Surveillance for Silicosis Deaths Among Persons Aged 15-44 Years - United States, 1999-2015.

Silicosis is usually a disease of long latency affecting mostly older workers; therefore, silicosis deaths in young adults (aged 15-44 years) suggests acute or accelerated disease.* To understand the circumstances surrounding silicosis deaths among young persons, CDC analyzed the underlying and contributing causes† of death using multiple cause-of-death data (1999-2015) and industry and occupation information abstracted from death certificates (1999-2013). During 1999-2015, among 55 pneumoconiosis deaths of young adults with International Classification of Diseases, Tenth Revision (ICD-10) code J62 (pneumoconiosis due to dust containing silica),§ 38 (69%) had code J62.8 (pneumoconiosis due to other dust containing silica), and 17 (31%) had code J62.0 (pneumoconiosis due to talc dust) listed on their death certificate. Decedents whose cause of death code was J62.8 most frequently worked in the manufacturing and construction industries and production occupations where silica exposure is known to occur. Among the 17 decedents who had death certificates listing code J62.0 as cause of death, 13 had certificates with an underlying or a contributing cause of death code listed that indicated multiple drug use or drug overdose. In addition, 13 of the 17 death certificates listing code J62.0 as cause of death had information on decedent's industry and occupation; among the 13 decedents, none worked in talc exposure-associated jobs, suggesting that their talc exposure was nonoccupational. Examining detailed information on causes of death (including external causes) and industry and occupation of decedents is essential for identifying silicosis deaths associated with occupational exposures and reducing misclassification of silicosis mortality.

Malignant Mesothelioma Mortality - United States, 1999-2015.

Malignant mesothelioma is a neoplasm associated with occupational and environmental inhalation exposure to asbestos* fibers and other elongate mineral particles (EMPs) (1-3). Patients have a median survival of approximately 1 year from the time of diagnosis (1). The latency period from first causative exposure to malignant mesothelioma development typically ranges from 20 to 40 years but can be as long as 71 years (2,3). Hazardous occupational exposures to asbestos fibers and other EMPs have occurred in a variety of industrial operations, including mining and milling, manufacturing, shipbuilding and repair, and construction (3). Current exposures to commercial asbestos in the United States occur predominantly during maintenance operations and remediation of older buildings containing asbestos (3,4). To update information on malignant mesothelioma mortality (5), CDC analyzed annual multiple cause-of-death records† for 1999-2015, the most recent years for which complete data are available. During 1999-2015, a total of 45,221 deaths with malignant mesothelioma mentioned on the death certificate as the underlying or contributing cause of death were reported in the United States, increasing from 2,479 deaths in 1999 to 2,597 in 2015 (in the same time period the age-adjusted death rates§ decreased from 13.96 per million in 1999 to 10.93 in 2015). Malignant mesothelioma deaths increased for persons aged ≥85 years, both sexes, persons of white, black, and Asian or Pacific Islander race, and all ethnic groups. Despite regulatory actions and the decline in use of asbestos the annual number of malignant mesothelioma deaths remains substantial. The continuing occurrence of malignant mesothelioma deaths underscores the need for maintaining measures to prevent exposure to asbestos fibers and other causative EMPs and for ongoing surveillance to monitor temporal trends.

Silicosis mortality trends and new exposures to respirable crystalline silica - United States, 2001-2010.

