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1.  Airway Symptoms and Biological Markers in Nasal Lavage Fluid in Subjects Exposed to Metalworking Fluids 
PLoS ONE  2013;8(12):e83089.
Backgrounds
Occurrence of airway irritation among industrial metal workers was investigated. The aims were to study the association between exposures from water-based metal working fluids (MWF) and the health outcome among the personnel, to assess potential effects on the proteome in nasal mucous membranes, and evaluate preventive actions.
Methods
The prevalence of airway symptoms related to work were examined among 271 metalworkers exposed to MWF and 24 metal workers not exposed to MWF at the same factory. At the same time, air levels of potentially harmful substances (oil mist, morpholine, monoethanolamine, formaldehyde) generated from MWF was measured. Nasal lavage fluid was collected from 13 workers and 15 controls and protein profiles were determined by a proteomic approach.
Results
Airway symptoms were reported in 39% of the workers exposed to MWF although the measured levels of MWF substances in the work place air were low. Highest prevalence was found among workers handling the MWF machines but also those working in the same hall were affected. Improvement of the ventilation to reduce MWF exposure lowered the prevalence of airway problems. Protein profiling showed significantly higher levels of S100-A9 and lower levels of SPLUNC1, cystatin SN, Ig J and β2-microglobulin among workers with airway symptoms.
Conclusions
This study confirms that upper airway symptoms among metal workers are a common problem and despite low levels of MWF-generated substances, effects on airway immune proteins are found. Further studies to clarify the role of specific MWF components in connection to airway inflammation and the identified biological markers are warranted.
doi:10.1371/journal.pone.0083089
PMCID: PMC3877012  PMID: 24391738
2.  Development of OASYS-2: a system for the analysis of serial measurement of peak expiratory flow in workers with suspected occupational asthma. 
Thorax  1996;51(5):484-489.
BACKGROUND: Serial peak expiratory flow (PEF) measurement is usually the most appropriate first step in the confirmation of occupational asthma. Visual assessment of the plotted record is more sensitive and specific than statistical methods so far reported. The use of visual analysis is limited by lack of widespread expertise in the methods. A computer assisted diagnostic aid (OASYS-2) has been developed which is based on a scoring system developed from visual analysis. This removes the requirement for an experienced interpreter and should lead to the more widespread use of the technique. METHODS: PEF records were collected from workers attending an occupational lung disease clinic for investigation of suspected occupational asthma and from workers participating in a study of respiratory symptoms in a postal sorting office. PEF records were divided into two development sets and two gold standard sets. The latter consisted of records from workers in which a final diagnosis had been reached by a method other than PEF recording. An experienced observer scored individual work and rest periods for the two development set PEF records; linear discriminant analysis was used to compare measurements taken from development set 1 records with visual scores. Two equations were produced which allowed prediction of scores for individual work or rest periods. The development set 2 was used to determine how these scores should be used to produce a whole record score. The first gold standard set was used to determine the whole record score which best separated those with and without occupational asthma. The second set determined the sensitivity and specificity of the chosen score. RESULTS: Two hundred and sixty eight PEF records were collected from 169 workers and divided into two development sets (81 and 60 records) and two gold standard sets (60 and 67 records). Linear discriminant analysis produced equations predicting the score for work periods incorporating five indices of PEF change and one for rest periods using seven indices. These equations correctly predicted the score for development set 1 work and rest periods on 61% of occasions (kappa = 0.47). The whole record score for development set 2 records, after weighting for definite or definitely no occupational effect, correlated with the visual score (correlation coefficient 0.86). Comparison with gold standard set 1 identified a cut off which proved to have a sensitivity of 75% and a specificity of 94% for an independent diagnosis of occupational asthma when applied to gold standard set 2. CONCLUSIONS: These results suggest that the sensitivity and specificity of analysing PEF records for occupational asthma using OASYS-2 approaches that of visual analysis, but it should be absolutely reproducible. The performance of OASYS-2 is more specific and approaches the sensitivity of other statistical methods of analysis. The evaluation of a large number of PEF records from workers exposed to different sensitising agents suggests that these results should be robust and should be repeatable in clinical practice.
Images
PMCID: PMC473592  PMID: 8711675
3.  Occupation and Bladder Cancer in a Population-Based Case-control Study in Northern New England 
Objectives
We used data from a large, population-based case-control study in New England to examine relationships between occupation, industry, and bladder cancer risk.
Methods
Lifetime occupational histories were obtained by personal interview from 1,158 patients newly diagnosed with urothelial carcinoma of the bladder between 2001 and 2004 among residents of Maine, New Hampshire, and Vermont, and from 1,402 population controls selected from Department of Motor Vehicle records (ages 30 to 64 years) or Medicare beneficiary records (65 to 79 years). Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for demographic factors, smoking, and employment in high-risk occupations other than the one being analyzed.
Results
Male precision metalworkers and metalworking/plasticworking machine operators had significantly elevated risks and significant trends in risk with duration of employment (precision metalworkers: OR=2.2; CI: 1.4, 3.4, Ptrend =0.0065; metalworking/plasticworking machine operators: OR=1.6; CI: 1.01, 2.6, Ptrend=0.047). Other occupations/industries for which risk increased significantly with duration of employment included: for men, textile machine operators, mechanics/repairers, automobile mechanics, plumbers, computer systems analysts, information clerks, and landscape and horticultural services industry workers; and for women, service occupations, health services, cleaning and building services, management-related occupations, electronic components and accessories manufacturing, and transportation equipment manufacturing. Men reporting use of metalworking fluids (MWF) had a significantly elevated bladder cancer risk (OR=1.7; 95% CI: 1.1, 2.5),
Conclusions
Our findings for metalworkers and for MWF exposure support the hypothesis that some component(s) of MWF may be carcinogenic to the bladder in humans. Our results also corroborate many other previously-reported associations between bladder cancer risk and various occupations. More detailed analyses using information collected in job-specific questionnaires administered in this study may help to identify components of MWF that may be carcinogenic, and other bladder carcinogens to which people are exposed in a variety of occupations.
doi:10.1136/oem.2009.052571
PMCID: PMC3010477  PMID: 20864470
bladder cancer; occupation; case-control study; epidemiology
4.  Microbial Exposure Assessment in Sawmill, Livestock Feed Industry, and Metal Working Fluids Handling Industry 
Safety and Health at Work  2010;1(2):183-191.
Objectives
The objective of this study is to investigate the distribution patterns and exposure concentrations of bioaerosols in industries suspected to have high levels of bioaerosol exposure.
Methods
We selected 11 plants including 3 livestock feed plants (LF industry), 3 metal working fluids handling plants (MWFs industry), and 5 sawmills and measured total airborne bacteria, fungi, endotoxins, as well as dust. Airborne bacteria and fungi were measured with one stage impactor, six stage cascade impactor, and gelatin filters. Endotoxins were measured with polycarbonate filters.
