Low-Level Respirable Crystalline Silica and Silicosis: Long-Term Follow-Up of Vermont Granite Workers.

The lifetime risk of silicosis associated with low-level occupational exposure to respirable crystalline silica remains unclear because most previous radiographic studies included workers with varying exposure concentrations and durations. This study assessed the prevalence of silicosis after lengthy exposure to respirable crystalline silica at levels ≤ 0.10 mg/m3. Vermont granite workers employed any time during 1979-1987 were traced and chest radiographs were obtained for 356 who were alive in 2017 and residing in Vermont. Work history, smoking habits and respiratory symptoms were obtained by interview, and exposure was estimated using a previously developed job-exposure matrix. Associations between radiographic findings, exposure, and respiratory symptoms were assessed by ANOVA, chi-square tests and binary regression. Fourteen workers (3.9%) had radiographic evidence of silicosis, and all had been employed ≥30 years. They were more likely to have been stone cutters or carvers and their average exposure concentrations and cumulative exposures to respirable crystalline silica were significantly higher than workers with similar durations of employment and no classifiable parenchymal abnormalities. This provides direct evidence that workers with long-term exposure to low-level respirable crystalline silica (≤0.10 mg/m3) are at risk of developing silicosis.

Acute Myopericarditis with Pericardial Effusion and Cardiac Tamponade in a Patient with COVID-19.

BACKGROUND Coronavirus disease 2019 (COVID-19) is primarily a respiratory illness. However, with rising numbers of cases, multiple reports of cardiovascular manifestations have emerged. We present a case of COVID-19 infection complicated by myopericarditis and tamponade requiring drainage. CASE REPORT An 82-year-old woman with multiple comorbidities presented with five days of productive cough, fever with chills, and intermittent diarrhea. She tested positive for COVID-19. Index EKG revealed new diffuse T-wave inversions and a prolonged QT interval (>500 ms). Troponin was mildly elevated without any anginal symptoms. Hydroxychloroquine and azithromycin were not initiated due to concerns about QT prolongation. The echocardiogram revealed preserved left ventricular (LV) function, a small global pericardial effusion, and apical hypokinesis. Serial echocardiograms revealed an enlarging circumferential pericardial effusion with pacemaker wire reported as 'piercing' the right ventricular (RV) apex alongside early diastolic collapse of the right ventricle, suggesting echocardiographic tamponade. Chest CT revealed extension of the RV pacemaker lead into the pericardial fat. Interestingly, on comparison with a previous chest CT from 2019, similar lead positions were confirmed. Pericardiocentesis was performed with removal of 400 cc exudate. CONCLUSIONS Acute myopericarditis and pericardial effusion can occur in COVID-19 infection, even in the absence of severe pulmonary disease. This case highlights the importance of awareness of rare cardiac manifestations of COVID-19 in the form of acute myopericarditis and cardiac tamponade and their early diagnosis and management.

Membrane characteristics tune activities of endosomal and autophagic human VPS34 complexes.

The lipid kinase VPS34 orchestrates diverse processes, including autophagy, endocytic sorting, phagocytosis, anabolic responses and cell division. VPS34 forms various complexes that help adapt it to specific pathways, with complexes I and II being the most prominent ones. We found that physicochemical properties of membranes strongly modulate VPS34 activity. Greater unsaturation of both substrate and non-substrate lipids, negative charge and curvature activate VPS34 complexes, adapting them to their cellular compartments. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) of complexes I and II on membranes elucidated structural determinants that enable them to bind membranes. Among these are the Barkor/ATG14L autophagosome targeting sequence (BATS), which makes autophagy-specific complex I more active than the endocytic complex II, and the Beclin1 BARA domain. Interestingly, even though Beclin1 BARA is common to both complexes, its membrane-interacting loops are critical for complex II, but have only a minor role for complex I.

Comparing Surfactant Penetration into Human Skin and Resulting Skin Dryness Using In Vivo and Ex Vivo Methods.