Silicosis is a preventable occupational lung disease caused by the inhalation of respirable crystalline silica dust and can progress to respiratory failure and death. No effective specific treatment for silicosis is available; patients are provided supportive care, and some patients may be considered for lung transplantation. Chronic silicosis can develop or progress even after occupational exposure has ceased. The number of deaths from silicosis declined from 1,065 in 1968 to 165 in 2004. Hazardous occupational exposures to silica dust have long been known to occur in a variety of industrial operations, including mining, quarrying, sandblasting, rock drilling, road construction, pottery making, stone masonry, and tunneling operations. Recently, hazardous silica exposures have been newly documented during hydraulic fracturing of gas and oil wells and during fabrication and installation of engineered stone countertops. To describe temporal trends in silicosis mortality in the United States, CDC analyzed annual multiple cause-of-death data for 2001-2010 for decedents aged ≥15 years. During 2001-2010, a total of 1,437 decedents had silicosis coded as an underlying or contributing cause of death. The annual number of silicosis deaths declined from 164 (death rate† = 0.74 per 1 million population) in 2001 to 101 (0.39 per 1 million) in 2010 (p = 0.002). Because of new operations and tasks placing workers at risk for silicosis, efforts to limit workplace exposure to crystalline silica need to be maintained.

Notes from the Field: Update: Silicosis Mortality - United States, 1999-2013.

Silicosis is a potentially fatal but preventable occupational lung disease caused by inhaling respirable crystalline silica (silica). Chronic silicosis, the most common form, occurs after exposure to relatively low silica concentrations for >10 years. Accelerated silicosis occurs after 5-10 years of exposure to higher silica levels, and acute silicosis can occur after only weeks or months of exposure to extremely high silica concentrations. New national mortality data for silicosis have become available since a previous report on silicosis surveillance was published earlier this year. CDC reviewed multiple cause-of-death mortality files from the National Center for Health Statistics to analyze deaths from silicosis (International Classification of Diseases, 10th Revision diagnosis code J62: a pneumoconiosis due to dust containing silica) reported during 1999-2013. Each record lists one underlying cause of death (the disease or injury that initiated the chain of events that led directly and inevitably to death), and up to 20 contributing causes of death (other significant conditions contributing to death but not resulting in underlying cause). Available death certificates from 35 states were reviewed for the period 2004-2006 to identify occupations associated with silicosis among decedents aged 15-44 years. Results indicate that despite substantial progress in eliminating silicosis, silicosis deaths continue to occur. Of particular concern are silicosis deaths in young adults (aged 15-44 years). These young deaths likely reflect higher exposures than those causing chronic silicosis mortality in older persons, some of sufficient magnitude to cause severe disease and death after relatively short periods of exposure. A total of 12 such deaths occurred during 2011-2013, with nine that had silicosis listed as the underlying cause of death.

Diseases attributable to asbestos exposure: years of potential life lost, United States, 1999-2010.

BACKGROUND: Although asbestos use has been restricted in recent decades, asbestos-associated deaths continue to occur in the United States. OBJECTIVES: We evaluated premature mortality and loss of potentially productive years of life attributable to asbestos-associated diseases. METHODS: Using 1999-2010 National Center for Health Statistics mortality data, we identified decedents aged ≥25 years whose death certificate listed asbestosis and malignant mesothelioma as the underlying cause of death. We computed years of potential life lost to life expectancy (YPLL) and to age 65 (YPLL65 ). RESULTS: During 1999-2010, a total of 427,005 YPLL and 55,184 YPLL65 were attributed to asbestosis (56,907 YPLL and 2,167 YPLL65 ), malignant mesothelioma (370,098 YPPL and 53,017 YPLL65 ). Overall and disease-specific asbestos-attributable total YPLL and YPLL65 and median YPLL and YPLL65 per decedent did not change significantly from 1999 to 2010. CONCLUSIONS: The continuing occurrence of asbestos-associated diseases and their substantial premature mortality burden underscore the need for maintaining prevention efforts and for ongoing surveillance to monitor temporal trends in these diseases.

Silicosis mortality with respiratory tuberculosis in the United States, 1968-2006.

