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Biomedical subjects

S J Lane

Publications and source records attributed to S J Lane.

At least 37 records · Page 2Linked to original sources
PubMed1997

Effect of inhaled glucocorticoids on IL-1 beta and IL-1 receptor antagonist (IL-1 ra) expression in asthmatic bronchial epithelium.

BACKGROUND: Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and the existence of naturally occurring cytokine antagonists has added to this complexity. Upregulation of both interleukin 1 beta (IL-1 beta) and its naturally occurring receptor antagonist, interleukin 1 receptor antagonist (IL-1ra), has previously been observed on asthmatic bronchial epithelium compared with normal airways. METHODS: The effect of inhaled beclomethasone dipropionate (BDP) on asthmatic bronchial epithelial expression of IL-1 beta and IL-1ra was studied. Frozen bronchial biopsy specimens from nine asthmatic subjects receiving 1000 micrograms BDP daily for eight weeks and from six asthmatic subjects receiving matching placebo were stained with anti-IL-1 beta and anti-IL-1ra antibodies. Hue-saturation-intensity (HSI) colour image analysis was used to quantify the brown immunoperoxidase reaction colour present on the bronchial epithelium. RESULTS: There was a significant twofold decrease in the epithelial expression of IL-1 beta after treatment with BDP but no significant change was seen in IL-1ra (P = 0.175). CONCLUSION: The selective inhibition of IL-1 beta, without effect on IL-1ra, provides a novel mechanism for the anti-inflammatory action of glucocorticosteroids.

Adult↗
PubMed1997

Equivalence reliability of the functional independence measure for children (WeeFIM) administration methods.

OBJECTIVE: This study examined the equivalence reliability of two administration methods for the Functional Independence Measure for Children (WeeFIM). The two methods were direct observation of child performance and parental interview. METHOD: Thirty children between the ages of 19 months and 71 months with identified developmental disabilities were included in this study. The direct observation and interview methods were administered in random order to each subject within a 3-week period. The direct observation was completed in the educational setting, and the WeeFIM interview was obtained by either in-person interview or telephone interview with the parent. RESULTS: The intraclass correlation coefficient (ICC) for total WeeFIM ratings was .93, indicating consistency between the two administration methods. Analysis of the WeeFIM Motor (13 items) and Cognitive (5 items) domains yielded ICC values of .93 and .75, respectively, suggesting greater consistency for items measuring motor-related skills. CONCLUSION: The results demonstrate good agreement for total ratings when the WeeFIM is administered by direct observation and by interview with a parent. The findings establish the clinical usefulness of information collected by clinical interview.

Activities of Daily Living↗
PubMed1996

The effects of prednisolone on the cutaneous tuberculin response in patients with corticosteroid-resistant bronchial asthma.

We have used the classical tuberculin cutaneous delayed hypersensitivity immune response to investigate the effects of corticosteroids on mononuclear cell function in nine subjects with corticosteroid-resistant asthma (CRA) and six subjects with corticosteroid-sensitive asthma (CSA), who demonstrated sensitivity to intradermal purified protein derivative (PPD) of Mycobacterium tuberculosis. In a double-blind, crossover, placebo-controlled study, patients were given oral prednisolone or placebo, starting on day 0, and a predetermined intradermal dose of PPD on day 7. On day 9 the site of the induration was measured and biopsied for immunohistochemical analysis. There was no difference in skin induration between the CSA and CRA groups during the placebo arm of the study (p = 0.38). Prednisolone significantly suppressed the cutaneous induration (p, 0.003) in the CSA group but not in the CRA group. As compared with placebo, the number of macrophages (p = 0.018), eosinophils (p = 0.009), and T memory cells (p = 0.009) was suppressed by prednisolone in the CSA group but not in the CRA group. No significant suppression of the number of neutrophils or monocytes/immature macrophages was induced by prednisolone in either group. There was no difference in intracellular adhesion molecule-1, vascular cell adhesion molecule-1, and endothelial leukocyte adhesion molecule-1 expression in blood vessels or epidermis between the CSA and CRA groups, with no suppression by prednisolone in either group. These findings suggest a defect in the responsiveness of cellular immune mechanisms to the suppressive effects of corticosteroids in steroid-resistant asthma. The differential suppressive effects of corticosteroids on cellular recruitment in the PPD response between the individuals with CSA and those with CRA are not due to modulation of expression of endothelial adhesion molecules.

Adrenal Cortex Hormones↗
PubMed1996

Mast cell effector mechanisms.

