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F J Kelly

Publications and source records attributed to F J Kelly.

At least 73 records · Page 4Linked to original sources
PubMed1997

Detecting comorbid substance misuse among people with schizophrenia in the community: a study comparing the results of questionnaires with analysis of hair and urine.

Substance misuse among people with schizophrenia is thought to be common and to adversely affect the outcome of the illness. The shortcomings of studies in this area include patient samples that are not epidemiologically-based, and methods for detecting substance misuse that have serious limitations. We investigated the frequency and severity of substance misuse among people with schizophrenia living in the community in London. Interviews were conducted with a community-based sample of 39 people with schizophrenia aged 35 years or less, living in Inner London. The assessments included ratings of psychopathology, movement disorders and substance misuse, and co-informant histories. Urine and hair specimens were analysed for a range of substances. Urine samples were collected from 37 patients and hair samples were provided by 36 patients. Comorbid substance misuse was reported or detected in 63% of the sample. The information elicited using a structured questionnaire for both informants and subjects represented an under-estimate of psychostimulant misuse and opiate misuse compared with the results obtained by hair or urine analysis. Hair analysis revealed that 12 (33%) of those patients providing samples had covertly abused amphetamines, opiates or cocaine in the previous 3 months. The study demonstrated that hair analysis is a well-tolerated, sensitive test for substance misuse. The technique has several advantages over questionnaires and urine analysis for clinical and research purposes. Further applications include the assessment of comorbid substance use in particular groups of patients with schizophrenia, such as during first-episode or psychotic relapse, or those with forensic problems or apparent resistance to treatment.

Adult↗
PubMed1997

Plasma RRR-alpha-tocopherol concentrations are lower in smokers than in non-smokers after ingestion of a similar oral load of this antioxidant vitamin.

1. Using deuterium-labelled alpha-tocopherol (vitamin E), the plasma kinetics of alpha-tocopherol derived from supplemental RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate were determined in asymptomatic individuals who smoke and, for comparison, in a group of healthy non-smokers. 2. Venous blood samples were withdrawn 6, 12 and 27 h after the oral administration of a gelatin capsule containing an equimolar mixture of RRR-alpha-tocopheraol and RRR-alpha-tocopheryl acetate. Plasma concentrations of endogenous and administered forms of alpha-tocopherol were determined by a combination of HPLC and GC-MS. 3. Both the free phenol and the acetate ester concentrations of alpha-tocopherol were lower in smokers than in non-smokers: 0.99 versus 1.60 (P < 0.05) and 0.66 versus 1.49 (P < 0.05) mumol/mmol cholesterol for RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate respectively. The highest concentation of alpha-tocopherol derived from administered RRR-alpha-tocopherol and its acetate ester were observed in plasma at 12 h (compared with 6-h and 27-h measurements) in most subjects. 4. Although the two forms of alpha-tocopherol were administered in equal doses, plasma from smokers contained significantly higher concentrations of RRR-alpha-tocopherol derived from the free phenol form than from the acetate form (0.99 versus 0.66 mumol/mmol cholesterol, P < 0.05, 12 h). Non-smokers did not exhibit preferential uptake of either form of vitamin E. 5. These results suggest that individuals who smoke have either a reduced ability to absorb alpha-tocopherol, particularly when it is presented as the acetate ester, or increased clearance of newly absorbed alpha-tocopherol compared with non-smokers.

Administration, Oral↗
PubMed1997

Cloning of guinea pig surfactant protein A defines a distinct cellular distribution pattern within the lung.

A full-length cDNA to guinea pig pulmonary surfactant protein (SP) A was cloned by screening a newborn guinea pig lung cDNA library with a human SP-A cDNA probe. The full-length guinea pig SP-A cDNA consists of 1,839 bp and is highly conserved at both nucleotide and amino acid sequence levels with those from other species. As expected, guinea pig SP-A mRNA is abundantly expressed in adolescent lung tissue and is undetectable in nonpulmonary tissues. In situ hybridization studies clearly show a unique cellular distribution pattern of SP-A mRNA within the guinea pig lung. SP-A mRNA expression is confined to cells of the alveolar epithelium with no expression in the bronchiolar epithelial cells, whereas SP-B mRNA is expressed in both alveolar and bronchiolar epithelial cell populations. This distinct expression pattern suggests that the guinea pig lung will be a useful model in which to study expression of transcription factors implicated in the regulation of SP genes.

