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1.  Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant 
Thorax  2007;62(11):981-990.
Background
Exposure to metal working fluid (MWF) has been associated with outbreaks of extrinsic allergic alveolitis (EAA) in the USA, with bacterial contamination of MWF being a possible cause, but is uncommon in the UK. Twelve workers developed EAA in a car engine manufacturing plant in the UK, presenting clinically between December 2003 and May 2004. This paper reports the subsequent epidemiological investigation of the whole workforce. The study had three aims: (1) to measure the extent of the outbreak by identifying other workers who may have developed EAA or other work‐related respiratory diseases; (2) to provide case detection so that those affected could be treated; and (3) to provide epidemiological data to identify the cause of the outbreak.
Methods
The outbreak was investigated in a three‐phase cross‐sectional survey of the workforce. In phase I a respiratory screening questionnaire was completed by 808/836 workers (96.7%) in May 2004. In phase II 481 employees with at least one respiratory symptom on screening and 50 asymptomatic controls were invited for investigation at the factory in June 2004. This included a questionnaire, spirometry and clinical opinion. 454/481 (94.4%) responded and 48/50 (96%) controls. Workers were identified who needed further investigation and serial measurements of peak expiratory flow (PEF). In phase III 162 employees were seen at the Birmingham Occupational Lung Disease clinic. 198 employees returned PEF records, including 141 of the 162 who attended for clinical investigation. Case definitions for diagnoses were agreed.
Results
87 workers (10.4% of the workforce) met case definitions for occupational lung disease, comprising EAA (n = 19), occupational asthma (n = 74) and humidifier fever (n = 7). 12 workers had more than one diagnosis. The peak onset of work‐related breathlessness was Spring 2003. The proportion of workers affected was higher for those using MWF from a large sump (27.3%) than for those working all over the manufacturing area (7.9%) (OR = 4.39, p<0.001). Two workers had positive specific provocation tests to the used but not the unused MWF solution.
Conclusions
Extensive investigation of the outbreak of EAA detected a large number of affected workers, not only with EAA but also occupational asthma. This is the largest reported outbreak in Europe. Mist from used MWF is the likely cause. In workplaces using MWF there is a need to carry out risk assessments, to monitor and maintain fluid quality, to control mist and to carry out respiratory health surveillance.
doi:10.1136/thx.2006.072199
PMCID: PMC2117138  PMID: 17504818
2.  Predictors of mortality in α1-antitrypsin deficiency 
Thorax  2003;58(12):1020-1026.
Methods: Over a 5 year period, 256 patients with α1-antitrypsin deficiency (PiZ phenotype) were assessed, of whom 254 underwent lung function testing and 197 had thoracic CT scans. Lung function, CT scans, health status (St George's Respiratory Questionnaire, SGRQ), and other clinical data of survivors and non-survivors were compared and these parameters were applied to survival analyses.
Results: There were 22 deaths in this patient cohort, 10 of which were classified as "respiratory" deaths. Baseline lung function parameters (forced expiratory volume in 1 second (FEV1), carbon monoxide transfer coefficient (KCO)), and CT scores were significantly lower in the non-survivors than in the survivors. 170 of the 256 patients had complete data for entry into multiple regression analyses (Cox proportional hazards model). In the univariate analysis, upper zone expiratory scan had the best association with all cause (p = 0.001) and respiratory mortality (p<0.001), whereas FEV1 (p = 0.158 all cause, 0.015 respiratory) and KCO (p = 0.002 all cause, 0.012 respiratory) had poorer associations with mortality. Only age gave further independent predictive information regarding all cause or respiratory mortality when the CT scan was entered into the survival analyses.
Conclusions: CT scanning predicts respiratory and all cause mortality in α1-antitrypsin deficiency and appears to be superior to lung function parameters, especially FEV1.
doi:10.1136/thorax.58.12.1020
PMCID: PMC1746543  PMID: 14645964
3.  Animal models of chronic obstructive pulmonary disease 
Thorax  2001;56(12):972-977.
doi:10.1136/thorax.56.12.972
PMCID: PMC1745992  PMID: 11713362
4.  Non-tuberculous mycobacteria in cystic fibrosis 
Thorax  1998;53(3):182-185.
