Biomedical subjects
Publications and source records attributed to R Hubbard.
We report increased proportional mortality from cryptogenic fibrosing alveolitis in the workforce of a major UK engineering company. Measures of metal exposure from unbiased historical occupational records showed that among employees who have worked with metal, the risk of death from or with cryptogenic fibrosing alveolitis increased in relation to the duration of metal-working.
The explanations for the emergence of cryptogenic fibrosing alveolitis as a new clinical entity during the second half of the 20th century are unclear. The authors have previously reported evidence of an increased risk of cryptogenic fibrosing alveolitis in relation to the use of antidepressant drugs. The authors have now tested this hypothesis a priori in an analysis of computerized general practice records for 890 cases of cryptogenic fibrosing alveolitis and 5,884 matched controls drawn from the UK General Practice Research Database. Exposure to antidepressants at the time of diagnosis was increased in cases compared to controls (odds ratio (OR) 1.52, 95% confidence interval (95% CI) 1.24-1.86), and this increase remained if the analysis was restricted to exposures 4 yrs prior to diagnosis (OR 1.50, 95% CI 0.98-2.30). However this increased prescribing was not specific to any particular class of antidepressant or individual drug, and there was no evidence of a dose-response relationship between exposure to amitriptyline (the most commonly prescribed antidepressant) and disease. The presented data do not allow any firm conclusion to be made as to whether there is a causal relationship between antidepressant exposure and cryptogenic fibrosing alveolitis, but it seems unlikely that exposure to tricyclic antidepressants shortly before diagnosis is a strong risk factor for cryptogenic fibrosing alveolitis.
Crytogenic fibrosing alveolitis is the commonest intersititial lung disease but, until recently, very little has been known about its aetiology. The histopathologist usually sees this disease at transbronchial biopsy or at autopsy. This article reviews the current knowledge of the aetiology of cryptogenic fibrosing alveolitis looking at possible infective, occupational, drug-related, smoking-associated, genetic and dietary factors. Knowledge of the possible roles of these factors in the disease process informs histopathologists when they are reporting these biopsies and enables them to make a larger contribution to defining the pathogenetic mechanisms.
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.
BACKGROUND: The reasons why cryptogenic fibrosing alveolitis has emerged as a new clinical entity during the second half of the 20th century are unclear. Some environmental exposures have been identified as potential risk factors including occupational dust, cigarette smoking and antidepressants, but there have been no studies of the role of early life exposures. Since adult height reflects, in part, early life experience, we have examined the relation between adult height and the risk of cryptogenic fibrosing alveolitis. METHODS: A case-control study of 569 cases and 3669 age, sex, and community matched controls drawn from the UK General Practice Research Database was undertaken. RESULTS: Evidence was found of an inverse association between quintile of height and cryptogenic fibrosing alveolitis (odds ratio (OR) per increase in height quintile 0.93, 95% CI 0.86 to 0.99). This association was not diminished by adjustment for smoking status (OR 0.93, 95% CI 0.87 to 1.00), but some minor attenuation did occur after adjustment for oral corticosteroid use (OR 0.94, 95% CI 0.88 to 1.02). There was a significant interaction with sex such that the effect of height was strong in women (OR 0.85, 95% CI 0.75 to 0.97) and absent in men (OR 1.00, 95% CI 0.91 to 1.09). CONCLUSIONS: These findings raise the possibility that early life exposures may be important in determining the lifetime risk of developing cryptogenic fibrosing alveolitis.
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.
Fibrosing alveolitis (FA) is characterized by persistent inflammation and elevated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1ra) in the lung. Single base variations at position +2018 in the IL-1ra gene (IL-1RN) and position -308 in the TNF-alpha gene (TNF-A) are overrepresented in other chronic inflammatory disease populations. We have tested the hypothesis that predisposition to FA may also be influenced by these polymorphisms by genotyping 88 cases and matched controls from England and 61 cases and 103 unmatched controls from Italy. The rarer allele for IL-1RN and TNF-A was designated allele 2 in each case. For IL-1RN allele 2, in the English group, the relative odds of FA were increased in homozygous subjects by an odds ratio (OR) of 10.2 (95% confidence intervals [CI], 1.26 to 81.4; p = 0.03) and for carriers by an OR of 1.85 (95% CI, 0.94 to 3.63; p = 0.075). In the Italian population, the risk of FA was increased, in IL-1RN allele 2 homozygotes (OR, 2.54; 95% CI, 0.68 to 9.50; p = 0.2) and in carriers (OR 2.40; 95% CI, 1.26 to 4.60; p = 0.008). Carriage of TNF-A allele 2 was also associated with increased risk of FA in the English (OR, 1.85; 95% CI, 0.94 to 3.63; p = 0.075) and Italian (OR, 2.50; 95% CI, 1.14 to 5.47; p = 0.022) populations. These data suggest IL-1RN (+2018) allele 2 and TNF-A (-308) allele 2 confer increased risk of developing FA and, therefore, that unopposed IL-1beta and/or excessive TNF-alpha may play a pathophysiologic role in this condition.
STUDY OBJECTIVES: To compare international trends in mortality from cystic fibrosis. DESIGN: Comparison of trends in median age at death using national mortality data. SETTING: Data from 10 countries in North America, Europe, and Australasia. PARTICIPANTS: All persons registered as having died of cystic fibrosis in specified years from 1980 to 1994. INTERVENTIONS: Comparison of relative odds of death at the international median age at death for the year of death between countries for two periods of time; from 1980 to 1987 (10 countries) and from 1980 to 1994 (7 countries). MEASUREMENTS AND RESULTS: The international median age at death increased from 8 years in 1974 to 21 years in 1994. Median age at death also increased within all countries, was consistently highest in the United States, and varied significantly by a factor of > twofold between countries. Women were significantly more likely to die at a younger age than the median age at death than men. CONCLUSIONS: Median age at death from cystic fibrosis is increasing, but our findings imply that clinically significant differences in survival with cystic fibrosis persist between countries.
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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.
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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'.
Transmission efficiencies in excess of 75% were obtained in the optical guiding of subpicosecond, terawatt laser pulses in a 2-cm-long capillary discharge plasma channel at the Naval Research Laboratory. The guided laser beam size at the exit of the channel was measured using far field imaging and Thomson scattering techniques. The guided laser intensity was >1 x 10(17) W/cm(2) at a guided beam diameter of 35 microm for a propagation length of 22 Rayleigh ranges. There is evidence that the plasma channel extends beyond the ends of the capillary and affects the far field beam structure of the transmitted laser pulse.
This case study will explain the 5S concepts and how The Clarkson Company has begun implementing such a program, and how it is a foundation for continuous improvement.
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