Numerous tests have been developed to estimate a surfactant's mildness in rinse-off formulations. In this study, mixed surfactant systems were examined for their impact on surfactant penetration into the skin and skin hydration using in vivo and ex vivo methods. A forearm controlled application test (FCAT) was conducted, and skin hydration was evaluated using corneometry and visual dryness grading. Tape strip and cup scrub extractions were completed within the FCAT to examine the penetration of five individual surfactants into the skin in vivo. The ratio of surfactant mass extracted by five pooled tape strips to surfactant mass extracted by cup scrubs was found to be in the range of 40-59%. Furthermore, cup scrub collection and analysis was less time-consuming and less expensive to conduct than tape stripping. Thus, we recommend cup scrub extraction as a suitable substitute for tape stripping in future surfactant skin penetration analyses. In vivo results were compared with ex vivo 14C-sodium dodecyl sulfate (14C-SDS) penetration into human cadaver skin from the same surfactant systems. In vivo measurements conducted in the FCAT, including corneometer reading, visual dryness score, and individual surfactant (sodium laureth (1) ether sulfate and cocamidopropyl betaine) extracted from the skin, were found to correlate well with 14C-SDS penetration into the skin ex vivo for anion-based surfactant systems. Thus, 14C-SDS skin penetration may be a useful preclinical test for skin dryness induced by rinse-off products containing anionic surfactants.

Mechanisms of anionic surfactant penetration into human skin: Investigating monomer, micelle and submicellar aggregate penetration theories.

OBJECTIVE: Once penetrated into the stratum corneum, anionic surfactants bind to and denature stratum corneum proteins as well as intercalate into and extract intercellular lipids. With repeated exposures, this leads to skin dryness and irritation, compromising barrier function and skin health. The mechanisms of anionic surfactant penetration into the skin, however, are still widely debated. The objective of this study was to evaluate current theories of surfactant penetration into human skin. METHODS: A test set comprising 15 anionic surfactant systems and one non-ionic surfactant, all having either dodecyl or lauryl alkyl chains, was tested for surfactant penetration into split-thickness human cadaver skin in vitro using radiolabelled sodium dodecyl sulphate (14 C-SDS). Select physical properties of these formulations thought to be associated with skin penetration including critical micelle concentration, micelle diameter, filtrate concentration and zeta potential were also measured. RESULTS: 14 C-SDS penetration into human cadaver skin from surfactant systems in vitro was found to correlate well with CMC (R2  = 0.34, P < 0.05), filtrate concentration (R2  = 0.36, P < 0.05) and zeta potential (R2  = 0.76, P < 0.001), but poorly with micelle diameter (R2  = 0.12). Furthermore, the latter measure correlated inversely with penetration compared to what would be expected based on the micelle penetration theory. CONCLUSION: Neither monomer nor micelle penetration theories are sufficient to explain anionic surfactant penetration into human skin. Submicellar (or premicellar) aggregate penetration theory is difficult to defend at relevant surfactant concentrations. We propose a new hypothesis for this mechanism in which short-term penetration is based on monomer concentration and longer term penetration is based on surfactant-induced damage to the skin barrier.

OBJECTIF: Une fois pénétrés dans la couche cornée, les tensioactifs anioniques se lient aux protéines de la couche cornée, le dénaturent, s'intercalent dans les lipides intercellulaires et les extraient. Avec des expositions répétées, ceci entraîne un assèchement et une irritation de la peau, compromettant ainsi la fonction de barrière et la santé de la peau. Les mécanismes de pénétration du tensioactif anionique dans la peau restent toutefois largement débattus. L'objectif de cette étude est d'évaluer les théories actuelles de la pénétration de surfactant dans la peau humaine. MÉTHODES: Un ensemble de contrôle comprenant 15 systèmes de tensioactifs anioniques et un tensioactif non ionique, tous possédant des chaînes dodécyles ou lauryle alkyles, a été testé vis-à-vis de la pénétration du tensioactif dans la peau d'un cadavre humain partiellement épaisse in vitro en utilisant du sulfate de sodium dodécyl radiomarqué (14 C-SDS). Certaines propriétés physiques de ces formulations supposées être associées à la pénétration dans la peau, notamment la concentration critique micellaires, le diamètre des micelles, la concentration de filtrat, et le potentiel zêta, ont également été mesurées. RÉSULTATS: La pénétration du 14 C-SDS dans la peau de cadavre humain provenant de systèmes de tensioactifs in vitro était bien corrélée avec la CMC (R2  = 0,34, P < 0,05), la concentration de filtrat (R2  = 0,36, P < 0,05) et le potentiel zêta (R2  = 0,76, P < 0,001), mais faiblement avec un diamètre de micelle (R2  = 0,12). De plus, cette dernière mesure était inversement corrélée à la pénétration par rapport à ce que l'on pouvait attendre de la théorie de la pénétration des micelles. CONCLUSION: Ni les théories de pénétration de monomères ni de micelles ne sont suffisantes pour expliquer la pénétration de tensioactif anionique dans la peau humaine. La théorie de la pénétration des agrégats submicellaires (ou prémicellaires) est difficile à défendre aux concentrations pertinentes de surfactant. Nous proposons une nouvelle hypothèse pour ce mécanisme dans laquelle la pénétration à court terme est basée sur la concentration en monomères et la pénétration à plus long terme est basée sur les dommages à la barrière cutanée induits par les tensioactifs.