Results
The geometric means (GM) of the airborne concentrations of bacteria, fungi, and endotoxins were 1,864, 2,252 CFU/m3, and 31.5 EU/m3, respectively at the sawmills, followed by the LF industry (535, 585 CFU/m3, and 22.0 EU/m3) and MWFs industry (258, 331 CFU/m3, and 8.7 EU/m3). These concentrations by industry type were significantly statistically different (p < 0.01). The ratio of indoor to outdoor concentration was 6.2, 1.9, 3.2, and 3.2 for bacteria, fungi, endotoxins, and dust in the LF industry, 5.0, 0.9, 2.3, and 12.5 in the MWFs industry, and 3.7, 4.1, 3.3, and 9.7 in sawmills. The respiratory fractions of bioaerosols were differentiated by bioaerosol types and industry types: the respiratory fraction of bacteria in the LF industry, MWF industry, and sawmills was 59.4%, 72.0%, and 57.7%, respectively, and that of fungi was 77.3%, 89.5%, and 83.7% in the same order.
Conclusion
We found that bioaerosol concentration was the highest in sawmills, followed by LF industry facilities and MWFs industry facilities. The indoor/outdoor ratio of microorganisms was larger than 1 and respiratory fraction of microorganisms was more than 50% of the total microorganism concentrations which might penetrate respiratory tract easily. All these findings suggest that bioaerosol in the surveyed industries should be controlled to prevent worker respiratory diseases.
doi:10.5491/SHAW.2010.1.2.183
PMCID: PMC3430895  PMID: 22953179
Bioaerosols; Biological agents; Microbial risK; Sawmill; Livestock feed industry; Endotoxin
5.  Presence of a Single Genotype of the Newly Described Species Mycobacterium immunogenum in Industrial Metalworking Fluids Associated with Hypersensitivity Pneumonitis 
Applied and Environmental Microbiology  2002;68(11):5580-5584.
Outbreaks of hypersensitivity pneumonitis (HP) among industrial metal-grinding machinists working with water-based metalworking fluids (MWF) have frequently been associated with high levels of mycobacteria in the MWF, but little is known about these organisms. We collected 107 MWF isolates of mycobacteria from multiple industrial sites where HP had been diagnosed and identified them to the species level by a molecular method (PCR restriction enzyme analysis [PRA]). Their genomic DNA restriction fragment length polymorphism (RFLP) patterns, as determined by pulsed-field gel electrophoresis (PFGE), were compared to those of 15 clinical (patient) isolates of the recently described rapidly growing mycobacterial species Mycobacterium immunogenum. A total of 102 of 107 (95%) MWF isolates (from 10 industrial sites within the United States and Canada) were identified as M. immunogenum and gave PRA patterns identical to those of the clinical isolates. Using genomic DNA, PFGE was performed on 80 of these isolates. According to RFLP analysis using the restriction enzymes DraI and XbaI, 78 of 80 (98%) of the MWF isolates represented a single clone. In contrast, none of the 15 clinical isolates had genetic patterns the same as or closely related to those of any of the others. Given the genomic heterogeneity of clinical isolates of M. immunogenum, the finding that a single genotype was present at all industrial sites is remarkable. This suggests that this genotype possesses unusual features that may relate to its virulence and its potential etiologic role in HP and/or to its resistance to biocides frequently used in MWF.
doi:10.1128/AEM.68.11.5580-5584.2002
PMCID: PMC129929  PMID: 12406752
6.  Long-Term Exposure to Silica Dust and Risk of Total and Cause-Specific Mortality in Chinese Workers: A Cohort Study 
PLoS Medicine  2012;9(4):e1001206.
A retro-prospective cohort study by Weihong Chen and colleagues provides new estimates for the risk of total and cause-specific mortality due to long-term silica dust exposure among Chinese workers.
Background
Human exposure to silica dust is very common in both working and living environments. However, the potential long-term health effects have not been well established across different exposure situations.
Methods and Findings
We studied 74,040 workers who worked at 29 metal mines and pottery factories in China for 1 y or more between January 1, 1960, and December 31, 1974, with follow-up until December 31, 2003 (median follow-up of 33 y). We estimated the cumulative silica dust exposure (CDE) for each worker by linking work history to a job–exposure matrix. We calculated standardized mortality ratios for underlying causes of death based on Chinese national mortality rates. Hazard ratios (HRs) for selected causes of death associated with CDE were estimated using the Cox proportional hazards model. The population attributable risks were estimated based on the prevalence of workers with silica dust exposure and HRs. The number of deaths attributable to silica dust exposure among Chinese workers was then calculated using the population attributable risk and the national mortality rate. We observed 19,516 deaths during 2,306,428 person-years of follow-up. Mortality from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 per 100,000 person-years). We observed significant positive exposure–response relationships between CDE (measured in milligrams/cubic meter–years, i.e., the sum of silica dust concentrations multiplied by the years of silica exposure) and mortality from all causes (HR 1.026, 95% confidence interval 1.023–1.029), respiratory diseases (1.069, 1.064–1.074), respiratory tuberculosis (1.065, 1.059–1.071), and cardiovascular disease (1.031, 1.025–1.036). Significantly elevated standardized mortality ratios were observed for all causes (1.06, 95% confidence interval 1.01–1.11), ischemic heart disease (1.65, 1.35–1.99), and pneumoconiosis (11.01, 7.67–14.95) among workers exposed to respirable silica concentrations equal to or lower than 0.1 mg/m3. After adjustment for potential confounders, including smoking, silica dust exposure accounted for 15.2% of all deaths in this study. We estimated that 4.2% of deaths (231,104 cases) among Chinese workers were attributable to silica dust exposure. The limitations of this study included a lack of data on dietary patterns and leisure time physical activity, possible underestimation of silica dust exposure for individuals who worked at the mines/factories before 1950, and a small number of deaths (4.3%) where the cause of death was based on oral reports from relatives.
Conclusions
Long-term silica dust exposure was associated with substantially increased mortality among Chinese workers. The increased risk was observed not only for deaths due to respiratory diseases and lung cancer, but also for deaths due to cardiovascular disease.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Walk along most sandy beaches and you will be walking on millions of grains of crystalline silica, one of the commonest minerals on earth and a major ingredient in glass and in ceramic glazes. Silica is also used in the manufacture of building materials, in foundry castings, and for sandblasting, and respirable (breathable) crystalline silica particles are produced during quarrying and mining. Unfortunately, silica dust is not innocuous. Several serious diseases are associated with exposure to this dust, including silicosis (a chronic lung disease characterized by scarring and destruction of lung tissue), lung cancer, and pulmonary tuberculosis (a serious lung infection). Moreover, exposure to silica dust increases the risk of death (mortality). Worryingly, recent reports indicate that in the US and Europe, about 1.7 and 3.0 million people, respectively, are occupationally exposed to silica dust, figures that are dwarfed by the more than 23 million workers who are exposed in China. Occupational silica exposure, therefore, represents an important global public health concern.
Why Was This Study Done?
Although the lung-related adverse health effects of exposure to silica dust have been extensively studied, silica-related health effects may not be limited to these diseases. For example, could silica dust particles increase the risk of cardiovascular disease (diseases that affect the heart and circulation)? Other environmental particulates, such as the products of internal combustion engines, are associated with an increased risk of cardiovascular disease, but no one knows if the same is true for silica dust particles. Moreover, although it is clear that high levels of exposure to silica dust are dangerous, little is known about the adverse health effects of lower exposure levels. In this cohort study, the researchers examined the effect of long-term exposure to silica dust on the risk of all cause and cause-specific mortality in a large group (cohort) of Chinese workers.