The presence of tuberculosis (TB) in patients with silicosis increases mortality risk. To characterize silicosis-respiratory TB comortality in the United States, the authors used 1968-2006 National Center for Health Statistics multiple cause-of-death data for decedents aged ≥25 years. The authors calculated proportionate mortality ratios (PMRs) using available information on decedents' industries and occupations reported from 26 states from 1985 through 1999. Among 16,648 silicosis deaths, 2,278 (13.7%) had respiratory TB listed on the death certificate. Of silicosis-respiratory TB deaths, 1,666 decedents (73.1%) were aged ≥65 years, 2,255 (99.0%) were male, and 1,893 (83.1%) were white. Silicosis-respiratory TB deaths declined 99.5% during the study period (P < 0.001 for time-related trend), from 239.8 per year during 1968-1972 to 1.2 per year during 2002-2006, with no reported deaths in 2006. Silicosis-respiratory TB deaths reported from Pennsylvania (n = 525; 1.29 per million population), Ohio (n = 258; 0.81 per million), and West Virginia (n = 146; 2.35 per million) accounted for 40.8% of all such deaths in the United States. The highest PMR for silicosis-respiratory TB death was associated with the "miscellaneous nonmetallic mineral and stone products" industry (PMR = 73.7, 95% confidence interval: 33.8, 139.8). In the United States, 2006 marked the first year since 1968 with no silicosis-respiratory TB deaths. The substantial decline in silicosis-respiratory TB comortality probably reflects prevention and control measures for both diseases.

Reproducibility of serologic assays for influenza virus A (H5N1).

Hemagglutination-inhibition (HI) and neutralization are used to evaluate vaccines against influenza virus A (H5N1); however, poor standardization leads to interlaboratory variation of results. A candidate antibody standard (07/150) was prepared from pooled plasma of persons given clade 1 A/Vietnam/1194/2004 vaccine. To test human and sheep antiserum, 15 laboratories used HI and neutralization and reassortant A/Vietnam/1194/2004, A/turkey/Turkey/1/2005 (clade 2.2), and A/Anhui/1/2005 (clade 2.3.4) viruses. Interlaboratory variation was observed for both assays, but when titers were expressed relative to 07/150, overall percentage geometric coefficient of variation for A/Vietnam/1194/2004 was reduced from 125% to 61% for HI and from 183% to 81% for neutralization. Lack of reduced variability to clade 2 antigens suggested the need for clade-specific standards. Sheep antiserum as a standard did not reliably reduce variability. The World Health Organization has established 07/150 as an international standard for antibody to clade 1 subtype H5 and has an assigned potency of 1,000 IU/ampoule.

Cholesterol regulates melanogenesis in human epidermal melanocytes and melanoma cells.

Cholesterol is important for membrane stability and is the key substrate for the synthesis of steroid hormones and vitamin D. Furthermore, it is a major component of the lipid barrier in the stratum corneum of the human epidermis. Considering that steroid hormone synthesis is taking place in epidermal melanocytes, we tested whether downstream oestrogen receptor/cAMP signalling via MITF/tyrosine hydroxylase/tyrosinase/pigmentation could be possibly modulated by cholesterol. For this purpose, we utilized human primary melanocyte cell cultures and human melanoma cells with different pigmentation capacity applying immunofluorescence, RT-PCR, Western blotting and determination of melanin content. Our in situ and in vitro results demonstrated that melanocytes can synthesize cholesterol via HMG-CoA reductase and transport cholesterol via LDL/Apo-B100/LDLR. Moreover, we show that cholesterol increases melanogenesis in these cells and in human melanoma cells of intermediate pigmentation (FM55) in a time- and dose-dependent manner. Cellular cholesterol levels in melanoma cells with different pigmentation patterns, epidermal melanocytes and keratinocytes do not differ except in the amelanotic (FM3) melanoma cell line. This result is in agreement with decreasing cholesterol content versus increasing pigmentation in melanosomes. Cholesterol induces cAMP in a biphasic manner i.e. after 30 min and later after 6 and 24 h, meanwhile protein expression of oestrogen receptor beta, CREB, MITF, tyrosine hydroxylase and tyrosinase is induced after 72 h. Taken together, we show that human epidermal melanocytes have the capacity of cholesterol signalling via LDL/Apo-B100/LDL receptor and that cholesterol under in vitro conditions increases melanogenesis.