Exposure‒response relationships for silicosis and its progression in industrial sand workers.

Objectives This study aimed to characterize the relationship between radiographic silicosis and exposure to respirable quartz and determine how exposure affects disease progression. Methods Surveillance chest radiographs from a cohort of 1902 workers were examined to identify 67 cases of radiographic silicosis and 167 matched controls. Exposures were estimated by linking work histories to a job exposure matrix (JEM) based on samples collected by the participating companies and historical estimates. Conditional logistic regression was used to examine exposure‒response relationships. Sequential radiographs from silicosis cases were used to assess associations between exposure and disease progression. Results Risk of silicosis increased with cumulative exposure [odds ratio (OR) 1.43 per 1 mg/m 3years, 95% confidence interval (CI) 1.23-1.66], average exposure concentration (OR 1.30 per 0.10 mg/m 3, 95% CI 1.11-1.51) and net exposure duration (OR 1.10 per year, 95% CI 1.05-1.16). Multivariate analyses indicated that the risk associated with cumulative exposure varied depending on exposure duration and concentration. Analysis of the time worked at differing exposure levels indicated that exposures ≤0.05 mg/m 3were not significantly associated with silicosis risk after adjustment for years worked at higher concentrations. Disease progression was related to subsequent exposure concentration, with a yearly increase in small opacity profusion of 0.052 subcategory per each 0.10 mg/m 3increase in concentration. Conclusions Workers with longer exposure at lower concentrations were at higher risk for silicosis than those with the same cumulative exposure who worked for a shorter time at higher concentrations. The rate of silicosis progression was related to subsequent exposure concentration.

Retrospective Assessment of Respirable Quartz Exposure for a Silicosis Study of the Industrial Sand Industry.

Background: In 2016, the OSHA PEL for crystalline silica was reduced, renewing interest in evaluating risk of silicosis from occupational exposures. The industrial sand industry, which deals with high-purity quartz sands, is the setting for a current epidemiologic investigation of silicosis risk and progression. In support of that investigation, respirable quartz (RQ) exposures were retrospectively estimated for 67 workers with silicosis and 167 matched control workers from 21 industrial sand plants, in which some started work as early as 1929. Methods: A job exposure matrix (JEM) was constructed by integrating a modern (post-1970) RQ exposure database containing more than 40000 measurements with archival particle count exposure data from a 1947 survey. A simulation algorithm was used to develop a conversion factor to convert the archival particle count data into modern measures of RQ by randomly generating 100000 virtual dust particles of varying diameters corresponding to the size distributions of 14 archival particle size distribution samples. The equivalent respirable mass and particle counts of the virtual particles were calculated, totalled, and ratioed to derive the conversion factor. The JEM was integrated with individual job histories to calculate average and cumulative exposure for each case and control. Multiple exposure estimates were derived for unprotected exposures as well as for exposures adjusted for estimated respiratory protective equipment use and efficiency. Results: The mean of the count to respirable mass conversion factors derived from 14 archival particle size samples was 157 µg m-3 per mppcf (SD: 42; range: 96-263) with no statistical difference across process areas (drying, screening, vibrating, binning, bulk loading, bagging), P = 0.29. The JEM demonstrated an industry-wide decrease in prevailing exposures to RQ of up to about 2 orders of magnitude from the distant (1929) to the recent (2012) past. Unadjusted cumulative exposures for cases and controls were statistically different (P < 0.001) with respective medians (range) of 3764 µg m-3 year (221-25121) and 1595 µg m-3 year (0-16446). Adjustment of exposure for use of respiratory protection showed modest reductions in estimated exposure: median adjusted cumulative exposures assuming a protection factor of 5 were 86% and 77% of the unadjusted values for cases and controls, respectively. Conclusions: The industrial sand industry offers a unique setting for examination of silicosis risk because of the high silica content of industrial sand and a long history of radiographic silicosis surveillance of industry workers. However, the great majority of silicosis cases in this industry are found among former workers and are associated with exposures occurring in the distant past, which necessitates extensive retrospective exposure assessment and increases the likelihood of exposure misclassification. Nonetheless, the estimated cumulative exposures for silicosis cases and controls in this work were significantly different, with the median cumulative exposure for cases being more than twice that of their matched controls.