What Did the Researchers Do and Find?
The researchers estimated the cumulative silica dust exposure for 74,040 workers at 29 metal mines and pottery factories from 1960 to 2003 from individual work histories and more than four million measurements of workplace dust concentrations, and collected health and mortality data for all the workers. Death from all causes was higher among workers exposed to silica dust than among non-exposed workers (993 versus 551 deaths per 100,000 person-years), and there was a positive exposure–response relationship between silica dust exposure and death from all causes, respiratory diseases, respiratory tuberculosis, and cardiovascular disease. For example, the hazard ratio for all cause death was 1.026 for every increase in cumulative silica dust exposure of 1 mg/m3-year; a hazard ratio is the incidence of an event in an exposed group divided by its incidence in an unexposed group. Notably, there was significantly increased mortality from all causes, ischemic heart disease, and silicosis among workers exposed to respirable silica concentrations at or below 0.1 mg/m3, the workplace exposure limit for silica dust set by the US Occupational Safety and Health Administration. For example, the standardized mortality ratio (SMR) for silicosis among people exposed to low levels of silica dust was 11.01; an SMR is the ratio of observed deaths in a cohort to expected deaths calculated from recorded deaths in the general population. Finally, the researchers used their data to estimate that, in 2008, 4.2% of deaths among industrial workers in China (231,104 deaths) were attributable to silica dust exposure.
What Do These Findings Mean?
These findings indicate that long-term silica dust exposure is associated with substantially increased mortality among Chinese workers. They confirm that there is an exposure–response relationship between silica dust exposure and a heightened risk of death from respiratory diseases and lung cancer. That is, the risk of death from these diseases increases as exposure to silica dust increases. In addition, they show a significant relationship between silica dust exposure and death from cardiovascular diseases. Importantly, these findings suggest that even levels of silica dust that are considered safe increase the risk of death. The accuracy of these findings may be affected by the accuracy of the silica dust exposure estimates and/or by confounding (other factors shared by the people exposed to silica such as diet may have affected their risk of death). Nevertheless, these findings highlight the need to tighten regulations on workplace dust control in China and elsewhere.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001206.
The American Lung Association provides information on silicosis
The US Centers for Disease Control and Prevention provides information on silica in the workplace, including links to relevant US National Institute for Occupational Health and Safety publications, and information on silicosis and other pneumoconioses
The US Occupational Safety and Health Administration also has detailed information on occupational exposure to crystalline silica
What does silicosis mean to you is a video provided by the US Mine Safety and Health Administration that includes personal experiences of silicosis; Dont let silica dust you is a video produced by the Association of Occupational and Environmental Clinics that identifies ways to reduce silica dust exposure in the workplace
The MedlinePlus encyclopedia has a page on silicosis (in English and Spanish)
The International Labour Organization provides information on health surveillance for those exposed to respirable crystalline silica
The World Health Organization has published a report about the health effects of crystalline silica and quartz
doi:10.1371/journal.pmed.1001206
PMCID: PMC3328438  PMID: 22529751
7.  Occupational asthma due to glutaraldehyde and formaldehyde in endoscopy and x ray departments. 
Thorax  1995;50(2):156-159.
BACKGROUND--Glutaraldehyde is the best disinfectant for fibreoptic endoscopes. It is also used in the processing of x ray films. A number of studies have reported eye, nose, and respiratory symptoms in exposed workers. Three individual case reports of occupational asthma in endoscopy workers and a radiographer have also been published. We describe a further seven cases of occupational asthma due to glutaraldehyde in endoscopy and x ray departments, together with exposure levels measured during the challenge tests and in 19 endoscopy and x ray departments in the region. METHODS--Eight workers were referred for investigation of suspected occupational asthma following direct or indirect exposure to glutaraldehyde at work. They were investigated by serial measurements of peak expiratory flow (PEF) and specific bronchial provocation tests. Glutaraldehyde levels were measured using personal and static short and longer term air samples during the challenge tests and in 13 endoscopy units and six x ray darkrooms in the region where concern about glutaraldehyde exposure had been expressed. Three of the workers investigated with occupational asthma came from departments where glutaraldehyde air measurements had been made; the others came from other hospitals or departments. RESULTS--The diagnosis of occupational asthma was confirmed in seven workers, all of whom had PEF records suggestive of occupational asthma and positive specific bronchial challenge tests to glutaraldehyde. Bronchial provocation testing was negative in one worker who was no longer exposed and who had a less clearcut history of occupational asthma. Three workers also had a positive specific bronchial challenge to formaldehyde. The mean level of glutaraldehyde in air during the challenge tests was 0.068 mg/m3, about one tenth of the short term occupational exposure standard of 0.7 mg/m3. The levels obtained in the challenge chamber were similar to those measured in 13 endoscopy suites and six x ray darkrooms where median short term levels were 0.16 mg/m3 during decantation in endoscopy suites and < 0.009 mg/m3 in darkrooms. CONCLUSIONS--Glutaraldehyde can cause occupational asthma. The exposure levels measured in the workplace suggest that sensitisation may occur at levels below the current occupational exposure standard.
PMCID: PMC473910  PMID: 7701454
8.  Role of interleukin 4 and its receptor in clinical presentation of chronic extrinsic allergic alveolitis: a pilot study 
Background
Th-2 cytokine milieu including interleukin 4 (IL-4) was detected in fibrotic lung diseases. Chronic extrinsic allergic alveolitis (EAA) may be also accompanied by marked fibrogenesis. The aim of this study was to determine if IL-4 and its receptor (IL-4R-alpha) play any role in the clinical presentation and pathogenesis of chronic EAA.
Methods
Twenty patients originally investigated for interstitial lung disease and finally diagnosed affected with chronic EAA and sarcoidosis were prospectively enrolled into the study. Concentrations of IL-4, IL-4R-aplha and total protein were assessed in the bronchoalveolar lavage fluid (BALF) of all enrolled subjects as well as high resolution computed tomography (HRCT) scores and pulmonary function tests.
Results
BALF IL-4R-alpha and total protein concentrations were significantly higher in chronic EAA patients (p < 0.05). Concentrations of BALF IL-4R-alpha were significantly higher in men than in women (p < 0.05) in EAA group. Total protein BALF levels were significantly elevated in ex-smokers with EAA compared to nonsmokers (p < 0.05). A positive correlation (p < 0.01) between IL-4R-alpha BALF concentrations and HRCT interstitial scores were observed in chronic EAA group; the IL-4R-alpha/total protein ratio showed the same significant positive correlation. A negative correlation between lung function results and IL-4R-alpha, and IL-4R-alpha/total protein as well, was also found (p < 0.05).
