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Biomedical subjects

R Hubbard

Publications and source records attributed to R Hubbard.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Lymphocyte subset infiltration patterns and HLA antigen status in colorectal carcinomas and adenomas.

Fifty eight large bowel adenocarcinomas and 20 adenomas were studied immunohistochemically, using fresh frozen tissue sections, with regard to lymphocyte subpopulations (CD3, CD4, CD8, CD19, and CD20) in the inflammatory infiltrate and to expression of human leucocyte antigens (HLA-ABC, HLA-A2, and HLA-DR). The findings were related to differentiation and Duke's stage of carcinoma. The inflammatory infiltrate was found to have a phenotype that remained constant irrespective of the intensity of the inflammation. CD4 and CD3 positive cells predominated with fewer CD8 positive cells and a scanty diffuse CD19/20 positive cell population. CD19/20 follicular aggregates were common at the advancing margin of the carcinomas. There was no significant association with Duke's stage, differentiation or HLA status. HLA changes (ABC loss, A2 loss, and DR gain) were associated with differentiation, being more common and more extensive in poorly differentiated carcinomas. HLA-A2 loss was also associated with stage of progression of carcinoma. Inflammation associated with adenomas was found to have a similar phenotype to that associated with carcinomas. HLA changes in adenomas were uncommon, being seen in only one of our 20 cases.

Adenocarcinoma↗
PubMed1996

Mortality rates from cryptogenic fibrosing alveolitis in seven countries.

BACKGROUND: Registered mortality from cryptogenic fibrosing alveolitis (CFA) in England and Wales has increased substantially since the specific International Classification of Diseases code for CFA was introduced in 1979. However, since a significant proportion of deaths from CFA are misclassified as post inflammatory fibrosis (PIF), it is possible that the observed rise in CFA mortality is due to diagnostic transfer from this code. To investigate this, and to assess mortality trends in other countries, annual CFA and PIF mortality data from England and Wales, USA, Australia, Scotland, Canada, New Zealand, and Germany were analysed. METHODS: Crude annual mortality rates were calculated and rates standardised by Poisson regression to allow assessment of changes over time and comparison between countries, sexes, and age groups. The relative trends in mortality from CFA and PIF were assessed by calculating the annual ratio of CFA to PIF deaths. RESULTS: Men were more likely than women to die from both CFA and PIF in all countries. The highest standardised CFA mortality rate occurred in England and Wales, and the lowest in Germany. Since 1979 mortality from CFA has increased in England and Wales, Australia, Scotland and Canada, but there was no trend in CFA mortality in New Zealand or Germany. In the USA mortality from CFA was low and has fallen. Mortality from PIF increased in all countries except New Zealand and Germany, and the highest PIF mortality, together with the greatest increase over time, was seen in the USA. Changes over time in the annual ratio of CFA to PIF deaths in all countries were small, implying that diagnostic transfer is not a major cause of the increasing CFA mortality. CONCLUSIONS: Mortality from CFA continues to increase in England and Wales and in many other countries. Diagnostic transfer from PIF does not appear to be a major cause of this.

Adolescent↗