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Accepted for publication 24 April 1998 It is widely believed among chest physicians that patients with cryptogenic fibrosing alveo litis (CFA) are at substantially increased risk of death from lung cancer. This belief is largely the result of a follow up study by Turner Warwick and colleagues reported in 1980.1 Of 205 patients attending the Brompton Hospital between 1955 and 1973 with CFA, 20 (9.8%) died from lung cancer; an excess relative risk of 14.1. This association is often taken to suggest that pulmonary fibrosis in itself entails a mechanism that predisposes to malignancy and that this in turn may explain the observed risk between other fibrotic diseases such as asbest

OBJECTIVES: To estimate past exposure to phthalic (PA), trimellitic (TMA) and maleic anhydride (MA) in three alkyd resin and one cushioned flooring factory to estimate exposure-response relations in a retrospective cohort study. METHODS: Personal exposure measurements were carried out in 1992 and quantitative and qualitative information on past exposure and production processes were collected. Job titles were ranked by decreasing exposure and amalgamated into job categories and exposure groups. Multiplication factors for back calculating past exposure levels were estimated with past exposure data, or if no such data were available these factors were estimated by a panel of occupational hygienists. Exposure levels were back calculated starting with the exposure levels in 1992. RESULTS: High exposures to PA were estimated to have occurred among workers operating the PA melting pots in factory 1 (estimated exposure in 1960-9 was 2480 micrograms.m-3). Highest concentrations of TMA were estimated to have occurred among the ink mixers in factory 2 from 1979 to 1986 (554 micrograms.m-3). Exposure in most other job titles was thought to be fairly constant over time for PA, TMA, and MA. CONCLUSIONS: Exposure to acid anhydride at these factories has fallen during the period covered by the study. However, it is estimated that in only one job in factory 2 did past exposure to acid anhydride exceed the current occupational exposure standard. Accuracy of the estimated exposure is limited by a paucity of reliable past exposure data.

Fish stocks are depressed worldwide. The resultant economic hardships on many fishermen have forced changes in fishing operations and effort. In general, gear use and losses in trap or pot fisheries appear to be increasing concurrent with a shift to more durable gear and designs. Modifications in trawl construction and operations have resulted in increased net damage and loss. Evidence from a number of locations around the world indicates that recent demersal gillnet- ting practices are leaving more gear per fishing unit in the oceans; in some cases this lost gear is heavily concentrated on productive fishing grounds. These changes in traditional gear types and fishing methods are certainly increasing the potential for loss of commercial and noncommercial species because of ghost-fishing.

Results Intra-observer variability was assessed using intraclass correlation coefficient (ICC); inter-observer variability was assessed using Bland Altman plots for agreement. Intra-observer variability was low for both observers (ICC; observer 1 EDV: 0.99, ESV: 0.93, mass: 0.94 vs observer 2 EDV: 0.97, ESV: 0.97, mass: 0.94). Interobserver variability was lowest for volumes and highest for mass (Table 1).

Objectives To assess the probability of a causal relationship between mortality ascribed to renal cancer and chronic renal disease in two cohorts, one of American industrial sand workers and the other of British pottery workers. Methods The two cohorts were quite similar in that both were designed to determine whether occupational exposure to silica was a cause of lung cancer. Both studies then turned to the question of whether the same was true of renal cancer and chronic renal disease. Both cohorts were redefined with minor changes and continued their efforts at tracing all surviving members in relation to quantitative re-estimation of quartz exposure. Results The sand workers study was terminated at the end of 2000 and the pottery workers at the end of 2008. By then the total number of deaths in the American cohort had reached 1021 (SMR 1.21) and the British cohort 1904 (SMR 1.04). The later data were confined to Stoke on Trent, the main location of the pottery industry. Mortality in sand workers related to renal disease was, for renal cancer 10 (SMR 2.02) and chronic renal disease 14 (SMR 3.50). Mortality in pottery workers was, for renal cancer 19 (SMR 1.47) and chronic renal disease 19 (SMR 2.39). Conclusions The number of deaths from renal disease in these two cohorts was small but the pattern in the two cohorts is similar. The findings in the sand workers cohort were published in 2005 when it was concluded that excess mortality from renal disease lacked causal explanation. The same remains true of both cohorts.

Objectives To investigate deaths recorded as lung cancer or COPD (as distinct from other non-malignant respiratory disease), in a cohort occupationally exposed to silica. Methods Vital status and cause of death were ascertained for a cohort of 5115 pottery workers previously followed to 1992. SMRs were calculated for underlying cause of death 1985–2008 compared to reference data from Stoke on Trent. Analysis of ‘mentioned’ cause of death was restricted to 1993–2008. Information on duration of employment and smoking was available for the whole cohort but exposure data were restricted to those included in an earlier validation cohort and those who were still employed in 1981 or later. Results Of 5115 in the original cohort, 27 were duplicates, 29 were not traced and 258 had died before 1985, leaving 4801, with 1904 deaths. Deaths from lung cancer (N=243) were raised SMR=1.15 (1.01–1.30) as were deaths from COPD (N=158) both as an underlying (SMR=1.46 (1.24–1.71)) and as a ‘mentioned’ (SMR=1.31 (1.14–1.50)) cause. In a survival analysis duration of exposure was not related to deaths recorded as lung cancer or COPD for the cohort as a whole. In those (N=1943) with exposure data, early deaths (before July 1992) from either lung cancer or COPD were related to mean exposure in smokers but this relation was not seen in those dying from these causes in more recent years. Conclusions Silica exposure appears to have contributed to early, but not recent, deaths although an excess of COPD deaths continues to be recorded.

