correlation between B6 deficiency and oxalate removal rate was not found. Plasma oxalate was correlated with time on dialysis (all patients) (P = 0.02). In a separate study of 15 hemodialysis patients followed over 2.3 +/- 0.2 yr, both plasma oxalate and oxalate removal rate significantly increased, P less than 0.001 and 0.05, respectively. It was concluded that oxalate removal rate is increased in hemodialysis patients and that the increased total body oxalate burden in these patients is not due to decreased removal. Although the increase may result from increased oxalate synthesis or gastrointestinal absorption, B6 deficiency and increased plasma ascorbate do not play a role.

Alanine Transaminase↗
PubMed1991

Direct correlation between methylation status and expression of the human O-6-methylguanine DNA methyltransferase gene.

To assess the role of DNA cytosine methylation in the expression of the O-6-methylguanine DNA methyltransferase (MGMT) gene, the methylation status of selected CpG-containing dinucleotides in and surrounding the coding regions of the gene were examined and correlated with steady state expression of MGMT mRNA in 13 human cell lines. Additionally, tumor cells which exhibited very high levels of MGMT expression were chronically exposed to 5-azacytidine to assess the effects of changes in gene methylation on MGMT expression. Results of these studies demonstrate that the degree of methylation of multiple MGMT gene regions correlates with gene expression, but in a direct rather than an inverse fashion, and that 5-azacytidine-induced demethylation of the MGMT gene correlates with a significant reduction, rather than induction, of MGMT steady-state mRNA expression. These results suggest a unique, potentially alterable methylation-related regulatory mechanism for the MGMT gene.

Azacitidine↗
PubMed1990

Leukotriene B4 and oral cancer.

The quantitation of leukotriene B4 (LTB4) in induced squamous cell carcinoma (SCC) of the Syrian hamster cheek pouch and histologically proven human oral SCC was investigated by a combination of reverse phase-high performance liquid chromatography (RP-HPLC) and radioimmunoassay (RIA). Healthy tissue obtained from these same patients and animals treated with vehicle alone were used as controls. From both animal and human studies our results show a 10 to 30 fold increase in the levels of LTB4 found in tumour compared to control tissue. Furthermore, this dihydroxy acid was not detected in the mucosal tissue of normal subjects undergoing routine surgery. Since LTB4 is a potent inflammatory mediator and modulator of immune responses, its presence at biologically active concentrations in human squamous cell carcinoma suggests a possible role in the pathogenesis of head and neck cancer.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1990

The generation and metabolism of leukotrienes in the ionophore-stimulated blood of normal and asthmatic subjects.

The generation and metabolism of leukotrienes (LTs) B4, C4, D4, and E4 were studied in vitro in the A23187-stimulated whole blood of normal (N) and atopic asthmatic (AA) human subjects. Using a combination of reversed-phase high performance liquid chromatography and radioimmunoassay, we have demonstrated that the blood cells of atopic asthmatic patients have an enhanced ability to release LTB4 and LTC4 when compared to those of normal subjects. The release of LTB4 and LTC4 in response to ionophore is dose- and time-dependent. Half-maximal doses of ionophore caused the generation of high, sustained levels of LTB4, which are significantly higher in the AA blood than in N blood. Incubations of 3H-LTB4 in ionophore-stimulated N and AA blood revealed a slow metabolism to 20-OH-LTB4 and 20-COOH-LTB4. LTC4 is generated in smaller amounts than LTB4, with an early peak after 10 min which is significantly higher (p less than 0.01) in the AA blood compared to the N blood. Subsequent metabolism of LTC4 elicits significantly greater amounts of LTD4, and consistently higher levels of LTE4, in the AA blood. Parallel incubations of 3H-LTC4 in ionophore-stimulated N and AA blood demonstrated rapid metabolism of LTC4 by the glutathione detoxification pathway. The elevated production of LTB4 and LTC4 in AA blood was not accounted for by differences in leukocyte sub-type counts in the two groups, nor by differences in their rates of catabolism. The novel, selective 5-lipoxygenase inhibitor BW A4C [N-(3-phenoxycinnamyl) acetohydroxamic acid] caused dose-dependent inhibition of LTB4 and LTC4 generation and was equipotent in N and AA blood.

Asthma↗
PubMed1990

Platelet activating factor does not cause a reproducible increase in bronchial responsiveness in normal man.

The reproducibility of acute effects of inhaled PAF on airway calibre, circulating neutrophil count and any subsequent increase in bronchial responsiveness has been studied in six normal subjects and compared to the effects of inhaled lyso-PAF, the inactive precursor and metabolite of PAF. PAF caused acute bronchoconstriction and a transient fall in neutrophil count on two separate occasions in five out of six subjects (minimum percentage of baseline values (mean): first PAF challenge; sGaw 69%, Vmax30 72%; neutrophil count 70%; second PAF challenge; sGaw 61%, Vmax30 74%, neutrophil count 63%). In one subject inhaled PAF caused bronchoconstriction and a transient fall in neutrophil count once, but a second challenge resulted in no detectable changes. There was no significant increase in bronchial responsiveness to methacholine in any subject studied on five occasions over a 2-week period following each PAF challenge. Challenge with lyso-PAF did not cause acute effects or any subsequent changes in bronchial responsiveness. These findings demonstrate that any effects of inhaled PAF on bronchial responsiveness in normal man are small and probably not of clinical significance. It would also be inappropriate to use this human model to study the mechanisms of bronchial hyperresponsiveness or for the preliminary assessment of potential new anti-asthma drugs.