Conclusions
We suggest a clinical relevance for the IL-4/IL-4R axis in the etiopathogenesis of chronic EAA. IL-4R-alpha could serve as a potential biomarker of lung fibrogenesis.
doi:10.1186/2049-6958-8-35
PMCID: PMC3682858  PMID: 23721656
Chronic extrinsic allergic alveolitis; High resolution computed tomography score; Interleukin 4; Interleukin 4 receptor; Sarcoidosis
9.  Survey of symptoms, respiratory function, and immunology and their relation to glutaraldehyde and other occupational exposures among endoscopy nursing staff 
OBJECTIVES—To find the nature and incidence of symptoms experienced by a large sample of hospital endoscopy nurses. To find whether nurses in endoscopy units develop asthma under current working conditions in endoscopy units. To obtain analytically reliable data on exposure concentrations of glutaraldehyde (GA) vapour in endoscopy units, and to relate them to individual hygiene and work practices. To characterise any exposure-response relations between airborne GA and the occurrence of work related symptoms (WRSs). Due to the growing concern about the perceived increase in WRSs among workers regularly exposed to biocides, all of whom work within a complex multiexposure environment, a cross sectional study was designed.
METHODS—Current endoscopy nurses (n=348) from 59 endoscopy units within the United Kingdom and ex-employees (who had left their job for health reasons (n=18) were surveyed. Symptom questionnaires, end of session spirometry, peak flow diaries, skin prick tests (SPTs) to latex and common aeroallergens, and measurements of total immunoglobulin E (IgE) and IgE specific to GA and latex were performed. Exposure measurements included personal airborne biocide sampling for peak (during biocide changeover) and background (endoscopy room, excluding biocide changeover) concentrations.
RESULTS—All 18 ex-employees and 91.4% of the current nurses were primarily exposed to GA, the rest were exposed to a succinaldehyde-formaldehyde (SF) composite. Work related contact dermatitis was reported by 44% of current workers exposed to GA, 56.7% of those exposed to SF composite, and 44.4% of ex-employees. The prevalence of WRSs of the eyes, nose, and lower respiratory tract in current workers exposed to GA was 13.5%, 19.8%, and 8.5% respectively and 50%, 61.1%, and 66.6% in the ex-employees. The mean percentage predicted forced expired volume in 1 second (ppFEV1) for ex-employees (93.82, 95% confidence interval (95% CI) 88.53 to 99.11) was significantly lower (p<0.01) than that of current workers exposed to GA (104.08, 95% CI 102.35 to 105.73). Occupational peak flow diaries completed by current workers with WRSs of the lower respiratory tract showed no evidence of bronchial asthma (<15% variation). Six per cent of the population had positive latex SPTs. Positive indications of one GA specific IgE and 4.1% latex specific IgE occurred. There was no conformity between the latex specific IgE and positive SPTs. Positive SPTs to latex were associated with WRSs of dermatitis and ocular WRSs, but no other WRSs. Exposures were above the current maximum exposure limit (MEL) of 0.2 mg/m3 (0.05 ppm) in eight of the units investigated. A significant relation existed between peak GA concentrations and work related chronic bronchitis and nasal symptoms (after adjustment for types of local ventilation) but not to other WRSs. Peak GA concentrations were significantly higher in units that used both negative pressure room and decontaminating unit ventilation.
CONCLUSION—This study documents a significant level of symptoms reported in the absence of objective evidence of the physiological changes associated with asthma. Ex-employees and current workers with WRSs warrant further study to elucidate the cause and mechanisms for their symptoms. Ventilation systems used for the extraction of aldehydes from the work area may be less effective than expected and due to poor design may even contribute to high peak exposures.


Keywords: glutaraldehyde; occupational asthma; latex
doi:10.1136/oem.57.11.752
PMCID: PMC1739887  PMID: 11024199
10.  Deficient MWF mapping in multiple sclerosis using 3D whole-brain multi-component relaxation MRI 
NeuroImage  2011;59(3):2670-2677.
Recent multiple sclerosis (MS) MRI research has highlighted the need to move beyond the lesion-centric view and to develop and validate new MR imaging strategies that quantify the invisible burden of disease in the brain and establish much more sensitive and specific surrogate markers of clinical disability. One of the most promising of such measures is myelin-selective MRI that allows the acquisition of myelin water fraction (MWF) maps, a parameter that is correlated to brain white matter (WM) myelination. The aim of our study was to apply the newest myelin-selective MRI method, multi-component Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT) in a controlled clinical MS pilot trial. This study was designed to assess the capabilities of this new method to explain differences in disease course and degree of disability in subjects spanning a broad spectrum of MS disease severity. The whole-brain isotropically-resolved 3D acquisition capability of mcDESPOT allowed for the first time the registration of 3D MWF maps to standard space, and consequently a formalized voxel-based analysis of the data. This approach combined with image segmentation further allowed the derivation of new measures of MWF deficiency: total deficient MWF volume (DV) in WM, in WM lesions, in diffusely abnormal white matter and in normal appearing white matter (NAWM). Deficient MWF volume fraction (DVF) was derived from each of these by dividing by the corresponding region volume. Our results confirm that lesion burden does not correlate well with clinical disease activity measured with the extended disability status scale (EDSS) in MS patients. In contrast, our measurements of DVF in NAWM correlated significantly with the EDSS score (R2 = 0.37; p < 0.001). The same quantity discriminated clinically isolated syndrome patients from a normal control population (p < 0.001) and discriminated relapsing–remitting from secondary-progressive patients (p < 0.05); hence this new technique may sense early disease-related myelin loss and transitions to progressive disease. Multivariate analysis revealed that global atrophy, mean whole-brain myelin water fraction and white matter atrophy were the three most important image-derived parameters for predicting clinical disability (EDSS). Overall, our results demonstrate that mcDESPOT-defined measurements in NAWM show great promise as imaging markers of global clinical disease activity in MS. Further investigation will determine if this measure can serve as a risk factor for the conversion into definite MS and for the secondary transition into irreversible disease progression.
doi:10.1016/j.neuroimage.2011.08.052
PMCID: PMC3673309  PMID: 21920444
Multiple sclerosis; Normal appearing white matter; Quantitative relaxation MRI; Myelin water fraction; Deficient MWF
11.  Risk of upper aerodigestive tract cancers in a case-cohort study of autoworkers exposed to metalworking fluids 
Aims: To re-examine aerodigestive cancer risk in a cohort of autoworkers exposed to metal working fluids (MWF), using improved case definition and more recently diagnosed cases.
Methods: The autoworker cohort included 31 100 hourly workers alive on 1 January 1985 who worked at three automobile plants in Michigan. A case-cohort design was carried out that included incident cases of cancers of the larynx, oesophagus, and stomach, and a 10% sample of the cohort. A Cox proportional hazards model was used to estimate MWF exposure effects. The smoothing method of penalised splines was used to explore the shape of the underlying exposure-response curves.
Results: The most important finding was the association between larynx cancer incidence and cumulative straight MWF exposure. The results for oesophageal cancer were less consistent. For stomach cancer there was no evidence of excess risk.
Conclusion: This association between larynx cancer and straight MWF exposures was consistent with a previous finding in this cohort, providing further support for a causal relation.
doi:10.1136/oem.2003.010157
PMCID: PMC1740767  PMID: 15090663
12.  The Occupational Exposure Limit for Fluid Aerosol Generated in Metalworking Operations: Limitations and Recommendations 
Safety and Health at Work  2012;3(1):1-10.