Amino Acid Sequence↗
PubMed1997

The inflammatory effects of 2 ppm NO2 on the airways of healthy subjects.

Nitrogen dioxide (NO2) is a free radical and a common oxidant in polluted air. Here we present data on the time course of inflammation after NO2 exposure, as reflected in bronchial biopsy and airway lavage specimens. Healthy, nonsmoking subjects were exposed to air or 2 ppm NO2 for 4 h in random order on separate occasions. Endobronchial biopsies, bronchial washing (BW), and bronchoalveolar lavage (BAL) were done at 1.5 h (n = 15) or 6 h (n = 15) after exposure. In BW, exposure to NO2 induced a 1.5-fold increase in interleukin-8 (IL-8) (p < 0.05) at 1.5 h and a 2.5-fold increase in neutrophils (p < 0.01) at 6 h. In BAL fluid (BALF), small increases were observed in CD45RO+ lymphocytes, B-cells, and natural killer (NK) cells only. Immunohistologic examination of bronchial biopsy specimens showed no signs of upregulation of adhesion molecules, and failed to reveal any significant changes in inflammatory cells at either time point after NO2 exposure. In summary, NO2 induced a neutrophilic inflammation in the airways that was detectable in BW at 6 h after NO2 exposure. The increase in neutrophils could be related to the enhanced IL-8 secretion observed at 1.5 h after exposure. The absence of adhesion-molecule upregulation or cellular inflammation in mucosal biopsy specimens indicates that the major site of inflammation following exposure to NO2 may be in the smaller airways and not in the alveoli.

Adult↗
PubMed1996

Differential patterns of antioxidant enzyme mRNA expression in guinea pig lung and liver during development.

cDNA clones for guinea pig antioxidant enzymes, copper-zinc (Cu-Zn) and manganese (Mn-) superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were isolated by reverse transcription (RT)-polymerase chain reaction (PCR) cloning, to explore the mechanism regulating the differential expression of antioxidant enzymes (AOEs) in guinea pig lung and liver, during development. Increases in MnSOD, CAT and GPx mRNA expression in lung and, MnSOD mRNA in liver, were seen during the final period of gestation, whereas CuZnSOD and CAT mRNA expression in liver, which was constant during gestation, increased in the postnatal period. In lung, CuZnSOD mRNA level decreased just prior to birth while in liver, GPx mRNA expression declined markedly over the last third of gestation. In lung, while the mRNA levels of MnSOD, CAT, and GPx increased pre-natally, they declined following birth. In contrast, the postnatal increase in mRNA for CuZnSOD and CAT and the prenatal increase in MnSOD mRNA expression in liver remained at least to adolescence. In adolescent guinea pigs, CuZnSOD and CAT mRNA were most abundantly expressed in liver, while MnSOD and GPx mRNA were most abundant in heart and spleen, respectively. These results demonstrate markedly different developmental patterns of AOEs expression in guinea pig lung and liver during both the pre- and post-natal period. The short-lasting, late-gestational increases of MnSOD, CAT, and GPx mRNA expression in lung, may be responsible for the temporary increases in the activity of these antioxidants in the late gestational period, whereas the steady increases of CuZnSOD, CAT mRNA following birth, and also the prenatal increases in MnSOD mRNA expression, are probably responsible for the higher postnatal activity of these antioxidants in liver.

Aging↗
PubMed1996

Ventricular arrhythmias induced by ischaemia-reperfusion are unaffected by myocardial glutathione depletion.

