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Biomedical subjects

R Hubbard

Publications and source records attributed to R Hubbard.

At least 19 recordsLinked to original sources
PubMed2000

Inhaled corticosteroid use and bone-mineral density in patients with asthma.

BACKGROUND: Inhaled corticosteroids are absorbed into the systemic circulation, but the extent to which they have adverse effects on bone is uncertain. The question is important since 3% of the European population take an inhaled corticosteroid regularly and may do so for many years. METHODS: We studied the dose-response relation between cumulative inhaled corticosteroid dose and bone-mineral density at the lumbar spine and proximal femur in 196 adults (119 women) with asthma aged 20-40 years. Patients had taken an inhaled corticosteroid regularly for at least 6 months, and had had limited exposure to systemic steroids. Cumulative dose of inhaled corticosteroid was calculated from questionnaires and computerised and written general-practice records, and its effect on bone-mineral density was estimated by multiple regression analysis. FINDINGS: Median duration of inhaled corticosteroid treatment was 6 years (range 0.5-24), and median cumulative dose was 876 mg (87-4380). There was a negative association between cumulative dose of inhaled corticosteroid and bone-mineral density at the lumbar spine (L2-L4), femoral neck, Ward's triangle, and trochanter, both before and after adjustment for the effects of age and sex. A doubling in dose of inhaled corticosteroid was associated with a decrease in bone-mineral density at the lumbar spine of 0.16 SD (95% CI 0.04-0.28). Similar decreases were found at the femoral neck, Ward's triangle, and trochanter. Adjustment for potential confounding factors including physical activity and past oral, nasal, dermal, and parenteral corticosteroids did not weaken the associations. INTERPRETATION: This study provides evidence of a negative relation between total cumulative dose of inhaled corticosteroid and bone-mineral density in patients with asthma.

Absorptiometry, Photon↗
PubMed2000

Local road traffic activity and the prevalence, severity, and persistence of wheeze in school children: combined cross sectional and longitudinal study.

OBJECTIVES: To investigate the relation between local road traffic activity and the occurrence, severity, and persistence of wheeze in children. METHODS: Data on wheeze and asthma were collected in a cross sectional questionnaire survey of 22,968 primary school children (age 4-11) and 27,826 secondary school children (age 11-16) in the Nottingham area. Direct measures of road traffic flow were made in the locality of each school and combined with Local Authority traffic data for major roads to estimate local traffic activity in vehicle metres/day/km2. Assessment of the effects of potential confounders was performed in nested case-control groups of 6576 primary and 5936 secondary children. Data on frequency of wheeze were collected for the cases to study disease severity. Longitudinal data on a historical cohort of 883 children who reported wheeze when aged 4-11 in 1988 were used to study the persistence of wheeze into adolescence. RESULTS: Unadjusted prevalence of wheeze in the past year within schools varied widely but was not associated with traffic activity in the school locality (weighted regression coefficient beta = -0.01, p = 0.93 for primary schools, beta = -0.18, p = 0.26 for secondary schools). The risk of wheeze in individual primary school children was not associated with traffic activity analysed as a continuous variable, although there was some suggestion of a weak, non-linear plateau effect. Similar effects were found for diagnosed asthma and recent cough. There was no evidence of any relation between traffic activity and risk of wheeze in secondary school children. There were positive but non-significant dose related effects of traffic activity on wheeze severity in primary and secondary children and on persistence of wheeze in the longitudinal cohort. CONCLUSIONS: Traffic activity in the school locality is not a major determinant of wheeze in children.

Adolescent↗
PubMed2000

Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study.

Cryptogenic fibrosing alveolitis has been reported to be associated with an increased risk of lung cancer. However, it has recently become apparent that cigarette smoking may be a risk factor for cryptogenic fibrosing alveolitis as well as for lung cancer, and so may confound the association between these conditions. We have therefore estimated the independent increase in lung cancer incidence in patients with cryptogenic fibrosing alveolitis compared with the general population in a population-based cohort study involving 890 subjects with cryptogenic fibrosing alveolitis and 5, 884 control subjects drawn from the United Kingdom General Practice Research Database. The incidence of lung cancer was markedly increased among patients with cryptogenic fibrosing alveolitis (rate ratio [RR] 7.31, 95% confidence interval [95% CI] 4.47 to 11.93, p < 0.001), and adjustment for previous smoking history had little effect on this odds ratio (adjusted RR: 8.25, 95% CI 4.70 to 11.48, p < 0.001). This increase in lung cancer incidence remained when the analysis was restricted to current smokers (RR 7.36, 95% CI 1.54 to 35.19, p = 0.012). This study provides clear evidence that the incidence of lung cancer is increased in patients with cryptogenic fibrosing alveolitis, and that this effect is independent of the effect of cigarette smoking.

Aged↗
PubMed1999

Association of CCR5 delta32 with reduced risk of asthma.