The aim of this review was to assess current knowledge related to the occupational exposure limit (OEL) for fluid aerosols including either mineral or chemical oil that are generated in metalworking operations, and to discuss whether their OEL can be appropriately used to prevent several health risks that may vary among metalworking fluid (MWF) types. The OEL (time-weighted average; 5 mg/m3, short-term exposure limit ; 15 mg/m3) has been applied to MWF aerosols without consideration of different fluid aerosol-size fractions. The OEL, is also based on the assumption that there are no significant differences in risk among fluid types, which may be contentious. Particularly, the health risks from exposure to water-soluble fluids may not have been sufficiently considered. Although adoption of The National Institute for Occupational Safety and Health's recommended exposure limit for MWF aerosol (0.5 mg/m3) would be an effective step towards minimizing and evaluating the upper respiratory irritation that may be caused by neat or diluted MWF, this would fail to address the hazards (e.g., asthma and hypersensitivity pneumonitis) caused by microbial contaminants generated only by the use of water-soluble fluids. The absence of an OEL for the water-soluble fluids used in approximately 80-90 % of all applicants may result in limitations of the protection from health risks caused by exposure to those fluids.
doi:10.5491/SHAW.2012.3.1.1
PMCID: PMC3430924  PMID: 22953224
Metalworking fluid; Oil mist; Straight fluid; Water-soluble fluid; Metalworking operation
13.  Influence of horse stable environment on human airways 
Background
Many people spend considerable amount of time each day in equine stable environments either as employees in the care and training of horses or in leisure activity. However, there are few studies available on how the stable environment affects human airways. This study examined in one horse stable qualitative differences in indoor air during winter and late summer conditions and assessed whether air quality was associated with clinically detectable respiratory signs or alterations to selected biomarkers of inflammation and lung function in stable personnel.
Methods
The horse stable environment and stable-workers (n = 13) in one stable were investigated three times; first in the winter, second in the interjacent late summer and the third time in the following winter stabling period. The stable measurements included levels of ammonia, hydrogen sulphide, total and respirable dust, airborne horse allergen, microorganisms, endotoxin and glucan. The stable-workers completed a questionnaire on respiratory symptoms, underwent nasal lavage with subsequent analysis of inflammation markers, and performed repeated measurements of pulmonary function.
Results
Measurements in the horse stable showed low organic dust levels and high horse allergen levels. Increased viable level of fungi in the air indicated a growing source in the stable. Air particle load as well as 1,3-β-glucan was higher at the two winter time-points, whereas endotoxin levels were higher at the summer time-point. Two stable-workers showed signs of bronchial obstruction with increased PEF-variability, increased inflammation biomarkers relating to reported allergy, cold or smoking and reported partly work-related symptoms. Furthermore, two other stable-workers reported work-related airway symptoms, of which one had doctor's diagnosed asthma which was well treated.
Conclusion
Biomarkers involved in the development of airway diseases have been studied in relation to environmental exposure levels in equine stables. Respirable dust and 1,3-β-glucan levels were increased at winter stabling conditions. Some employees (3/13) had signs of bronchial obstruction, which may be aggravated by working in the stable environment. This study contributes to the identification of suitable biomarkers to monitor the indoor horse stable environment and the personnel. An improved management of the stable climate will be beneficial for the health of both stable workers and horses.
doi:10.1186/1745-6673-4-10
PMCID: PMC2693518  PMID: 19467158
14.  Signs of alveolar inflammation in non-smoking Swedish wood trimmers. 
Wood trimmers are periodically exposed to mould and may develop extrinsic allergic alveolitis (EAA). To investigate if there were any signs of EAA in wood trimmers with low exposure, 19 non-smoking wood trimmers underwent bronchoalveolar lavage (BAL), spirometry, and measurement of diffusion capacity (TLCO). The group was subdivided into those with (n = 9) and without serological antibodies against mould. In 14 workers the TLCO was measured both at the beginning and at the end of a week at work. Twenty five healthy non-smokers served as BAL controls and 19 healthy non-smokers as lung function controls. The median exposure of total dust was well below the Swedish threshold value, and the exposure of mould and bacteria was also low. The cell concentrations and the proportions of the various alveolar cells did not differ between the groups. The concentrations of the soluble components albumin, fibronectin, and hyaluronan were, however, significantly increased (p less than 0.001 for all) in the workers. No difference was found in lung function between the workers and the controls, and the TLCO was not impaired during a week at work. The groups of seropositive and seronegative workers did not differ in any of these parameters. The results are interpreted as a low intensity alveolar inflammation. The presence of precipitating antibodies against mould did not predict any greater risk of developing a more intense inflammation. Analysis of soluble non-cellular BAL components seems to reflect a discrete ongoing alveolar inflammation better than cell counts only.
PMCID: PMC1012125  PMID: 1606029
15.  Two Outbreaks of Occupationally Acquired Histoplasmosis: More than Workers at Risk 
Environmental Health Perspectives  2005;113(5):585-589.
Objective: The objective of this study was to determine the etiology and risk factors for acute histoplasmosis in two outbreaks in Illinois among laborers at a landfill in 2001 and at a bridge reconstruction site in 2003.
Design: We performed environmental investigations during both outbreaks and also performed an analytic cohort study among bridge workers.
Participants: Workers at the landfill during May 2001 and those at the bridge site during August 2003 participated in the study. At the landfill, workers moved topsoil from an area that previously housed a barn; at the bridge, workers observed bat guano on bridge beams.
Evaluations/Measurements: We defined a case by positive immunodiffusion serology, a ≥ 4-fold titer rise in complement fixation between acute and convalescent sera, or positive urinary Histoplasma capsulatum (HC) antigen. Relative risks (RR) for disease among bridge workers were calculated using bivariate analysis.
Results: Eight of 11 landfill workers (73%) and 6 of 12 bridge workers (50%) were laboratory-confirmed histoplasmosis cases. Three bridge workers had positive urinary HC antigen. At the bridge, seeing or having contact with bats [RR = 7.0; 95% confidence interval (CI), 1.1–43.0], jack-hammering (RR = 4.0; 95% CI, 1.2–13.3), and waste disposal (RR = 4.0; 95% CI, 1.2–13.3) were the most significant job-related risk factors for acquiring histoplasmosis.
Conclusions: Workers performing activities that aerosolized topsoil and dust were at increased risk for acquiring histoplasmosis.
Relevance to Professional and Clinical Practice: Employees should wear personal protective equipment and use dust-suppression techniques when working in areas potentially contaminated with bird or bat droppings. Urinary HC antigen testing was important in rapidly identifying disease in the 2003 outbreak.
doi:10.1289/ehp.7484
PMCID: PMC1257551  PMID: 15866767
antigen; bat guano; bridge; dust; histoplasmosis; landfill; occupationally acquired; spores; workers
16.  Nutritional balance of essential amino acids and carbohydrates of the adult worker honeybee depends on age 
Amino Acids  2014;46:1449-1458.