Reduced glutathione (GSH) is a major myocardial antioxidant. Since reperfusion phenomena such as ventricular fibrillation (VF) are associated with oxygen free radical production during ischaemia, myocardial GSH depletion might be expected to increase susceptibility to such phenomena. This possibility was tested in isolated rat hearts using diethylmaleate (DEM) or L-buthionine-SR-sulfoximine (BSO) to deplete myocardial GSH. High dose DEM (860 mg/kg) depleted myocardial GSH from a control mean of 7.64 +/- 0.73 to 3.18 +/- 0.56, low dose DEM (215 mg/kg) to 4.29 +/- 0.53 nmol/mg protein and BSO (4 mmol/kg) from a control mean of 6.94 +/- 0.54 to 2.18 +/- 0.14 nmol/mg protein. Hearts were perfused in the Langendorff mode at 37 degrees C with bicarbonate buffer (K+ = 4.3 mM). Regional ischaemia was induced for 5, 8.5, 10, 20 or 40 min (DEM groups: n = 10/treatment/time point) or 8.5 min only (BSO groups: n = 10/treatment) then hearts were reperfused for 5 min. Reperfusion VF incidence showed a classical "bell-shaped" curve, but there was no difference in VF incidence, VF time-to-onset, arrhythmia duration and "arrhythmia scores" between GSH-depleted and control hearts. Depleting myocardial GSH is not proarrhythmic for reperfusion-induced arrhythmias. It would appear GSH is not significantly involved in protecting against the oxidant stress of reperfusion, or conversely that the reserve of this redox system is so high only severe depletion might show an effect.

Animals↗
PubMed1996

Vitamin E supplementation in cystic fibrosis.

Vitamin E is an antioxidant and may have a role in the protection of lung tissue against oxidative damage in cystic fibrosis. Previous studies of vitamin E status in cystic fibrosis have used plasma or serum concentrations, which vary with levels of carrier lipoproteins and hence may not reflect the concentration of vitamin E in tissues, where it is found in highest concentration in membranes. Erythrocyte vitamin E concentration has been shown to correlate well with tissue concentrations of the vitamin in animals, but it has not previously been studied in patients with cystic fibrosis. Current guidelines on vitamin supplementation in cystic fibrosis include vitamin E. It is not presently clear which level of supplementation is most appropriate. To address this question, we examined the effect on erythrocyte vitamin E levels of supplementation with either 15 mg or 100 mg per day of vitamin E. Analysis was performed by high performance liquid chromatography before and 1 year after initiation of supplementation in children with cystic fibrosis. Erythrocyte vitamin E concentrations were below the normal range in almost all unsupplemented patients and rose into the normal range with a supplement of 100 mg per day, but not 15 mg per day. This rise was not accounted for by changes in general dietary treatment. We conclude that tissue vitamin E levels are low in patients with cystic fibrosis who do not receive supplements but can be normalized in most children with 100 mg of vitamin E. per day.

Adolescent↗
PubMed1996

Antioxidant kinetics in lung lavage fluid following exposure of humans to nitrogen dioxide.

To determine if nitrogen dioxide (NO2), a gaseous free radical, modifies the protective antioxidant pool present in respiratory tract lining fluids, a random, double-blind study utilizing flexible fiberoptic bronchoscopy with bronchial and bronchoalveolar lavage was performed. Healthy, nonsmoking, asymptomatic subjects were exposed to filtered air and 2 ppm NO2 for 4 h on separate occasions. To examine the kinetics of the NO2-induced antioxidant reactions, 44 subjects were randomly assigned to one of three groups. Bronchoscopy was performed 1.5 h (group 1), 6 h (group 2) or 24 h (group 3) after each exposure. Reduced glutathione (GSH), uric acid, and ascorbic acid concentrations were determined in both bronchial and bronchoalveolar lavage fluid fractions. In addition, bronchoalveolar lavage fluid was screened for malondialdehyde as a marker of lipid peroxidation. Exposure to NO2 resulted in a rapid (1.5 h) loss of uric acid from the bronchial region, however by 6 h after exposure it had increased significantly above control uric acid concentration in this region. At 24 h after exposure, uric acid concentration had returned to the control level. A similar response of uric acid to NO2 was seen in the bronchoalveolar region. Ascorbic acid was also decreased in bronchial and bronchoalveolar lavage fluids 1.5 h after exposure to NO2, but returned to control values by 6 h. In marked contrast, significant increases in GSH concentration were seen at 1.5 and 6 h in bronchial lavage fluid after exposure to NO2, which subsequently returned to control levels by 24 h. No change in bronchoalveolar lavage fluid GSH concentration or malondialdehyde content was seen after NO2 exposure. These data support the view that antioxidants present in lung fluids react with, and hence modulate the impact of, NO2 on the lung.