We report that individuals carrying the CCR5 delta32 mutation, a naturally occurring variant of the C-C chemokine receptor 5 (CCR5), are at reduced risk of developing asthma. These data suggest a possible explanation for the high prevalence of this mutation in the general population.

Adolescent↗
PubMed1999

George Wald memorial talk.

George Wald was born in 1906 in New York City to immigrant parents. An early and voracious reader, he soon developed a wide range of interests and entered New York University as a pre-law student, the first in his family to attend college. Shortly shifting to pre-medicine, he graduated college in biology. For graduate work, he joined the laboratory of Selig Hecht, a pioneer in vision research, at Columbia University. In 1932, four months before Hitler came to power, George went to Berlin to do postdoctoral work in the laboratory of Otto Warburg and there found vitamin A in the retina. This launched his life-long explorations of the molecular basis of vision for which he received the Nobel Prize in Physiology or Medicine in 1967. During the 1960s, George became increasingly involved in anti-war and anti-nuclear activities, writing and travelling widely, including multiple trips to commemorations of the bombings of Hiroshima and Nagasaki sponsored by Japanese colleagues. He considered these activities part of being a biologist, someone concerned with life. In his final years, he turned to questions about consciousness, writing and speaking about 'Life and Mind in the Universe'.

Animals↗
PubMed1998

Exposure to commonly prescribed drugs and the etiology of cryptogenic fibrosing alveolitis: a case-control study.

Cryptogenic fibrosing alveolitis is an interstitial lung disease of unknown etiology. Since pulmonary fibrosis is a recognized, if rare, complication of certain drug exposures, including antidepressants, betablockers, antibiotics, anticonvulsants, and nonsteroidal antiinflammatory drugs (NSAIDs), we tested the hypothesis that exposure to these drugs might contribute to the etiology of cryptogenic fibrosing alveolitis. Lifetime drug exposure data were collected from general practitioner records for 141 cases of cryptogenic fibrosing alveolitis and 246 age-, sex-, and community-matched control subjects from the Trent region of England. Additional data on lifetime smoking habits were obtained by postal questionnaire. The odds of disease in relation to ever exposure to antidepressants, betablockers, antibiotics, anticonvulsants, and NSAIDs were calculated by conditional logistic regression. For drug groups significantly associated with cryptogenic fibrosing alveolitis, subset analyses were performed to investigate the effects of individual drugs. Cryptogenic fibrosing alveolitis was associated with exposure to antidepressants (odds ratio [OR] 1.79 [95% CI 1.09-2.95], p = 0.022) and specifically to imipramine (OR 4.79 [1.50-15.3], p = 0.01), dothiepin (OR 2.37 [0.99-5.69], p = 0.05), and mianserin (OR 3.27 [1.11-9.61], p = 0.03). The magnitude of the overall effect of antidepressants was not changed by excluding all drug exposures within the 5 yr preceding the diagnosis of cryptogenic fibrosing alveolitis (OR 1.62 [0.94-2.77], p = 0.081), nor were the strong individual effects of imipramine (OR 5.72 [1.54-21.2], p = 0.009) and dothiepin (OR 5.58 [1.12-27.8], p = 0.036). These estimates were not appreciably affected by controlling for smoking history. The attributable risk for antidepressant exposure was in the region of 9-14%. No significant association was noted between cryptogenic fibrosing alveolitis and the four other drug groups in the primary hypothesis. The results of this study suggest that some antidepressant drugs can cause cryptogenic fibrosing alveolitis.

Adrenergic beta-Antagonists↗
PubMed1998

Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study.

STUDY OBJECTIVES: To determine the median survival of patients with cryptogenic fibrosing alveolitis, in comparison to that expected of individuals of the same age and sex from the general population. To estimate the effect of survival bias incurred by studying both incident and prevalent cases. To identify factors associated with survival. DESIGN: Cohort study. SETTING: Nine hospitals from the Trent Region of England. PATIENTS: Two hundred forty-four cases of cryptogenic fibrosing alveolitis: 168 patients were alive on day 1 of the study (prevalent cases), and 76 patients had newly diagnosed conditions over a prospective 18-month period of patient recruitment (incident cases). MEASUREMENTS: Age, sex, date of diagnosis, lung function at presentation, and details of treatment prescribed were extracted from hospital clinical records. Data on lifetime smoking habits were collected by postal questionnaire. Vital status was established from the general practitioner. The expected survival of each case was extracted from the English life tables. RESULTS: Median survival for incident cases was 2.9 years and for prevalent cases 9 years, compared to expected values of 10 and 13 years, respectively. Incident cases had significantly worse survival than prevalent cases, even after adjustment for the effects of age, sex, smoking history, lung function at presentation, and treatment (hazard ratio, 4.53 [95% confidence interval, 2.71 to 7.56]; p<0.001). Lower FVC at presentation and the use of corticosteroid treatment were both associated with worse survival. CONCLUSIONS: The inclusion of prevalent cases leads to significant overestimation of the median survival for patients with cryptogenic fibrosing alveolitis. In newly diagnosed cases of cryptogenic fibrosing alveolitis, median survival is only 2.9 years, and expected life span is reduced by approximately 7 years.