Dietary sources of essential amino acids (EAAs) are used for growth, somatic maintenance and reproduction. Eusocial insect workers such as honeybees are sterile, and unlike other animals, their nutritional needs should be largely dictated by somatic demands that arise from their role within the colony. Here, we investigated the extent to which the dietary requirements of adult worker honeybees for EAAs and carbohydrates are affected by behavioural caste using the Geometric Framework for nutrition. The nutritional optimum, or intake target (IT), was determined by confining cohorts of 20 young bees or foragers to liquid diets composed of specific proportions of EAAs and sucrose. The IT of young, queenless bees shifted from a proportion of EAAs-to-carbohydrates (EAA:C) of 1:50 towards 1:75 over a 2-week period, accompanied by a reduced lifespan on diets high in EAAs. Foragers required a diet high in carbohydrates (1:250) and also had low survival on diets high in EAA. Workers exposed to queen mandibular pheromone lived longer on diets high in EAA, even when those diets contained 5× their dietary requirements. Our data show that worker honeybees prioritize their intake of carbohydrates over dietary EAAs, even when overeating EAAs to obtain sufficient carbohydrates results in a shorter lifespan. Thus, our data demonstrate that even when young bees are not nursing brood and foragers are not flying, their nutritional needs shift towards a diet largely composed of carbohydrates when they make the transition from within-hive duties to foraging.
Electronic supplementary material
The online version of this article (doi:10.1007/s00726-014-1706-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00726-014-1706-2
PMCID: PMC4021167  PMID: 24623119
Honeybee; Amino acid; Nutrition; Protein-to-carbohydrate ratio; Apis mellifera; Diet
17.  Risks of respiratory disease in the heavy clay industry 
OBJECTIVES: Little information is available on the quantitative risks of respiratory disease from quartz in airborne dust in the heavy clay industry. Available evidence suggested that these risks might be low, possibly because of the presence in the dust of other minerals, such as illite and kaolinite, which may reduce the harmful effects of quartz. The aims of the present cross sectional study were to determine among workers in the industry (a) their current and cumulative exposures to respirable mixed dust and quartz; (b) the frequencies of chest radiographic abnormalities and respiratory symptoms; (c) the relations between cumulative exposure to respirable dust and quartz, and risks of radiographic abnormality and respiratory symptoms. METHODS: Factories were chosen where the type of process had changed as little as possible during recent decades. 18 were selected in England and Scotland, ranging in size from 35 to 582 employees, representing all the main types of raw material, end product, kilns, and processes in the manufacture of bricks, pipes, and tiles but excluding refractory products. Weights of respirable dust and quartz in more than 1400 personal dust samples, and site histories, were used to derive occupational groups characterised by their levels of exposure to dust and quartz. Full size chest radiographs, respiratory symptoms, smoking, and occupational history questionnaires were administered to current workers at each factory. Exposure-response relations were examined for radiographic abnormalities (dust and quartz) and respiratory symptoms (dust only). RESULTS: Respirable dust and quartz concentrations ranged from means of 0.4 and 0.04 mg.m-3 for non-process workers to 10.0 and 0.62 mg.m-3 for kiln demolition workers respectively. Although 97% of all quartz concentrations were below the maximum exposure limit of 0.4 mg.m-3, 10% were greater than this among the groups of workers exposed to most dust. Cumulative exposure calculations for dust and quartz took account of changes of occupational group, factory, and kiln type at study and non-study sites. Because of the importance of changes of kiln type additional weighting factors were applied to concentrations of dust and quartz during previous employment at factories that used certain types of kiln. 85% (1934 employees) of the identified workforce attended the medical surveys. The frequency of small opacities in the chest radiograph, category > or = 1/0, was 1.4% (median reading) and seven of these 25 men had category > or = 2/1. Chronic bronchitis was reported by 14.2% of the workforce and breathlessness, when walking with someone of their own age, by 4.4%. Risks of having category > or = 0/1 small opacities differed by site and were also influenced by age, smoking, and lifetime cumulative exposure to respirable dust and quartz. Although exposures to dust and to quartz were highly correlated, the evidence suggested that radiological abnormality was associated with quartz rather than dust. A doubling of cumulative quartz exposure increased the risk of having category > or = 0/1 by a factor of 1.33. Both chronic bronchitis and breathlessness were significantly related to dust exposure. CONCLUSIONS: Although most quartz concentrations at the time of this study were currently below regulatory limits in the heavy clay industry, high exposures regularly occurred in specific processes and occasionally among most occupational groups. However, there are small risks of pneumoconiosis and respiratory symptoms in the industry, although frequency of pneumoconiosis is low in comparison to other quartz exposed workers.
 
PMCID: PMC1757705  PMID: 10448318
18.  Occupational Lung Disease Risk and Exposure to Butter-Flavoring Chemicals After Implementation of Controls at a Microwave Popcorn Plant 
Public Health Reports  2011;126(4):480-494.
Objectives
After an outbreak of severe lung disease among workers exposed to butter-flavoring chemicals at a microwave popcorn plant, we determined whether or not lung disease risk declined after implementation of exposure controls.
Methods
National Institute for Occupational Safety and Health staff performed eight serial cross-sectional medical and industrial hygiene surveys at the plant from November 2000 through August 2003. Medical surveys included standardized questionnaires and spirometry testing. Industrial hygiene surveys measured levels of production-related air contaminants, including butter-flavoring chemicals such as diacetyl. All diacetyl concentrations above detectable limits were corrected for the effects of absolute humidity and days to sample extraction.
Results
Ventilation and isolation of the production process resulted in one to three orders of magnitude reductions in diacetyl air concentrations in different areas of the plant. Workers with past high exposures had stable chest symptoms over time; nasal, eye, and skin irritation symptoms declined. New workers had lower symptom prevalences and higher lung function than workers with past high exposures, and they did not worsen over time. In workers who had at least three spirometry tests, those with past high exposures were more likely to experience rapid declines in lung function than new workers.
Conclusions
Implemented controls lowered exposures to butter-flavoring chemicals and decreased lung disease risk for much of the plant workforce. Some workers with continuing potential for intermittent, short-term peak and measurable time-weighted exposures remain at risk and should use respiratory protection and have regularly scheduled spirometry to detect rapid lung function declines that may be work-related. Close follow-up of such workers is likely to yield additional information on risks due to peak and time-weighted exposure levels.
PMCID: PMC3115208  PMID: 21800743
19.  Evaluation of white matter myelin water fraction in chronic stroke☆ 
NeuroImage : Clinical  2013;2:569-580.
Multi-component T2 relaxation imaging (MCRI) provides specific in vivo measurement of myelin water content and tissue water environments through myelin water fraction (MWF), intra/extra-cellular water fraction (I/EWF) and intra/extracellular and global geometric mean T2 (GMT2) times. Quantitative MCRI assessment of tissue water environments has provided new insights into the progression and underlying white matter pathology in neural disorders such as multiple sclerosis. It has not previously been applied to investigate changes in white matter in the stroke-affected brain. Thus, the purposes of this study were to 1) use MCRI to index myelin water content and tissue water environments in the brain after stroke 2) evaluate relationships between MWF and diffusion behavior indexed by diffusion tensor imaging-based metrics and 3) examine the relationship between white matter status (MWF and fractional anisotropy) and motor behavior in the chronic phase of stroke recovery. Twenty individuals with ischemic stroke and 12 matched healthy controls participated. Excellent to good test/re-test and inter-rater reliability was observed for region of interest-based voxelwise MWF data. Reduced MWF was observed in whole-cerebrum white matter (p < 0.001) and in the ipsilesional (p = 0.017) and contralesional (p = 0.037) posterior limb of internal capsule (PLIC) after stroke compared to whole-cerebrum and bilateral PLIC MWF in healthy controls. The stroke group also demonstrated increased I/EWF, I/E GMT2 and global GMT2 times for whole-cerebrum white matter. Measures of diffusion behavior were also significantly different in the stroke group across each region investigated (p < 0.001). MWF was not significantly correlated with specific tensor-based measures of diffusion in the PLIC for either group. Fractional anisotropy in the ipsilesional PLIC correlated with motor behavior in chronic stroke. These results provide novel insights into tissue-specific changes within white matter after stroke that may have important applications for the understanding of the neuropathology of stroke.