Adult↗
PubMed1996

Pulmonary dysfunction in cystic fibrosis is associated with oxidative stress.

The aim of this study was to determine whether a relationship exists between the circulating concentration of antioxidants, or markers of oxidative stress, and pulmonary function in cystic fibrosis patients. Plasma was obtained from 34 patients attending a cystic fibrosis clinic. Oxidative stress was investigated by measuring the concentrations of circulating lipid hydroperoxides and malondialdehyde (lipid peroxidation) and protein carbonyls (protein oxidation). Antioxidant status was determined from the plasma concentrations of alpha-tocopherol, ascorbic acid, uric acid and total sulphydryls. Forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and forced mid-expiratory flow (FEF25-75) were measured in 25 of the subjects by spirometry, and expressed as percentage predicted for normal height, weight and age. Lung function decreased significantly with age and was associated with decreased plasma alpha-tocopherol, ascorbic acid and sulphydryl concentrations. The reduction in pulmonary function correlated with elevated plasma malondialdehyde, but not with lipid hydroperoxide or protein carbonyl concentrations. Patients with severe lung dysfunction (FEV1 < 50% predicted) had higher plasma concentrations of lipid hydroperoxides than those with mild-to-moderate lung dysfunction (FEV1 > 50% pred). This study provides evidence that cystic fibrosis patients have inadequate antioxidant defences to cope with the elevated oxidative stress that they regularly experience. We believe that recurring oxidative lung injury contributes to the decline in pulmonary function in these patients.

Adolescent↗
PubMed1996

Differential depletion of human respiratory tract antioxidants in response to ozone challenge.

The toxicity of ozone, the major component of photochemical smog, is related to its powerful oxidising ability, and many of its deleterious effects are mediated through free radical reactions. As the majority of ozone oxidation events are thought to be confined to the pulmonary epithelial lining fluid, we studied the interaction of ozone with a range of small molecular weight antioxidants found within this compartment: ascorbic acid (AH2), uric acid (UA), and reduced glutathione (GSH). Epithelial lining fluid obtained as bronchoalveolar lavage (BAL) fluid, was taken from 16 male subjects and the antioxidant concentrations determined for each subject. BAL fluid samples from nine of these subjects were then exposed, using an interfacial exposure system, to a range (50-1000 ppb) of ozone concentrations. Both AH2 and UA were consumed by ozone in a time and ozone concentration dependent manner, with mean consumption rates of 1.7 +/- 0.8 and 1.0 +/- 0.5 pmol L-1 s-1 ppb-1, respectively. Considerable intersubject variation was however observed. The individual rates of consumption for each antioxidant were significantly correlated with the respective initial antioxidant concentration. In contrast, although GSH was consumed at 50 ppb ozone, the rate of consumption did not change with increasing ozone concentration. We conclude that there is differential depletion of BAL fluid antioxidants, suggesting a reactivity hierarchy toward ozone in human ELF of AH2 > UA > > GSH.

Antioxidants↗
PubMed1996

Respiratory tract lining fluid antioxidants: the first line of defence against gaseous pollutants.

All tissues are vulnerable to oxidant damage, but by virtue of its location, anatomy and function, the epithelial surface of the lung is one of the most vulnerable targets in the body. Recent studies have shown that epithelial lining fluid (ELF), a thin layer of fluid which covers the epithelial surface of the respiratory tract, contains an interesting complement of antioxidants, some of which, like glutathione, are present in concentrations much higher than those found in plasma. It is likely that ELF forms the first line of defence against inhaled toxins such as ozone and nitrogen dioxide. By employing an ex vivo exposure system we have demonstrated that when lung lining fluid is in contact with environmentally relevant concentrations of ozone or nitrogen dioxide, there is differential consumption of the water-soluble antioxidants in the order, uric acid > ascorbic acid >> glutathione. Given that the majority of ozone and nitrogen dioxide reacts within the ELF compartment, the antioxidant composition of this fluid is critically important in determining an individual's sensitivity to gaseous pollutants.