Introduction and objective The 2008 ERS Task Force1 recommended that preschool wheezing be classified as episodic (viral) wheeze (EVW) or multiple trigger wheeze (MTW). We investigated the relationship between these phenotypes and reported wheeze and medication use in later childhood. Methods Between 1993 and 1995, 658 consecutive mothers attending for routine ante-natal care (93% of those eligible) were recruited; they subsequently gave birth to 642 children. Detailed respiratory data were collected annually until the child reached the age of 5½ years (n=602; 94%). Further information was collected at age 8 (n=593; 92%) and 14 (n=497; 77%) years. EVW was defined as occasional wheeze in the past 12 months which occurred when the child had a cold or other infection; all other reported wheeze was defined as MTW. Using data from birth to age 5½, children were categorised as never wheezing (n=238); only EVW wheeze (n=208); both EVW and MTW wheeze (n=100) and only MTW wheeze (n=56). Results The prevalence of EVW fell from 32% at age 0–1 to 7% at age 4–5½; MTW prevalence was approximately 10% each year. Compared with never wheezers, in each wheezing group there was a higher proportion of boys (54%, 65%, 61%), (48%); p=0.02, higher exposure to ETS, and a greater prevalence of maternal and paternal asthma (p Conclusion At 8 and 14 years of age, never wheezers and pure EVW had lower prevalences of atopy, wheeze and current medication use than those with any MTW. These data provide external validity to the ERS phenotypes, and suggest that they provide useful prognostic information.

The Cancer Cell Line Encyclopedia represents a collaborative effort to assemble a comprehensive resource of human cancer models for basic and translational research. The CCLE aims to contain high-density SNP microarray data, gene expression microarray data and selected cancer gene mutation data for approximately 1000 human cancer cell lines spanning many tumor types. In addition, we are assessing sensitivity of some of these cell lines using a series of pharmacological compounds that represent both conventional cytotoxic and targeted agents. Another goal of the CCLE collaboration involves systematic integration of the genomic and pharmacologic datasets in order to identify putative targets of prevalent genetic alterations as well as predictors of pharmacologic sensitivity and resistance. The availability of high-quality data across hundreds of cell lines markedly enhances the statistical power to discover genetic alterations involved in carcinogenesis and molecular predictors of pharmacologic vulnerability. We are assembling systematic algorithms that identify genetic predictors of sensitivity or resistance to particular pharmacological compounds. Toward this end, we integrated a sensitivity dataset for 28 compounds profiled against more than 500 cell lines with all genomic data available in the CCLE. Gene expression, DNA copy-number and loss of heterozygosity values were combined with critical oncogene mutations and genotype information as inputs to multifaceted prediction models for pharmacological sensitivity, the accuracies of which were assessed using cross-validations. Two complementary paths were followed in order to predict for the sensitivity of cancer cell lines to pharmacological compounds. In a categorical classification-based model, we have used the Naïve Bayes algorithm to find the most significant features predictive of the sensitive or resistant status of the cell lines to each of the compounds. A second path that we followed is a regression-based machine learning approach, called the Elastic Net, where the goal is to predict a continuous value representing the sensitivity of each cell line, such as the GI50. For both approaches, we show examples of the results that we get for some compounds in the collection, such as AZD6244 (MEK), PHA-665752 (MET), Nutlin-3 (MDM2). We detail the performances of the prediction models as well as the most significant genetic determinants of sensitivity to these inhibitors. Several previously unappreciated genomic predictors of response or intrinsic resistance to targeted anticancer agents have been identified. Our results suggest that this integrative approach applied to a robust cancer cell line collection such as the CCLE has considerable power to discover novel associations that augment ongoing basic research into cancer biology and drug discovery. Citation Information: Clin Cancer Res 2010;16(14 Suppl):PR4.