Adrenal Cortex Hormones↗
PubMed1997

Characterization of the allosteric binding pocket of human liver fructose-1,6-bisphosphatase by protein crystallography and inhibitor activity studies.

The structures of three complexes of human fructose-1,6-bisphosphatase (FB) with the allosteric inhibitor AMP and two AMP analogues have been determined and all fully refined. The data used for structure determination were collected at cryogenic temperature (110 K), and with the use of synchrotron radiation. The structures reveal a common mode of binding for AMP and formycine monophosphate (FMP). 5-Amino-4-carboxamido-1 beta-D-5-phosphate-ribofuranosyl-1H-imidazole (AICAR-P) shows an unexpected mode of binding to FB, different from that of the other two ligands. The imidazole ring of AICAR-P is rotated 180 degrees compared to the AMP and FMP bases. This rotation results in a slightly different hydrogen bonding pattern and minor changes in the water structure in the binding pocket. Common features of binding are seen for the ribose and phosphate moieties of all three compounds. Although binding in a different mode, AICAR-P is still capable of making all the important interactions with the residues building the allosteric binding pocket. The IC50 values of AMP, FMP, and AICAR-P were determined to be 1.7, 1.4, and 20.9 microM, respectively. Thus, the approximately 10 times lower potency of AICAR-P is difficult to explain solely from the variations observed in the binding pocket. Only one water molecule in the allosteric binding pocket was found to be conserved in all four subunits in all three structures. This water molecule coordinates to a phosphate oxygen atom and the N7 atom of the AMP molecule, and to similarly situated atoms in the FMP and AICAR-P complexes. This implies an important role of the conserved water molecule in binding of the ligand.

Adenosine Monophosphate↗
PubMed1997

Alpha1-antitrypsin phenotypes in patients with cryptogenic fibrosing alveolitis: a case-control study.

Cryptogenic fibrosing alveolitis (CFA) is an interstitial lung disease, which by definition is of unknown aetiology. Recent evidence has suggested that smoking and occupational exposure to dusts may be environmental risk factors for the disease, but there has been little research into potential host risk factors. One previous study has suggested that the prevalence of abnormal alpha1-antitrypsin phenotypes may be increased in patients with CFA. Since alpha1-antitrypsin is important in regulating inflammation within the lung in response to environmental exposures, such abnormalities may be of aetiological importance in this disease. We have compared the alpha1-antitrypsin phenotypes of 189 patients with CFA with 189 age-, sex-, and community-matched controls. This sample size was sufficient to provide more than 95% power to detect an odds ratio (OR) of 2.5. Alpha1-antitrypsin phenotype was established by isoelectric focusing, and the prevalence of abnormal phenotypes in cases and controls was compared by conditional logistic regression. Personal smoking histories were obtained by postal questionnaire. The prevalence of abnormal alpha1-antitrypsin phenotypes was similar in cases and controls (12.7 versus 15.3%; OR 0.88; 95% confidence interval 0.49-1.57; p=0.66). No interaction was found between the presence of abnormal alpha1-antitrypsin phenotypes and a history of smoking. We conclude that cryptogenic fibrosing alveolitis is not associated with abnormal alpha1-antitrypsin phenotypes.

Adult↗
PubMed1996

Occupational exposure to metal or wood dust and aetiology of cryptogenic fibrosing alveolitis.

BACKGROUND: We have previously suggested that cryptogenic fibrosing alveolitis (CFA) may be caused by occupational exposures, particularly to metal or wood dust. We have specifically investigated this hypothesis in a case-control study of patients with CFA. METHODS: We obtained lifetime occupational histories by postal questionnaire from 218 patients with CFA and 569 controls matched for age, sex, and community, living in the Trent region of the UK. Information was subsequently verified by telephone interview in 165 cases and 408 controls. Serum IgE, rheumatoid factor, and antinuclear antibodies and skin sensitivity to common allergens were measured in cases and in one matched control for each. FINDINGS: The relative risk of CFA, after adjustment for smoking, was significantly increased in relation to questionnaire-reported exposure to metal dust (odds ratio 1.68 [95% CI 1.07-2.65], p = 0.024) or to wood dust (1.71 [1.01-2.92], p = 0.048). Similar results were obtained with the telephone interview data. Significant exposure-response effects were found for both metal-dust and wood-dust exposure. CFA was also associated with the presence of rheumatoid factor or antinuclear antibodies, but not with positive allergen skin tests or raised IgE concentrations. There was no evidence of interaction between the effects of rheumatoid factor, antinuclear antibodies, positive skin allergen tests, or IgE concentrations and exposure to metal or wood dust. The combined aetiological fraction attributable to exposure to metal or wood dust was of the order of 20%. INTERPRETATION: Occupational exposures to metal or wood dust are independent risk factors for CFA. Avoidance or limitation of these exposures may provide an opportunity to prevent the disease.

Autoantibodies↗