Quinones are reduced by 6-tetrahydrobiopterin in human keratinocytes, melanocytes, and melanoma cells.

Quinones are potentially dangerous substances generated from quinols via the intermediates semiquinone and hydrogen peroxide. Low semiquinone radical concentrations are acting as radical scavengers while high concentrations produce reactive oxygen species and quinones, leading to oxidative stress, apoptosis, and/or DNA damage. Recently it was recognised that thioredoxin reductase/thioredoxin (TR/T) reduces both p- and o-quinones. In this report we examine additional reduction mechanisms for p- and o-quinones generated from hydroquinone (HQ) and coenzyme Q10 and by 17beta-estradiol by the common cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin (6BH(4)). Our results confirmed that TR reduces the p-quinone 1,4 benzoquinone and coenzyme Q10-quinone back to HQ and coenzyme Q10-quinol, respectively, while 6BH(4) has the capacity to reduce coenzyme Q10-quinone and the o-quinone produced from 17beta-estradiol. 6BH(4) is present in the cytosol and in the nucleus of epidermal melanocytes and keratinocytes as well as melanoma cells and colocalises with TR/T. Therefore we conclude that both mechanisms are major players in the prevention of quinone-mediated oxidative stress and DNA damage.

A plaidoyer for cutaneous enzymology: our view of some important unanswered questions on the contributions of selected key enzymes to epidermal homeostasis.

This review highlights the importance of enzymology, a field of great neglect in current cutaneous biology research. It was therefore the aim by using selected examples of epidermal enzymes and their action including some open questions to demonstrate the importance of this area. Clearly a thorough understanding of basic knowledge in this field is needed which in turn offers a plethora of innovative research projects for a curious mind. Moreover, in order to gain the closest understanding to the truth instead of generating esoteric results, emphasis is put forward on a holistic view utilizing a combination of modern and sometimes old methods to get the answer. Last but not least the bench work is only useful for the welfare of our patients if we can apply our basic knowledge.

Computer simulation of heterogeneous single nucleotide polymorphisms in the catalase gene indicates structural changes in the enzyme active site, NADPH-binding and tetramerization domains: a genetic predisposition for an altered catalase in patients with vitiligo?

Patients with vitiligo have low levels/activities of catalase in their lesional and non-lesional epidermis as well as in their epidermal melanocytes under in vitro conditions while the levels of catalase mRNA are unaltered. This defect leads to a build-up of hydrogen peroxide (H(2)O(2)) in the 10(-3) m range in the epidermis of these patients. In this context, it was realized that 10(-3) m H(2)O(2) deactivates catalase. Along this line, it was also suspected that catalase in patients with vitiligo possesses a special sensitivity to this reactive oxygen species (ROS), and indeed several heterozygous single nucleotide polymorphisms (SNPs) have been documented in the cat gene of these patients. Based on the 3D structure of human catalase monomer, we have modelled the influence of three selected SNPs on the enzyme active site, on the NADPH- as well as the tetramerization-binding domains. Our results show that these SNPs severely alter catalase structurally, which in turn should make the enzyme more susceptible to ROS compared with wild-type enzyme. Taken together, the work presented herein together with the earlier results on SNPs in the cat gene suggests a genetic predisposition for an altered catalase in patients with vitiligo.

Presence of epidermal allantoin further supports oxidative stress in vitiligo.