Several lines of evidence support the central role of the cysteinyl leukotrienes in aspirin-sensitive asthma, although their cellular source is unknown. The two most likely cells are the mast cell and eosinophil. Compared with aspirin-tolerant patients with asthma, patients with aspirin-sensitive asthma have been found to have a greater infiltration of mast cells and eosinophils in bronchial biopsy samples, although proportions of activated eosinophils were similar. Findings that support the involvement of mast cells include elevated serum histamine and tryptase levels after aspirin challenge in sensitive subjects, in line with a decrease in lung function and increased histamine and leukotriene C4 levels in nasal secretions; release of high-molecular-weight neutrophil chemotactic factor into serum after challenge; and prevention of aspirin-induced bronchoconstriction by pretreatment with cromolyn sodium or nedocromil sodium. These agents are also effective in protecting against bronchoconstriction induced by hyperosmolar stimuli, a challenge that is not associated with increased leukotriene E4 responsiveness but that is followed by increased release of histamine and prostaglandin D2 into bronchoalveolar lavage fluid. Antihistamines are poorly effective at inhibiting aspirin-induced bronchoconstriction but have been shown to attenuate the bronchoconstrictor response to hyperosmolar challenge. The main effector mechanism in hyperosmolar-induced bronchoconstriction appears to be mast cell activation and histamine release.

Animals↗
PubMed1996

The stability and equivalence reliability of the functional independence measure for children (WeeFIM).

The reliability of the Functional Independence Measure for Children (WeeFIM) was examined in 37 non-disabled children and 30 children with disabilities, from 12 to 76 months of age. The WeeFIM is derived from the Functional Independence Measure (FIM) and includes 18 items involving six functional subscales. Stability was assessed by administering the WeeFIM instrument to each child's caregiver on two occasions separated by 7 to 14 days. Intraclass correlation co-efficients (ICCs) for individual items ranged from 0.90 to 0.99. The ICC for the six WeeFIM subscales ranged from 0.94 for social cognition to 0.99 for transfers and locomotion. The ICC value for total WeeFIM test-retest reliability was 0.98 for children with disabilities and 0.99 for children without disabilities. Equivalence reliability was examined by comparing ratings obtained when using personal assessment with ratings collected during a telephone interview. No statistically significant differences were found for individual items, subscale scores or total WeeFIM values.

Child Behavior↗
PubMed1996

Hypothalamic-pituitary-adrenal axis in corticosteroid-resistant bronchial asthma.

We have examined whether the lack of clinical response to corticosteroids seen in corticosteroid resistant (CR) bronchial asthma is reflected in abnormalities of endogenous cortisol secretion and in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in CR subjects by using a modification of the standard dexamethasone suppression test (DST) in response to 0.25 and 1 mg oral dexamethasone. Five corticosteroid-sensitive (CS) and five CR asthmatic subjects were studied on two occasions 1 mo apart. In the first limb of the study subjects received 0.25 mg of oral dexamethasone, and in the second limb they received 1 mg. Urinary cortisol was measured by fluorimetry after extraction, and plasma cortisol and adrenocorticotropic hormone (ACTH) concentrations were estimated by enzyme-linked immunosorbent assay (ELISA) and immunoradiometric assays, respectively. On Day 1, a 24-h urine sample was collected for estimation of urinary free cortisol. On Day 2, a fasting blood sample was taken at 9:00 A.M. for estimation of plasma cortisol and ACTH. At 11:00 P.M., 0.25 mg (1 mg) of dexamethasone was taken orally by each subject. On Day 3, blood was taken at 9:00 A.M. and 3:00 P.M. for similar estimations. The levels of urinary free cortisol (nmol/24 h) and predose plasma ACTH (ng/L) and cortisol (nmol/L) were 199 +/- 42, 27.4 +/- 5.7, and 300 +/- 48 (mean +/- SEM), respectively, in the CS group, and 210 +/- 74, 23.4 +/- 6.7, and 263 +/- 32 (mean +/- SEM), respectively, in the CR group (p > 0.05 for all comparisons). Plasma ACTH and cortisol concentrations were not significantly suppressed in either group after 0.25 mg dexamethasone, but were equally suppressed in both groups to undetectable levels by 1 mg dexamethasone. We conclude that CR asthma is not reflected in an altered secretory rate of endogenous cortisol or in an altered sensitivity of the HPA axis to dexamethasone suppression.

Adrenocorticotropic Hormone↗
PubMed1996

Expression of interleukin-1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic bronchial epithelium.

Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and recent findings have suggested that naturally occurring cytokine antagonists may also be involved. In this study we looked at the expression of interleukin-1 beta (IL-1beta) and its naturally occurring receptor antagonist, IL-1ra, in the normal and asthmatic bronchial wall. Frozen bronchial biopsies from 12 normal and 18 asthmatic individuals were double stained with EBM11 (a CD68 macrophage marker) and either a rabbit anti-IL-1beta or a rabbit anti-IL-1ra. Hue-saturation-intensity color image analysis (HSI) was used to quantify the brown immunoperoxidase reaction product present on the bronchial epithelium. There was an increased expression of both IL-1beta and IL-1ra in the asthmatic bronchial epithelium, p < 0.0002 and p < 0.0001, respectively. Additionally, the numbers of macrophages, of IL-1beta producing cells, and the percentage of macrophages producing IL-1beta were significantly increased in the asthmatic submucosa (p < 0.004, p < 0.002, and p < 0.008, respectively).