Air Pollutants↗
PubMed1995

Oxidative damage to DNA in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) may be more susceptible to oxidative-cell injury due to impaired absorption of dietary-antioxidants. In addition, recurring pulmonary infections regularly subject them to oxidative stress. Our objective was to determine whether the concentration of urinary 8-hydroxydeoxyguanosine (oh8dG), a marker of free radical-induced DNA damage, is elevated in CF patients and to correlate its excretion with clinical status. The first morning void of urine was collected from 13 CF patients and 10 control children of similar age. To determine clinical status, forced expiratory volume (FEV1) and forced ventilatory capacity (FVC) and a Taussing-Schwachman score were obtained for each patient. Urinary oh8dG was measured by high performance liquid chromatography (HPLC) with electrochemical detection and the concentration normalized against creatinine concentration. The mean concentration (+/- SD) of urinary oh8dG was significantly higher in the CF group (2.78 +/- 1.21 vs. 1.51 +/- 0.38 nmol/mmol creatinine). A significant positive correlation was found between urinary oh8dG concentration and plasma alpha-tocopherol concentration in the CF patients (r = 0.947, p = 0.0001), suggesting that vitamin E might be involved in the excretion of oh8dG. However, no correlation was found between urinary oh8dG in CF and markers of lung function or the qualitative index of clinical status. These results confirm that patients with CF are susceptible to oxidative-induced DNA damage, although this appears to be independent of clinical status. Increased DNA damage may explain, in part, why CF patients have a higher incidence of malignancy compared to normal healthy age-matched controls.

Adolescent↗
PubMed1995

Biokinetics in humans of RRR-alpha-tocopherol: the free phenol, acetate ester, and succinate ester forms of vitamin E.

The bioavailability of RRR-alpha-tocopherol from the oral administration of RRR-alpha-tocopherol itself and its acetate and succinate esters was determined in healthy human subjects. Venous blood samples were withdrawn periodically over a 51-h period following oral administration of a gelatin capsule containing an equimolar mixture of RRR-alpha-tocopherol and RRR-alpha-tocopheryl acetate. In a second study, subjects received a capsule containing an equimolar mixture of RRR-alpha-tocopheryl acetate and RRR-alpha-tocopheryl succinate. In Study 1, RRR-alpha-tocopherol was absorbed at similar rates from both the free phenol, and the acetate ester and maximum plasma levels occurred at 12 h in most subjects. The extent of absorption of RRR-alpha-tocopherol varied considerably between subjects in absolute terms, but the relative absorption from the two forms was remarkably consistent, and a ratio of 1.0 was found for parameters of relative bioavailability in plasma. The concentration of RRR-alpha-tocopherol from each form was maximal at approximately 27 h in red blood cells and, as seen with the plasma data, there was a large interindividual variability. In Study 2, there was no significant difference in the extent of absorption of RRR-alpha-tocopherol from the acetate ester and the succinate ester, although there was an apparently higher initial rate of absorption from the acetate ester.

Administration, Oral↗
PubMed1995

Oxygen-induced lung injury in the pre-term guinea pig: the role of leukotriene B4.