Acute Disease↗
PubMed1989

The biotransformation in vitro of cysteinyl leukotrienes in blood of normal and asthmatic subjects.

The metabolism of exogenous leukotriene C4 (LTC4), LTD4 and LTE4 (10(-8) M) was studied in vitro in blood of normal and asthmatic subjects for up to 2 hr by reverse-phase high performance liquid chromatography. In whole blood, incubation of LTC4 (T1/2 = 11.5 min) resulted in the formation of LTD4 and LTE4 whose biosynthesis was inhibited by serine borate (30 mM). Similar experiments performed with LTD4 (T1/2 = 5 min) produced a single metabolite (LTE4) which was inhibited by L-cysteine (10 mM). On the other hand, LTE4 represented a highly stable product in our in vitro system. The bioconversion of LTC4 or LTD4 was slower in plasma but this effect appeared more pronounced for the cysteinylglycinyl derivative. The bioconversion of LTD4 in whole blood or plasma was almost twice as rapid as LTC4. Experiments performed with asthmatic blood showed no significant difference in the survival of LTC4. These results suggest that blood may play a role in regulating the bioavailability of cysteinyl-containing LTs which could be of relevance to their excretion in man.

Adult↗
PubMed1989

L-648,051, a novel cysteinyl-leukotriene antagonist is active by the inhaled route in man.

1. We have studied some of the pharmacological properties of inhaled L-648,051 which has been shown to be a selective cysteinyl-leukotriene (LT) antagonist in vitro and in vivo in various animal models. 2. The effects of three different doses (1.6, 6.0 and 12.0 mg) on the bronchoconstriction induced by inhaled LTD4 have been investigated in normal male subjects in a series of double-blind, placebo controlled studies. Furthermore, the specificity of the drug has been investigated by challenging subjects with histamine after pre-inhalation of 12.0 mg L-648,051. 3. At all doses L-648,051 partially blocked the bronchoconstriction induced by LTD4 inhalation in a dose related manner. At a dose of 12.0 mg, L-648,051 decreased the maximum fall in specific airways conductance (sGaw) (placebo, 49% vs L-648,051, 21%, P less than 0.01) and shortened the time to recovery from LTD4-induced bronchoconstriction (placebo, 41 min vs L-648,051, 19 min, P less than 0.01). 4. There was no evidence of partial agonist activity, and no effect on histamine-induced bronchospasm. Inhaled L-648,051 at all doses was well tolerated. 5. We conclude that LT antagonism is possible by the inhaled route in man. Inhaled L-648,051 is an active and selective LT-antagonist in man which is well tolerated and may prove to be a useful drug for assessing the role of leukotrienes in asthma and other lung diseases.

Administration, Inhalation↗
PubMed1989

Non-specific bronchial airway hyperreactivity and the diagnosis of asthma.

In very mild and atypical cases of asthma, highly discriminative tests are needed to make the diagnosis. To demonstrate this, measurement of non-specific bronchial airway hyperreactivity by means of standardized bronchial inhalation challenge tests with histamine and methacholine were performed in 10 very mild asthmatic and nine normal control subjects; both groups included Nigerians who were temporarily resident in London at the time of the study. Bronchial reactivity was expressed as the provocative concentration of the agents causing a 20% fall in forced expiratory volume in 1 sec (PC20FEV1); higher values indicating lower levels of non-specific bronchial reactivity. The level of non-specific bronchial reactivity in these very mild asthmatics, whose baseline physiological data were not different from those in normals, was found to be 18-29 times higher than the normal control subjects. These tests very effectively discriminated between asthmatic and normal control subjects. With available resources it should be possible to study a large number of Nigerians in their own environment.

Adult↗
PubMed1988

The effect of nifedipine on bronchial reactivity to inhaled histamine and methacholine: a comparative study in normal and asthmatic subjects.

The effect of pretreatment with nifedipine 20 mg sublingually on the bronchoconstrictor response to inhaled histamine and methacholine in asthmatic and normal subjects has been studied. For each agonist the provocation concentration required to produce a 15% fall in FEV1 (PC15) and a 35% fall in specific conductance (PC35) was determined. In the group of asthmatic subjects the responses to histamine were significantly attenuated by histamine, PC15 increasing from 0.29 mg/ml to 0.68 mg/ml (P less than 0.001) and PC35 increasing from 0.25 mg/ml to 0.58 mg/ml (P less than 0.001). Responses to methacholine showed less modification by nifedipine. PC15 increased from 0.23 mg/ml to 0.32 mg/ml (P less than 0.05). Changes in PC35 were not significant. In the group of normal subjects no attenuation of the response to methacholine was produced by nifedipine but significant increases of PC15 (P less than 0.002) and PC35 (P less than 0.005) were produced by the agent. The results are consistent with nifedipine exerting an effect principally on mediators dependent on external calcium sources for stimulus-contraction coupling in the airways. The magnitude of change in the histamine response of the two groups was similar, suggesting calcium dependent mechanisms are not involved in asthmatic hyper-responsiveness.

Adult↗