Development of a preclinical surfactant skin penetration assay to reflect exposure times typical of consumer use.

Mixed surfactant and surfactant-polymer compositions have been reported to decrease surfactant deposition onto and penetration into the skin relative to single surfactant compositions, potentially improving the mildness of the product. Previous workers in this area [see Moore et al., J. Cosmet. Sci.54:29-46 (2003), and subsequent publications] employed a procedure in which excised porcine skin was exposed to a surfactant solution containing radiolabeled sodium dodecyl sulfate (14C-SDS) for 5 h. We have developed an improved SDS penetration assay using excised human skin that reflects typical consumer exposure times for rinse-off products. Using the new protocol, we were able to see a significant decrease in 14C-SDS penetration from a sodium lauryl sulfate (SLS)/polyethylene oxide composition applied to excised skin for either 2 or 10 min, as compared to SLS only. Furthermore, differences between the SDS penetration patterns on porcine skin and human skin were seen with a second SLS/polymer system; consequently, we do not recommend porcine skin for routine mildness screening by 14C-SDS penetration.

Improving marine disease surveillance through sea temperature monitoring, outlooks and projections.

To forecast marine disease outbreaks as oceans warm requires new environmental surveillance tools. We describe an iterative process for developing these tools that combines research, development and deployment for suitable systems. The first step is to identify candidate host-pathogen systems. The 24 candidate systems we identified include sponges, corals, oysters, crustaceans, sea stars, fishes and sea grasses (among others). To illustrate the other steps, we present a case study of epizootic shell disease (ESD) in the American lobster. Increasing prevalence of ESD is a contributing factor to lobster fishery collapse in southern New England (SNE), raising concerns that disease prevalence will increase in the northern Gulf of Maine under climate change. The lowest maximum bottom temperature associated with ESD prevalence in SNE is 12 °C. Our seasonal outlook for 2015 and long-term projections show bottom temperatures greater than or equal to 12 °C may occur in this and coming years in the coastal bays of Maine. The tools presented will allow managers to target efforts to monitor the effects of ESD on fishery sustainability and will be iteratively refined. The approach and case example highlight that temperature-based surveillance tools can inform research, monitoring and management of emerging and continuing marine disease threats.

T cells specific for different latent and lytic viral proteins efficiently control Epstein-Barr virus-transformed B cells.