Xanthine dehydrogenase/xanthine oxidase (XDH/XO) catalyses the hydroxylation of hypoxanthine to xanthine and finally to uric acid in purine degradation. These reactions generate H(2)O(2) yielding allantoin from uric acid when reactive oxygen species accumulates. The presence of XO in the human epidermis has not been shown so far. As patients with vitiligo accumulate H(2)O(2) up to mm levels in their epidermis, it was tempting to examine whether this enzyme and consequently allantoin contribute to the oxidative stress theory in this disease. To address this question, reverse transcription-polymerase chain reaction, immunoreactivity, western blot, enzyme kinetics, computer modelling and high performance liquid chromatography/mass spectrometry analysis were carried out. Our results identified the presence of XDH/XO in epidermal keratinocytes and melanocytes. The enzyme is regulated by H(2)O(2) in a concentration-dependent manner, where concentrations of 10(-6 )m upregulates the activity. Moreover, we demonstrate the presence of epidermal allantoin in acute vitiligo, while this metabolite is absent in healthy controls. H(2)O(2)-mediated oxidation of Trp and Met in XO yields only subtle alterations in the enzyme active site, which is in agreement with the enzyme kinetics in the presence of 10(-3 )m H(2)O(2). Systemic XO activities are not affected. Taken together, our results provide evidence that epidermal XO contributes to H(2)O(2)-mediated oxidative stress in vitiligo via H(2)O(2)-production and allantoin formation in the epidermal compartment.

National trends in silicosis mortality in the United States, 1981-2004.

BACKGROUND: This article describes trends in mortality with silicosis and identifies industries and occupations with elevated silicosis mortality. METHODS: A total of 6,326 deaths with silicosis for 1981-2004 were analyzed for trends and association with occupation and industry. Annual mortality rates were age-adjusted to the U.S. Year 2000 population. A linear regression model was used for analyzing mortality trends. Proportionate mortality ratios (PMRs) were based on 1,440 deaths with information on usual industry and occupation. RESULTS: Overall age-adjusted mortality rates per million declined from 2.4 in 1981 to 0.7 in 2004. Industries having significantly elevated PMRs for silicosis included mining and quarrying. Occupations with elevated PMRs included those associated with metal and mineral processing. CONCLUSIONS: The results suggest that considerable progress has been made towards elimination of this preventable disease. However, about 30 silicosis deaths per year have been recorded since 1995 among those of working age, warranting continued efforts to effectively limit workplace exposures.

Occupational risks for idiopathic pulmonary fibrosis mortality in the United States.

Metal and wood dust exposures have been identified as possible occupational risk factors for idiopathic pulmonary fibrosis (IPF). We analyzed mortality data using ICD-10 code J84.1--"Other interstitial pulmonary diseases with fibrosis," derived age-adjusted mortality rates for 1999-2003, and assessed occupational risks for 1999, by calculating proportionate mortality ratios (PMRs) and mortality odds ratios (MORs) using a matched case-control approach. We identified 84,010 IPF deaths, with an age-adjusted mortality rate of 75.7 deaths/million. Mortality rates were highest among males, whites, and those aged 85 and older. Three industry categories with potential occupational exposures recognized as risk factors for IPF were identified: "Wood buildings and mobile homes" (PMR = 4.5, 95% confidence interval (CI) 1.2-11.6 and MOR = 5.3, 95% CI 1.2-23.8), "Metal mining" (PMR = 2.4, 95% CI 1.3-4.0 and MOR = 2.2, 95% CI 1.1-4.4), and "Fabricated structural metal products" (PMR = 1.9, 95% CI 1.1-3.1 and MOR = 1.7, 95% CI 1.0-3.1). Workers in these industry categories may benefit from toxicological studies and improved surveillance for this disease.

Asbestosis mortality surveillance in the United States, 1970-2004.