Highlights
•Changes in structural properties of white matter may occur after stroke.•In vivo magnetic resonance techniques used to quantify brain myelin water fraction.•The imaging approach used showed excellent test/re-test and inter-rater reliability.•Local and global reductions in brain myelin water fraction shown in chronic stroke.•First report of in vivo changes in brain myelin in humans following stroke.
doi:10.1016/j.nicl.2013.04.006
PMCID: PMC3777839  PMID: 24179808
Stroke; Myelin water fraction; T2 relaxation; Motor recovery; White matter
20.  Prevalence of Ocular, Respiratory and Cutaneous Symptoms in Indoor Swimming Pool Workers and Exposure to Disinfection By-Products (DBPs) 
The objective of this cross-sectional study was to investigate the prevalence of self-reported respiratory, ocular and cutaneous symptoms in subjects working at indoor swimming pools and to assess the relationship between frequency of declared symptoms and occupational exposure to disinfection by-products (DBPs). Twenty indoor swimming pools in the Emilia Romagna region of Italy were included in the study. Information about the health status of 133 employees was collected using a self-administered questionnaire. Subjects working at swimming pools claimed to frequently experience the following symptoms: cold (65.4%), sneezing (52.6%), red eyes (48.9%) and itchy eyes (44.4%). Only 7.5% claimed to suffer from asthma. Red eyes, runny nose, voice loss and cold symptoms were declared more frequently by pool attendants (lifeguards and trainers) when compared with employees working in other areas of the facility (office, cafe, etc.). Pool attendants experienced generally more verrucas, mycosis, eczema and rash than others workers; however, only the difference in the frequency of self-declared mycosis was statistically significant (p = 0.010). Exposure to DBPs was evaluated using both environmental and biological monitoring. Trihalomethanes (THMs), the main DBPs, were evaluated in alveolar air samples collected from subjects. Swimming pool workers experienced different THM exposure levels: lifeguards and trainers showed the highest mean values of THMs in alveolar air samples (28.5 ± 20.2 μg/m3), while subjects working in cafe areas (17.6 ± 12.1 μg/m3), offices (14.4 ± 12.0 μg/m3) and engine rooms (13.6 ± 4.4 μg/m3) showed lower exposure levels. Employees with THM alveolar air values higher than 21 μg/m3 (median value) experienced higher risks for red eyes (OR 6.2; 95% CI 2.6–14.9), itchy eyes (OR 3.5; 95% CI 1.5–8.0), dyspnea/asthma (OR 5.1; 95% CI 1.0–27.2) and blocked nose (OR 2.2; 95% CI 1.0–4.7) than subjects with less exposure. This study confirms that lifeguards and trainers are more at risk for respiratory and ocular irritative symptoms and cutaneous diseases than subjects with other occupations at swimming pool facilities.
doi:10.3390/ijerph7041379
PMCID: PMC2872330  PMID: 20617036
respiratory, ocular and cutaneous symptoms; irritative symptoms; occupational exposure; swimming pools; trihalomethanes
21.  Endotoxemia in pediatric critical illness - a pilot study 
Critical Care  2011;15(3):R141.
Introduction
The aim was to investigate the prevalence of endotoxemia in children admitted to pediatric intensive care unit (PICU), and its association with disease severity and outcome.
Methods
We conducted a prospective, observational cohort study of children admitted to PICU at St. Mary's Hospital, London over a 6-month period. One hundred consecutive patients were recruited. Demographic and clinical data were collected. Severity of illness was assessed by the pediatric index of mortality 2 (PIM2) score. The pediatric logistic organ dysfunction (PELOD) score was performed daily for the first 4 days. Patients were categorized according to primary reason for PICU admission. Blood samples were taken within 24 hours of admission and endotoxemia was measured using the endotoxin activity assay (EAA). Patients were stratified according to EAA level (high, EAA > 0.4, low, EAA < 0.4) and categorized as septic, post-surgical, respiratory or other. Data were analyzed using appropriate non-parametric tests.
Results
EAA level was significantly lower in PICU controls versus other PICU admissions (P = 0.01). Fifty-five children had endotoxemia on admission. Forty-one (75%) of these were eventually diagnosed with an infectious cause of admission. Nine children without infection had elevated EAA on admission. An infectious cause of admission was significantly associated with endotoxemia (P < 0.005). Of 15 children with gram-negative infection, only 9 (60%) had endotoxemia on admission. Endotoxemia on admission was not associated with shock or death. However, there was a tendency for increased PELOD score and length of stay in endotoxemic children.
Conclusions
Endotoxemia is common in children admitted to intensive care. Understanding the implications of endotoxemia and potential anti-endotoxin strategies may have the potential to reduce severity of illness and length of PICU stay in critically ill children.
doi:10.1186/cc10264
PMCID: PMC3219013  PMID: 21651808
22.  An assessment of dermal exposure to semi-synthetic metal working fluids by different methods to group workers for an epidemiological study on dermatitis 
Background: Assessment of exposure assessment to metal working fluids (MWF) has almost exclusively focused on inhalation exposure.
Aims: To assess levels of, and factors affecting, dermal and inhalation exposure to semi-synthetic MWF, and to identify suitable dermal exposure grouping schemes among metal workers for an epidemiological survey on dermatitis of hands, forearms, and head.
Methods: A cross-sectional survey was conducted in four metal working machining departments of a truck manufacturing plant, estimating dermal and inhalation exposure levels to semi-synthetic metal working fluids (SMWF) in machine operators. Dermal exposure levels to SMWF were estimated by three different methods for dermal exposure assessment (VITAE, surrogate skin pad method, and a semi-quantitative dermal exposure assessment method (DREAM)).
Results: The identified factors affecting dermal exposure were similar for the three methods, although differences were found for estimated variability in dermal exposure levels between groups, within groups (among workers), and from day to day. With the VITAE method differences in exposure levels were detected between workers that were not detected with the surrogate skin pad method, and only partly with the DREAM method.
Conclusions: Considering the additional effort and costs that use of the VITAE method entailed, the observational semi-quantitative DREAM method appeared to be more efficient for grouping of dermal exposure levels for the epidemiological study on dermatitis.
doi:10.1136/oem.2004.015396
PMCID: PMC1741081  PMID: 16109820
23.  Myelin Water Imaging Reflects Clinical Variability in Multiple Sclerosis 
NeuroImage  2011;60(1):263-270.