This report details the structure-activity relationships of the HIV gag substrate analog Val-Ser-Gln-Asn-Leu psi[CH(OH)CH2]Val-Ile-Val (U-85548E), an inhibitor exhibiting subnanomolar affinity towards HIV type-1 aspartic proteinase (HIV-1 PR). Our data show that the P1-P2' tripeptidyl sequence provides the minimal chemical determinant for HIV-1 PR binding. We describe the structure-activity properties of Leu psi[CH(OH)CH2]Val substitution in other peptidyl ligands of nonviral substrate origin (e.g., angiotensinogen, insulin and pepstatin). Furthermore, the aspartic proteinase selectivities of a few key compounds are summarized relative to evaluation against human renin, human pepsin, and the fungal enzyme, rhizopuspepsin. These studies have led to the rational design of nanomolar potent inhibitors of both HIV-1 and HIV-2 PR. Finally, a 2.5 A resolution X-ray crystallographic structure of U-85548E complexed to synthetic HIV-1 PR dimer (Jaskolski et al., Biochemistry 30, 1600 [1991]) provided a 3-D picture of the inhibitor bound to the enzyme active site, and we performed computer-assisted molecular modeling studies to explore the possible binding modes of the above series of Leu psi[CH(OH)CH2]Val substituted HIV-1 PR inhibitors.

Spence’s sceptical reaction to the quality and outcomes framework (QOF) will have hit home with many general practitioners.1 Few of us spontaneously welcome the nagging computer prompts that interrupt our consultations, reduce our work to protocols and guidelines, and ignore the subtle, immeasurable aspects of the job. Nor do we like to acknowledge how …

Rationale Laboratory animal allergy is a common occupational health problem in occupationally exposed individuals. Exposure is a well-defined risk factor for sensitization and asthma to rats. However the incidence of sensitization is often reduced in the highest exposed categories. One explanation is the phenomenon of high dose tolerance. It has been shown that exposure to cat allergen induces an IgG and IgG4 antibody response, without sensitization or risk of asthma. This has been explained as a modified Th2 response. We have investigated the relationship between IgE, IgG and IgG 4 and exposure to rats. Methods A cross sectional study was carried out on individuals exposed to laboratory animals at six pharmaceutical sites across the UK. Specific IgE was measured using RAST. Specific IgG and IgG4 antibodies to rat urinary allergen were measured in 689 and 401 exposed individuals respectively using ELISA. Results Using two different measures of exposure to rats, the prevalence of sensitization increased with increasing exposure intensity. However in the highest exposure category, the prevalence of sensitization decreased. Conversely levels of IgG and IgG4 increased in parallel with increasing exposure to rats. In support of high IgG 4 :IgE ratio in non sensitized individuals at highest exposure, we also observed higher IgG 4 :IgE ratios in asymptomatics compared with those with symptoms. Conclusions High exposure to rats was associated with an increased production of specific IgG and IgG4 with a decreased production of IgE. The development of IgG 4 may protect against symptoms.

This translation of Your Handsome Captain was commissioned by Ubu Repertory Theater in New York City and was given its American premiere, in workshop, as part of the Ubu International Festival in March, 1988. Ubu Repertory Theater is a unique institution committed to introducing Americans to the works of contemporary Frenchspeaking playwrights from around the world through productions, festivals, panels, staged readings, and workshops. The theater also has its own publication series of English translations of contemporary plays from Africa, the Caribbean, France, Quebec, and Belgium. Your Handsome Captain is included in Ubu's Plays by Women: An International Anthology. The play will be given a new production, directed by Ubu's Artistic Director Franqoise Kourilsky, during the theater's Fall 1989 season.

Background Microvascular obstruction (MVO) by CMR is a predictor of poor prognosis following acute myocardial infarction. The index of microcirculatory resistance (IMR) is an invasive measurement of the microcirculation that has recently been shown to predict poor long-term outcomes [1]. The aim of the study was to determine the association between MVO by CMR and the IMR measured at the time of primary percutaneous intervention (PPCI) in patients with ST-elevation myocardial infarction (STEMI).

Summary This study investigates the role of CMR technologists in performing LV volume analysis in a busy clinical CMR service. Background Cardiac magnetic resonance (CMR) imaging studies are increasingly being used in clinical practice for assessment of viability following an acute coronary syndrome. There have been no previous studies investigating the role of CMR technologists in contributing to the analysis of these scans using semi-automated software. Methods 20 CMR studies of acute coronary syndromes were included in this study. Analysis was conducted using Argus, Siemens semi-automated volume analysis software. 3 observers conducted the image analysis with two levels of training: Observer 1) “Reference” CMR level 3 physician; Observer 2) and 3) CMR technologists with no previous experience on CMR analysis. Both technologists underwent a 2h tutorial on how to use the software. All 3 observers analysed 20 studies, and reanalysed 10 studies 24 hours after. Results Intra-observer variability was assessed using intraclass correlation coefficient (ICC); inter-observer variability was assessed using Bland Altman plots for agreement. We observed a good inter-observer variability between Observer 1 and 2, and between Observer 1 and 3 in assessing EDV, ESV, and LV mass (Table 1). Among these parameters, the lowest inter-observer variability was observed for ESV. Bland Altman plots suggested acceptable agreement. Technologist intra-observer variability was comparable to that of the reference observer (ICC technologist volumes and mass 0.94-0.99, ICC reference 0.97-0.99). Conclusions Following a short training, CMR technologists can perform an accurate analysis of LV volume using semiautomated software, compared to an expert CMR physician. These results suggest that technologists can play a role in assisting clinical reporting in a busy clinical CMR service.