BACKGROUND AIMS: Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disorders (PTLD) belong to the most dreaded complications of immunosuppression. The efficacy of EBV-specific T-cell transfer for PTLD has been previously shown, yet the optimal choice of EBV-derived antigens inducing polyclonal CD4(+) and CD8(+) T cells that cover a wide range of human leukocyte antigen types and efficiently control PTLD remains unclear. METHODS: A pool of 125 T-cell epitopes from seven latent and nine lytic EBV-derived proteins (EBVmix) and peptide pools of EBNA1, EBNA3c, LMP2a and BZLF1 were used to determine T-cell frequencies and to isolate T cells through the use of the interferon (IFN)-γ cytokine capture system. We further evaluated the phenotype and functionality of the generated T-cell lines in vitro. RESULTS: EBVmix induced significantly higher T-cell frequencies and allowed selecting more CD4(+)IFN-γ(+) and CD8(+)IFN-γ(+) cells than single peptide pools. T cells of all specificities expanded similarly in vitro, recognized cognate antigen, and, to a lower extent, EBV-infected cells, exerted moderate cytotoxicity and showed reduced alloreactivity. However, EBVmix-specific cells most efficiently controlled EBV-infected lymphoblastoid cell lines (LCLs). This control was mainly mediated by EBV-specific CD8(+) cells with an oligoclonal epitope signature covering both latent and lytic viral proteins. Notably, EBV-specific CD4(+) cells unable to control LCLs produced significantly less perforin and granzyme B, probably because of limited LCL epitope presentation. CONCLUSIONS: EBVmix induces a broader T-cell response, probably because of its coverage of latent and lytic EBV-derived proteins that may be important to control EBV-transformed B cells and might offer an improvement of T-cell therapies.

Bioreactivity of the crystalline silica polymorphs, quartz and cristobalite, and implications for occupational exposure limits (OELs).

Silica or silicon dioxides (SiO2) are naturally occurring substances that comprise the vast majority of the earth's crust. Because of their prevalence and commercial applications, they have been widely studied for their potential to induce pulmonary fibrosis and other disorders. Historically, the focus in the workplace has been on the development of inflammation and fibrotic lung disease, the basis for promulgating workplace standards to protect workers. Crystalline silica (CS) polymorphs, predominantly quartz and cristobalite, are used in industry but are different in their mineralogy, chemistry, surface features, size dimensions and association with other elements naturally and during industrial applications. Epidemiologic, clinical and experimental studies in the literature historically have predominantly focused on quartz polymorphs. Thus, in this review, we summarize past scientific evaluations and recent peer-reviewed literature with an emphasis on cristobalite, in an attempt to determine whether quartz and cristobalite polymorphs differ in their health effects, toxicity and other properties that may dictate the need for various standards of protection in the workplace. In addition to current epidemiological and clinical reports, we review in vivo studies in rodents as well as cell culture studies that shed light on mechanisms intrinsic to the toxicity, altered cell responses and protective or defense mechanisms in response to these minerals. The medical and scientific literature indicates that the mechanisms of injury and potential causation of inflammation and fibrotic lung disease are similar for quartz and cristobalite. Our analysis of these data suggests similar occupational exposure limits (OELs) for these minerals in the workplace.

Trypanocidal activities of trileucine methyl vinyl sulfone proteasome inhibitors.

Previous studies have shown that proteasome inhibitors are novel agents for chemotherapy of human African trypanosomiasis or sleeping sickness. In this study, five peptide trileucine methyl vinyl sulfones with different N-terminal substituents were tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of Trypanosoma brucei. Two inhibitors displayed promising anti-trypanosomal activities with ED50 values in the sub-micromolar range. Higher trypanocidal activity of the compounds generally corresponded to a higher k(obs)/[I] value for inhibition of the trypsin-like activity but not for the inhibition of the chymotrypsin-like activity of the proteasome. These data suggest that inhibitors with strong activity against the trypsin-like activity of the proteasome are the rational choice for future anti-sleeping sickness drug development.

Trypanocidal effect of alpha',beta'-epoxyketones indicates that trypanosomes are particularly sensitive to inhibitors of proteasome trypsin-like activity.

Previous studies have shown that the proteasome of Trypanosoma brucei is a candidate for novel chemotherapy of African sleeping sickness. In this study, two potent and highly selective alpha',beta'-epoxyketones peptide proteasome inhibitors, epoxomicin and YU101, have been tested for their trypanocidal activities in vitro using culture-adapted bloodstream forms of T. brucei. Both inhibitors displayed promising anti-trypanosomal activities with ED(50) and ED(90) values in the low to mid nanomolar range. Based on MIC values, epoxomicin exhibited a selectivity index approaching those of commercially available drugs. Enzymatic analyses of proteasomal peptidase activities revealed that, compared with mammalian cells, trypanosomes are particular sensitive to inhibition of the trypsin-like activity of the proteasome. In conclusion, the data suggests that proteasome inhibitors targeting the trypsin-like activity are the rational choice for future anti-trypanosomal drug development.