Urinary Metabolites of Organophosphate Flame Retardants: Temporal Variability and Correlations with House Dust Concentrations

Background: A reduction in the use of polybrominated diphenyl ethers (PBDEs) because of human health concerns may result in an increased use of and human exposure to organophosphate flame retardants (OPFRs). Human exposure and health studies of OPFRs are lacking. Objectives: We sought to define the degree of temporal variability in urinary OPFR metabolites in order to inform epidemiologic study design, and to explore a potential primary source of exposure by examining the relationship between OPFRs in house dust and their metabolites in urine. Methods: Nine repeated urine samples were collected from 7 men over the course of 3 months and analyzed for bis(1,3-dichloro-2-propyl) phosphate (BDCPP) and diphenyl phosphate (DPP), metabolites of the OPFRs tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and triphenyl phosphate (TPP), respectively. Intraclass correlation coefficients (ICCs) were calculated to characterize temporal reliability. Paired house dust and urine samples were collected from 45 men. Results: BDCPP was detected in 91% of urine samples, and DPP in 96%. Urinary BDCPP showed moderate-to-strong temporal reliability (ICC range, 0.55–0.72). ICCs for DPP were lower, but moderately reliable (range, 0.35–0.51). There was a weak [Spearman r (rS) = 0.31] but significant (p = 0.03) correlation between urinary BDCPP and TDCPP concentrations in house dust that strengthened when nondetects (rS = 0.47) were excluded. There was no correlation between uncorrected DPP and TPP measured in house dust (rS < 0.1). Conclusions: Household dust may be an important source of exposure to TDCPP but not TPP. Urinary concentrations of BDCPP and DPP were moderately to highly reliable within individuals over 3 months

Opposing shear senses in a subdetachment mylonite zone: Implications for core complex mechanics

[1] Global studies of metamorphic core complexes and low‐angle detachment faults have highlighted a fundamental problem: Since detachments excise crustal section, the relationship between the mylonitic rocks in their footwalls and the brittle deformation in their hanging walls is commonly unclear. Mylonites could either reflect ductile deformation related to exhumation along the detachment fault, or they could be a more general feature of the extending middle crust that has been “captured ” by the detachment. In the first case we would expect the kinematics of the mylonite zone to mirror the sense of movement on the detachment; in the second case both the direction and sense of shear in the mylonites could be different. The northern Snake Range décollement (NSRD) is a classic Basin and Range detachment fault with a well‐documented top‐east of displacement. We present structural, paleo-magnetic, geochronological, and geothermometric evidence to suggest that the mylonite zone below the NSRD locally experienced phases of both east ‐ and west‐directed shear, inconsistent with movement along a single detachment fault. We therefore propose that the footwall mylonites represent a predetachment dis-continuity in the middle crust that separated localized deformation above from distributed crustal flow below (localized‐distributed transition (LDT)). The mylonites were subsequently captured by a moderately dipping brittle detachment that soled down to the middle crust and exhumed them around a rolling hinge into a subhorizontal orientation at the surface, produc-ing the present‐day NSRD. In this interpretation the brittle hanging wall represents a series of rotated upper crustal normal faults, whereas the mylonitic footwall represents one or more exhumed middl

Detection of IgG4-Specific Autoantibodies in Rheumatoid Arthritis Serum Samples

Background: Rheumatoid arthritis (RA) is a chronic multi-system autoimmune disease characterized by inflammatory synovitis. Autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) have been implicated in the pathogenesis of RA, and are currently important criteria for diagnosis within the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria.1 Yet, many patients diagnosed with RA do not have measurable circulating ACPA or RF which may result in delayed diagnosis and treatment. After IgG1, IgG4 is the second most predominant isotype among ACPA and RF; however it is not detected in currently available diagnostic assays. Recent data have demonstrated that patients deemed “sero-negative” based on standard assays may have high titers of IgG4-specific ACPA and/or RF. Objectives: The purpose of this study is to quantitate and compare IgG1- to IgG4-specific anti-CCP antibodies and rheumatoid factor in patients with rheumatoid arthritis. We will determine the frequency of IgG4 autoantibodies, and examine whether they have a differential expression among RA patients. We will also correlate their presence with disease activity, anti-rheumatic drug therapy, and levels of serum cytokines. Ultimately, this work may help to determine if a diagnostic test that detects IgG4 isotype of ACPA and RF will aid in earlier diagnosis and better characterization of rheumatoid arthritis. Methods: To explore our objectives, we have initiated a cross-sectional study with the goal of enrolling 1,000 patients with a confirmed diagnosis of rheumatoid arthritis, based on the 2010 ACR/EULAR classification criteria.1 We are collecting clinical information about each patient including demographics, current treatments, clinical disease activity, laboratory values, and radiographic results. Concurrently, we are collecting serum samples from each patient that will be analyzed for 1) total levels of IgG4 and IgG1; 2) total ACPA and RF; 3) levels of IgG1-specific and IgG4-specific ACPA and RF; and 4) cytokine levels (IL-6, TNF, IL-1, IL-17, IFNy, IL-21, and G-CSF). Results: To date, we have recruited 102 RA patients including 70 females (68.6%) and 32 males (31.4%). Their ages range from 24 to 85 years (mean 58.4 ± 12.4 years). Acute phase reactant levels were available for 98 of the 102 patients, allowing calculation of the disease activity score using 28 joints (DAS28). The mean DAS28 was 3.67 ± 1.0, which is within the moderate disease activity range. The proportion of patients in each disease category was: remission (12.2%), low disease activity (21.4%), moderate disease activity (61.2%), and high disease activity (6.1%). Based on their medical records, at any point in time, 46.1% (n=47) of the recruited subjects had positive RF titers vs. 39.2% (n=40) without RF; 58.8% (n=60) had ACPA vs 26.5% (n=27) without ACPA. For 14.7% (n=15) of the subjects, RF and/or ACPA were either unknown or untested. Of patients with RF, 91.4% (n=43) also had ACPA; of patients with ACPA, 71.7% % (n=43) also had RF. Of the patients tested for both, 27.9% (n=24) were negative for both RF and ACPA. Conclusion: Subject recruitment and data collection are well underway for this large cross-sectional study that will shed light to the role of IgG4- specific autoantibodies in the pathogenesis and diagnosis of rheumatoid arthritis. Reference: 1Aletaha D Neogi T, Silman A, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9):2569-81/Ann Rheum Dis. 2010; 69:1580-8