To describe the demographic, geographic, and occupational distribution of asbestosis mortality in the United States during 1970-2004, we identified a total of 25,413 asbestosis deaths. We calculated national, state, and county death rates, age-adjusted to the 2000 U.S. standard population. We also calculated industry- and occupation-specific proportionate mortality ratios (PMRs), adjusted for age, sex, and race, and corresponding confidence intervals (CIs) using available data. The overall U.S. age-adjusted asbestosis death rate was 4.1 per million population per year; the rate for males (10.4) was nearly 35-fold higher than that for females (0.3). It increased significantly from 0.6 to 6.9 per million population from 1970 to 2000 (p<0.001), and then declined to 6.3 in 2004 (p=0.014). High asbestosis death rates occurred predominantly, though not exclusively, in coastal areas. Industries with highest PMRs included ship and boat building and repairing (18.5; 95% CI 16.3-20.9) and miscellaneous nonmetallic mineral and stone products (15.9; 95% CI 13.0-19.5). Occupations with highest PMRs included insulation workers (109.2; 95% CI 93.8-127.2) and boilermakers (21.3; 95% CI 17.0-26.6).

Standardisation of inactivated influenza vaccines-Learning from history.

The single radial immunodiffusion assay has been the accepted method for determining the potency of inactivated influenza vaccines since 1978. The worldwide adoption of this assay for vaccine standardisation was facilitated through collaborative studies that demonstrated a high level of reproducibility and its applicability to the different types of influenza vaccine being produced at that time. Clinical evidence indicated the relevance of SRID as a potency assay. Unique features of the SRID assay are likely responsible for its longevity even as newer technologies for vaccine characterisation have been developed and refined. Nevertheless, there are significant limitations to the SRID assay that indicate the need for improvement, and there has been a substantial amount of work undertaken in recent years to develop and evaluate alternative potency assays, including collaborative studies involving research laboratories, regulatory agencies and vaccine manufacturers. Here, we provide an overview of the history of inactivated influenza vaccine potency testing, the current state of alternative assay development and the some of the major challenges to be overcome before implementation of new assays for potency determination.

From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza.

Over the past eight years, cases of human infection with highly pathogenic avian influenza viruses have raised international concern that we could be on the brink of a global influenza pandemic. Many of these human infections have proved fatal and if the viruses had been able to transmit efficiently from person to person, the effects would have been devastating. How can we arm ourselves against this pandemic threat when these viruses are too dangerous to use in conventional vaccine production? Recent technological developments (reverse genetics) have allowed us to manipulate the influenza virus genome so that we can construct safe, high-yielding vaccine strains. However, the transition of reverse-genetic technologies from the research laboratory to the manufacturing environment has presented new challenges for vaccine manufacturers as well as veterinary and public health authorities.

Specific interaction of the diastereomers 7(R)- and 7(S)-tetrahydrobiopterin with phenylalanine hydroxylase: implications for understanding primapterinuria and vitiligo.

Pterin-4a-carbinolamine dehydratase (PCD) is an essential component of the phenylalanine hydroxylase (PAH) system, catalyzing the regeneration of the essential cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin [6(R)BH4]. Mutations in PCD or its deactivation by hydrogen peroxide result in the generation of 7(R,S)BH4, which is a potent inhibitor of PAH that has been implicated in primapterinuria, a variant form of phenylketonuria, and in the skin depigmentation disorder vitiligo. We have synthesized and separated the 7(R) and 7(S) diastereomers confirming their structure by NMR. Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor vs. 6(R)BH4 (Ki=2.3-4.9 microM). Kinetic and binding studies, as well as characterization of the pterin-enzyme complexes by fluorescence spectroscopy, revealed that the inhibitory effects of 7(R,S)BH4 on PAH are in fact specifically based on 7(S)BH4 binding. The molecular dynamics simulated structures of the pterin-PAH complexes indicate that 7(S)BH4 inhibition is due to its interaction with the polar region at the pterin binding site close to Ser-251, whereas its low efficiency as cofactor is related to a suboptimal positioning toward the catalytic iron. 7(S)BH4 is not an inhibitor for tyrosine hydroxylase (TH) in the physiological range, presumably due to the replacement of Ser-251 by the corresponding Ala297. Taken together, our results identified structural determinants for the specific regulation of PAH and TH by 7(S)BH4, which in turn aid in the understanding of primapterinuria and acute vitiligo.