Whilst MRI is routinely used for the assessment and diagnosis of multiple sclerosis, there is poor correspondence between clinical disability in primary progressive multiple sclerosis (PPMS) patients and conventional MRI markers of disease activity (e.g., number of enhancing lesions). As PPMS patients show diffuse and global myelin loss, the aim of this study was to evaluate the efficacy of whole-brain myelin water fraction (MWF) imaging in PPMS. Specifically, we sought to use full-brain analysis techniques to: 1) determine the reproducibility of MWF estimates in PPMS brain; 2) compare MWF values in PPMS brain to healthy controls; and 3) establish the relationship between MWF and clinical disability, regionally and globally throughout the brain. Seventeen PPMS patients and seventeen age-matched controls were imaged using a whole-brain multi-component relaxation imaging technique to measure MWF. Analysis of MWF reduction was performed on three spatial levels: 1) histogram; 2) white matter skeleton; and 3) voxel-wise at the single-subject level. From histogram analysis, PPMS patients had significantly reduced global normal appearing white matter MWF (6%, p=0.04) compared to controls. Focal lesions showed lower MWF values than white matter in controls (61%, p<0.001) and patients (59%, p<0.001). Along the white matter skeleton, MWF was diffusely reduced throughout the PPMS brain, with significant correlations between reduced MWF and increased clinical disability (more severe symptoms), as measured by the Expanded Disability Status Scale, within the corpus callosum and frontal, temporal, parietal and occipital white matter. Correlations with the more specific mental and sensory functional system scores were localized to clinically eloquent locations: reduced MWF was significantly associated with increased mental scores in anterior regions (i.e., frontal lobes and genu of the corpus callosum), and increased sensory scores in more posterior regions closer to the sensory cortex. Individual patient MWF maps were also compared to a normative population atlas, which highlighted areas of statistical difference between the individual patient and the population mean. A significant correlation was found between the volume of significantly reduced MWF and clinical disability (p=0.008, R = 0.58). Our results show that clinical disability is reflected in particular regions of cerebral white matter that are consistent between subjects, and illustrates a method to examine tissue alteration throughout the brain of individual patients. These results strongly support the use of MWF imaging to evaluate disease activity in PPMS.
doi:10.1016/j.neuroimage.2011.11.070
PMCID: PMC3671155  PMID: 22155325
multiple sclerosis (MS); magnetic resonance imaging (MRI); brain; myelin water imaging; multi-component relaxation
24.  Investigating white matter development in infancy and early childhood using myelin water faction and relaxation time mapping 
Neuroimage  2012;63(3):1038-1053.
The elaboration of the myelinated white matter is essential for normal neurodevelopment, establishing and mediating rapid communication pathways throughout the brain. These pathways facilitate the synchronized communication required for higher order behavioral and cognitive functioning. Altered neural messaging (or ‘disconnectivity’) arising from abnormal white matter and myelin development may underlie a number of neurodevelopmental psychiatric disorders. Despite the vital role myelin plays, few imaging studies have specifically examined its maturation throughout early infancy and childhood. Thus, direct investigations of the relationship(s) between evolving behavioral and cognitive functions and the myelination of the supporting neural systems have been sparse. Further, without knowledge of the ‘normative’ developmental time-course, identification of early abnormalities associated with developmental disorders remains challenging. In this work, we examined the use of longitudinal (T1) and transverse (T2) relaxation time mapping, and myelin water fraction (MWF) imaging to investigate white matter and myelin development in 153 healthy male and female children, 3 months through 60 months in age. Optimized age-specific acquisition protocols were developed using the DESPOT and mcDESPOT imaging techniques; and mean T1, T2 and MWF trajectories were determined for frontal, temporal, occipital, parietal and cerebellar white matter, and genu, body and splenium of the corpus callosum. MWF results provided a spatio-temporal pattern in-line with prior histological studies of myelination. Comparison of T1, T2 and MWF measurements demonstrates dissimilar sensitivity to tissue changes associated with neurodevelopment, with each providing differential but complementary information.
Highlights
► Investigate brain T1, T2 and myelin water fraction development across childhood ► Establish protocols for non-sedated infant and toddler imaging ► Regional T1, T2 and MWF trajectories spanning the first 5 years of life ► Comparison between, T1, T2 and MWF estimates across the age range
doi:10.1016/j.neuroimage.2012.07.037
PMCID: PMC3711836  PMID: 22884937
Brain development; White matter development; Infant imaging; Myelin; Myelin water fraction; Quantitative T1 and T2
25.  Mortality of employees of the Atomic Weapons Establishment, 1951-82. 
BMJ : British Medical Journal  1988;297(6651):757-770.
A total of 22,552 workers employed by the Atomic Weapons Establishment between 1951 and 1982 were followed up for an average of 18.6 years. Of the 3115 who died, 865 (28%) died of cancer. Mortality was 23% lower than the national average for all causes of death and 18% lower for cancer. These low rates were consistent with the findings in other workforces in the nuclear industry and reflect, at least in part, the selection of healthy people to work in the industry and the disproportionate recruitment of people from the higher social classes. At some time during their employment 9389 (42%) of the workers were monitored for exposure to radiation, the average cumulative whole body exposure to external radiation being 7.8 mSv. Their mortality was generally similar to that of other employees, even when exposures were lagged by 10 years. The rate ratio after a 10 year lag in workers with a radiation record compared with other workers was 1.01 (95% confidence interval 0.92 to 1.10) for all causes of death and 1.06 (0.89 to 1.27) for all malignant neoplasms. The only significant differences were for prostatic cancer (rate ratio 2.23; 95% confidence interval 1.13 to 4.40) and for cancers of ill defined and secondary sites (rate ratio 2.37; 1.23 to 4.56). Cancers of lymphatic and haemopoietic tissues were notable for their low occurrence in the study population, with only four deaths from leukaemia and two from multiple myeloma in workers with a radiation record, 9.16 and 3.55 deaths respectively being expected on the basis of national rates. Among workers who had a radiation record 3742 (40%) were also monitored for possible internal exposure to plutonium, 3044 (32%) to uranium, 1562 (17%) to tritium, 638 (7%) to polonium, and 281 (3%) to actinium. In these workers mortality from malignant neoplasms as a whole was not increased, but after a 10 year lag death rates from prostatic and renal cancers were generally more than twice the national average, these excesses arising in a small group of workers monitored for exposure to multiple radionuclides. Though mortality from lung cancer in workers monitored for exposure to plutonium was below the national average, it was some two thirds higher than in other radiation workers, the excess being of borderline statistical significance. Mortality from malignant neoplasms as a whole showed a weak and non-significant increasing trend with increasing level of cumulative whole body exposure to external radiation. When the exposures were lagged by 10 years the trend became stronger and significant, the estimated increase in relative risk per 10 mSv being 7.6% (95% confidence interval 0.4% to 15.3%). This trend was confined almost entirely to workers who were also monitored for exposure to radionuclides (p<0.001), the main contributions coming from lung cancer and prostatic cancer. Exposures of the lung and prostate from internal sources of radiation were not quantified, except for the contribution from tritium. It was therefore not possible to assess the extent to which the associations were due to internally deposited radionuclides rather than external exposure. The finding for prostatic cancer taken in conjunction with the results of other studies suggest a specific occupational hazard in a small group of workers in the nuclear industry who had comparatively high exposures to external radiation and who were also monitored for internal exposure to multiple radionuclides. Research is needed to discover whether any of the radionuclides and other substances concerned are concentrated in the prostate. The occurrence of lung cancer in this workforce requires further investigation taking into account smoking habits and tissue doses from inhaled radionuclides.
PMCID: PMC1834407  PMID: 3142540

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