BACKGROUND—The clinical significance of the presence of non-tuberculous mycobacteria in the sputum of patients with cystic fibrosis is unclear. A retrospective case-control study was performed to assess possible risk factors for non-tuberculous mycobacteria and its impact on clinical status in patients with cystic fibrosis.
METHODS—The records of all patients attending the Leeds cystic fibrosis clinics who were positive for non-tuberculous mycobacteria were examined. Each case was matched with two controls for sex, age, and respiratory function at the time of the first non-tuberculous mycobacteria isolate. Details of respiratory function, nutritional status, antibiotic and corticosteroid therapy, Shwachman-Kulczycki (S-K) score, Northern chest radiographic score, and the frequency of isolation of other bacteria and fungi were collected from two years before to two years after the first non-tuberculous mycobacteria isolate. The patients' genotype and the presence of diabetes mellitus were also recorded.
RESULTS—Non-tuberculous mycobacteria were isolated from 14 patients out of a cystic fibrosis population of 372 (prevalence = 3.8%). No significant effect of non-tuberculous mycobacteria was seen on respiratory function, nutritional status, or S-K score. There was a significant association with the number of intravenous antibiotic courses received before the first isolate with cases receiving, on average, twice as many courses as controls (cases 6.64, controls 2.86, 95% CI for difference 1.7 to 5.9). No significant difference was seen between cases and controls for Northern scores, previous steroid therapy, or the incidence of diabetes mellitus.
CONCLUSIONS—Non-tuberculous mycobacteria infection in patients with cystic fibrosis is uncommon and its clinical impact appears to be minimal over a two year period. Frequent intravenous antibiotic usage is a possible risk factor for colonisation with non-tuberculous mycobacteria.


PMCID: PMC1745162  PMID: 9659352
5.  Increased tissue concentrations of histamine in the duodenal mucosa of children with coeliac disease. 
Journal of Clinical Pathology  1982;35(6):596-598.
Tissue concentrations of histamine have been estimated in peroral duodenal biopsy specimens from five children with coeliac disease while on a gluten-free diet and after a three-month gluten challenge. Histamine concentrations in the patients on a diet did not differ significantly from a group of control children. However after gluten challenge, histological relapse of the duodenal mucosa in each patient was associated with increased tissue concentrations of histamine. The findings suggest that histamine may be involved in the pathogenesis of the small intestinal mucosal changes in children with coeliac disease.
PMCID: PMC497731  PMID: 7085909
7.  Increased tissue concentrations of 5-hydroxytryptamine in the duodenal mucosa of patients with coeliac disease. 
Gut  1977;18(11):882-886.
Tissue concentrations of 5-HT have been measured in the duodenal mucosa of adults and children with coeliac disease and were found to be significantly higher than those from a control group. This finding may be associated with hyperactivity or hyperplasia of enterochromaffin (EC) cells in the duodenum of patients with coeliac disease and could also be directly related to described abnormalities of 5-HT metabolism in this disease.
PMCID: PMC1411730  PMID: 590848
8.  Mode of Action of Antirheumatic Drugs 
British Medical Journal  1971;2(5763):677-679.
The concentrations of free and protein-bound L-tryptophan were measured in sera from normal subjects, patients with rheumatoid arthritis, pregnant women, and patients with jaundice. In the patients with rheumatoid arthritis receiving treatment with one or more antirheumatic drugs the percentage of the amino-acid bound to the circulating proteins was significantly depressed and in one patient returned to normal when therapy was stopped. Pregnancy and jaundice were also associated with raised free tryptophan and decreased bound tryptophan concentrations and bilirubin displaced the amino-acid from its binding sites on human serum proteins in vitro. It is suggested the behaviour of tryptophan mimics that of certain peptides which protect susceptible tissues against chronic inflammatory insults.
PMCID: PMC1796231  PMID: 5556051

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