Adult↗
PubMed1996

Lesions associated with mineral deposition in the lymph node and lung of the dog.

This report includes details of the clinical and pathologic features of 31 dogs with a range of systemic illness and granulomatous lymphadenopathy associated with the presence of birefringent crystalline material within lymph nodes. Similar crystalline material was found in the lymph nodes of dogs with lymphoma (n = 9) and as an incidental finding within the canine lung (n = 9). The mineral content of these crystals was determined by electron microprobe analysis and interpreted in light of the composition of known geological or human-made compounds. A wide range of elements was identified including silicon, sulfur, copper, calcium, and aluminium, with lesser proportions of phosphorus, sodium, potassium, iron, magnesium, titanium, nickel, and chromium. Many of these compounds may have originated from exogenous natural and human-made sources, but some compounds (notably phosphates and sulfates) are uncommon or not found in nature and may have been formed within the tissues of the body (biomineralization). The inflammatory response induced by the presence of these minerals within lymphoid tissue may trigger altered immunoregulation, accounting for the spectrum of disease observed.

Aluminum↗
PubMed1996

Effects of prednisolone on bone turnover in patients with corticosteroid resistant asthma.

BACKGROUND: Although corticosteroid resistant (CR) bronchial asthma is associated with impaired in vitro an din vivo glucocorticoid (GC) responsiveness in mononuclear cell function, it is not known whether this is a cell specific phenomenon or whether these patients are at risk of glucocorticoid side-effects as corticosteroid-sensitive (CS) subjects. In order to address this question we have examined the effects of GCs on biochemical indices of bone turnover in vivo. METHODS: Six CS and six CR subjects received prednisolone 40 mg orally at 09.00 daily for 5 days. At 08.30 on day 1 and day 6 a fasting blood was taken for estimation of serum osteocalcin, tartrate resistant acid phosphatase (TRAP) and alkaline phosphatase (ALP; total and bone isoenzyme), and a urine sample taken for estimation of free deoxy-pyridinoline crosslinks. TRAP and ALP were measured by a colorimetric method and osteocalcin and deoxy-pyridinoline crosslinks by ELISA. RESULTS: Serum osteocalcin (nmol/L) decreased from 1.39 +/- 0.09 (mean +/- SEM) to 1.14 +/- 0.07 (P = 0.023) and from 1.19 +/- 0.05 to 0.96 +/- 0.1 (P = 0.037) in the CS and CR groups respectively. There was no difference between baseline and post-treatment levels in either group. Serum total ALP (units/L) decreased from 178 +/- 7 to 168 +/- 4 (P = 0.02) and from 195 +/- 22 to 175 +/- 16 (P = 0.04) in the CS and CR groups, respectively. There was no difference between baseline and post-treatment levels in either group. There was no significant elevation of deoxy-pyridinoline crosslinks or TRAP and no suppression of bone ALP in either group. CONCLUSION: We suggest that CR asthmatics may be equally at risk from the metabolic side-effects of glucocorticoids.

Acid Phosphatase↗
PubMed1995

Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma.

Glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases. However, a small proportion of patients is resistant to the therapeutic effects of glucocorticoids. Pharmacokinetic and ligand binding studies suggest that the molecular abnormality in steroid resistance lies distal to nuclear translocation. We have previously reported that there is a decreased ability of glucocorticoid receptors (GR) to bind to the DNA-binding site in peripheral blood mononuclear cells (PBMC) after dexamethasone treatment. This reduced DNA binding was due to a decrease in the number of receptors available rather than an alteration in affinity for DNA. To study this reduced DNA binding, we examined the ability of the nuclear translocated transcription factors activator protein 1 (AP-1), nuclear factor kappa B (NF-kappa B) and cyclic AMP response element-binding protein (CREB) to bind to their DNA-binding sites and to interact with GR in PBMC from patients with steroid-sensitive and steroid-resistant asthma. There was a significant reduction in the interaction between GR and AP-1 in these steroid-resistant patients, although interaction with other transcription factors activated in inflammation (NF-kappa B and CREB) was unaffected. An increase in the basal levels of AP-1 DNA binding was also detected in the nuclei from steroid-resistant asthmatic patients. There were no differences in the amount of messenger RNA detected for the components of AP-1, c-Fos and c-Jun, nor in the sequences of these messenger RNAs. These results suggest either that the ability of the GR to bind to glucocorticoid response elements and AP-1 is altered in steroid-resistant patients or that increased levels of AP-1 prevent GR DNA binding, and that this may be the molecular basis of resistance to the antiinflammatory effect of steroids in these cells.