Leukotriene B4 (LTB4) has been reported to promote the formation of lung oedema when infused into the pulmonary circulation of adult animals. The present study evaluated the hypothesis that LTB4 was responsible, in part, for the oedema that develops during oxidative injury of the immature lung. Significant increases were found in LTB4 concentration in bronchoalveolar lavage fluid obtained from pre-term guinea pig pups maintained in 95% oxygen for 48 h (P < 0.05) and 72 h (P < 0.05) compared to pups maintained in 21% oxygen. Cellular analysis of lavage fluid revealed a concurrent influx of neutrophils into the hyperoxic-injured lung at these times. The protein concentration of lavage fluid was also increased by 48-h hyperoxia exposure indicating elevated pulmonary microvascular permeability. In a second series of experiments, pups exposed to 95% oxygen (and 21% oxygen controls) were treated with a specific LTB4 antagonist (U-75302), at either 0.5, 1.5 or 3.0 mg 100 g body wt to ascertain if LTB4 played a role in either neutrophil recruitment or oedema formation in the immature lung. The number of neutrophils recovered in bronchoalveolar lavage fluid was significantly reduced, compared to vehicle-treated pups, in pups treated with U-75302, at both 1.5 and 3.0 mg/100 g body wt but not 0.5 mg/100 g body wt. Histopathological analysis of pups treated with 1.5 mg U-75302/100 g body wt revealed fewer neutrophils in the pulmonary interstitium (198 vs. 218 mm-2, P < 0.05). The extent of lung microvascular permeability, elevated by hyperoxic exposure, was modulated by increasing concentrations of U-75302. Specifically, treatment with 0.5, 1.5 and 3.0 mg U-75302/100 g body wt reduced microvascular permeability by 17, 67 and 98%, respectively. In conclusion, LTB4 plays an important role in oedema formation in acute oxidative injury of the immature lung and this is mediated, in part, through neutrophils.

Animals↗
PubMed1995

Depletion of urate in human nasal lavage following in vitro ozone exposure.

Ozone, a strong oxidant present in summer smog, is thought to primarily react with antioxidant molecules found in the epithelial lining fluid of the respiratory tract. In humans, as much as 40% of inhaled ozone can be removed in the nasal cavity where the major extracellular antioxidant has been identified as uric acid. The present study was undertaken to examine urate/oxidant interactions in human nasal lavage fluid following in vitro exposure to ozone at concentrations relevant to the U.K. Lavage fluid was collected from 8 volunteers using a modified Foley catheter which permits prolonged contact of isotonic saline with the anterior nasal cavity. Nasal lavage samples in multiwell plates were exposed to ozone at concentrations of 50, 100 and 250 ppb. Samples were removed at intervals from 15 to 240 min following exposure and assayed for uric acid depletion. Uric acid concentrations in the nasal lavage were found to fall from 8.52 (time zero) to 3.99 microM, 0.05 and 0.07 microM after 240 min at 50, 100 and 250 ppb ozone respectively. At a non-environmentally relevant ozone concentration of 1000 ppb, uric acid was completely depleted after 60 min. Regression analysis showed a linear correlation between rate of loss of urate and ozone concentration (R2 = 0.97). A novel, non-invasive technique is described to investigate antioxidant compromise and its importance in individual subjects. We conclude that uric acid in nasal lavage samples is scavenged by ozone in a dose and time dependent manner.

Ascorbic Acid↗
PubMed1995

Hyperoxic injury of immature guinea pig lung is mediated via hydroxyl radicals.

Support of preterm infants with ventilation and oxygen therapy frequently leads to the development of chronic lung disease. Oxidative stress, through the generation of excess oxygen free radicals, is thought to play a major role in this condition. At present the radical species responsible for oxidative lung injury is not known, and effective antioxidant based therapies are not available. The purpose of this study was to determine whether hydroxyl radicals, potent reactive oxygen species, are involved in chronic oxidative lung injury. To obtain this information we developed a animal model of chronic lung injury using the preterm guinea pig and analyzed lung tissue from these pups for o-tyrosine, a specific marker of hydroxyl radical attack. In normoxia control pups the pulmonary content of o-tyrosine was low during the first 4 wk of life (range 0.11-0.12% tyrosine). Pups maintained in 85% oxygen were found to have increasing lung o-tyrosine over this period (d 7, 0.51%; d 14, 0.8%; d 21, 1.28%; d 28, 1.45% tyrosine). From d 21, the nonenzymatic glycosylation end product, N-epsilon-carboxymethyllysine was also present in significantly increased amounts in hyperoxic-exposed pups. These results implicate hydroxyl radicals as a significant oxidizing species in hyperoxic lung injury and provide a basis for understanding collagen deposition in the neonatal lung.

Animals↗