Asthma↗
PubMed1995

Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma.

Although glucocorticosteroids are a very effective treatment for asthma and other chronic inflammatory diseases, a small proportion of patients are resistant to their therapeutic effects. The molecular mechanism for this steroid resistance is unclear. Steroid resistance cannot be explained by pharmacokinetic mechanisms, by a defect in the binding of steroids to glucocorticoid receptors, nor by defective nuclear translocation of this receptor, thereby suggesting that the molecular abnormality lies distal to nuclear translocation. We examined the ability of nuclear translocated glucocorticoid receptors to bind to their DNA binding sites (GRE) using electrophoretic mobility shift assays in PBMC from patients with steroid-sensitive and steroid-resistant asthma. The binding of the glucocorticoid receptor to DNA in these patients was also studied using Scatchard analysis. Dexamethasone induced a significant rapid and sustained twofold increase in GRE binding in PBMCs from steroid-sensitive asthmatic patients and nonasthmatic individuals, but this was markedly reduced in steroid-resistant asthmatic patients. Scatchard analysis of glucocorticoid receptor-GRE binding showed no change in binding affinity but did show a reduced number of receptors available for DNA binding in the steroid-resistant patients. These results suggest that the ability of the glucocorticoid receptor to bind to GRE is impaired in steroid-resistant patients because of a reduced number of receptors available for binding to DNA.

Adult↗
PubMed1994

Increased expression of the monocyte chemoattractant protein-1 in bronchial tissue from asthmatic subjects.

The expression of the monocyte chemoattractant protein (MCP-1), a member of the chemokine family of low molecular weight cytokines, was assessed by immunohistochemistry in bronchial biopsies from 12 asthmatic and 12 normal subjects. Both a monoclonal antibody (F9) and a polyclonal antibody were employed to detect MCP-1, while the mouse myeloma protein (MOPC21) was used as a negative control. Strong positive reactions for MCP-1 were seen in the bronchial epithelium. Subepithelial macrophages, blood vessels, and bronchial smooth muscle were also stained. Hue-saturation-intensity color image analysis was used to quantify reactions of the monoclonal antibody in the epithelial and subepithelial layers. With the monoclonal antibody, asthmatic biopsies showed 51.8 +/- 3.7% (mean +/- SEM) of the epithelium staining positively, whereas normal subjects reacted much less, with 6.4 +/- 1.9% of the epithelium staining (P < 0.0001); there was no overlap between the two groups. Likewise, staining was increased in the subepithelium of asthmatic airway biopsies, with 11.5 +/- 3.1% and 2.0 +/- 1.0% staining positively in asthmatic and normal subepithelium, respectively, (P < 0.002). There was a significant correlation between staining of the epithelium and subepithelium (r = 0.77, P < 0.001). The polyclonal anti-MCP-1 antibody also gave strong reactions in the epithelium and subepithelium, with 34.0 +/- 7.8% of the asthmatic and 1.6 +/- 1.0% of the normal bronchial epithelium staining positively (P < 0.0001). These increased levels of MCP-1 in the asthmatic airways suggest that they may play a role in macrophage recruitment and activation and thereby contribute to the inflammatory pathology of bronchial asthma.

Adult↗
PubMed1994

Chemical mutational analysis of the human glucocorticoid receptor cDNA in glucocorticoid-resistant bronchial asthma.

Corticosteroid-resistant (CR) asthma is not caused by altered bioavailability of the administered drug, altered ligand-binding characteristics, or altered nuclear translocation of the activated human glucocorticoid receptor (hGR) complex. We have tested the hypothesis that CR asthma results from a consistent polymorphism in the functionally diverse hGR cDNA using the sensitive screening technique of polymerase chain reaction (PCR) amplification and chemical mutational analysis. Total RNA was extracted from peripheral blood monocytes derived from six corticosteroid-sensitive (CS) and six CR asthmatic subjects. The RNA was reverse transcribed, and overlapping hGR cDNA fragments were amplified by nested PCR. Double-stranded hGR cDNA fragments were hybridized to corresponding 32P-5'-labeled wild-type fragments, chemically modified with osmium and hydroxylamine, and cleaved with piperidine. The resultant cleaved strands were detected by autoradiography. As controls, single base pair mutated hGR cDNA fragments sensitive to hydroxylamine and osmium modification were used. Using this technique, we did not detect any base pair mismatch between the six CS and six CR patients and the corresponding wild-type hGR, despite a 100% detection of control mutations. We conclude that the defect in CR asthma does not lie in the structure of the hGR.

Adult↗