<i>C-elegans</i> model identifies genetic modifiers of alpha-synuclein inclusion formation during aging

Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a &lt;i&gt;C-elegans&lt;/i&gt; model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha-synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders

Dynamics of Immune Reconstitution and Activation Markers in HIV+ Treatment-Naïve Patients Treated with Raltegravir, Tenofovir Disoproxil Fumarate and Emtricitabine

Background: The dynamics of CD4+ T cell reconstitution and changes in immune activation and inflammation in HIV-1 disease following initiation of antiretroviral therapy (ART) are incompletely defined and their underlying mechanisms poorly understood. Methods: Thirty-nine treatment-naïve patients were treated with raltegravir, tenofovir DF and emtricitabine. Immunologic and inflammatory indices were examined in persons with sustained virologic control during 48 weeks of therapy. Results: Initiation of ART increased CD4+ T cell numbers and decreased activation and cell cycle entry among CD4+ and CD8+ T cell subsets, and attenuated markers of coagulation (D-dimer levels) and inflammation (IL-6 and TNFr1). These indices decayed at different rates and almost all remained elevated above levels measured in HIV-seronegatives through 48 weeks of viral control. Greater first and second phase CD4+ T cell restoration was related to lower T cell activation and cell cycling at baseline, to their decay with treatment, and to baseline levels of selected inflammatory indices, but less so to their changes on therapy. Conclusions: ART initiation results in dynamic changes in viral replication, T cell restoration, and indices of immune activation, inflammation, and coagulation. These findings suggest that determinants of T cell activation/cycling and inflammation/coagulation may have distinguishable impact on immune homeostasis. Trial Registration Clinicaltrials.gov NCT0066097

Global variations in H2O/Ce: 1. Slab surface temperatures beneath volcanic arcs

We have calculated slab fluid temperatures for 51 volcanoes in 10 subduction zones using the newly developed H2O/Ce thermometer. The slab fluid compositions were calculated from arc eruptives, using melt inclusion-based H2O contents, and were corrected for background mantle contributions. The temperatures, adjusted to h, the vertical depth to the slab beneath the volcanic arc, range from ~730 to 900°C and agree well (within 30°C on average for each arc) with sub-arc slab surface temperatures predicted by recent thermal models. The coherence between slab model and surface observation implies predominantly vertical transport of fluids within the mantle wedge. Slab surface temperatures are well reconciled with the thermal parameter (the product of slab age and vertical descent rate) and h. Arcs with shallow h (~80 to 100 km) yield a larger range in slab surface temperature (up to ~200°C between volcanoes) and more variable magma compositions than arcs with greater h (~120 to 180 km). This diversity is consistent with coupling of the subducting slab and mantle wedge, and subsequent rapid slab heating, at ~80 km. Slab surface temperatures at or warmer than the H2O-saturated solidus suggest that melting at the slab surface is common beneath volcanic arcs. Our results imply that hydrous melts or solute-rich supercritical fluids, and not H2O-rich aqueous fluids, are thus the agents of mass transport to the mantle wedge

The Role of the Magnetic Field in the Interstellar Medium of the Post-Starburst Dwarf Irregular Galaxy NGC 1569

(abridged) NGC 1569 is a nearby dwarf irregular galaxy which underwent an intense burst of star formation 10 to 40 Myr ago. We present observations that reach surface brightnesses two to eighty times fainter than previous radio continuum observations and the first radio continuum polarization observations. These observations allow us to probe the relationship of the magnetic field of NGC 1569 to the rest of its interstellar medium. We confirm the presence of an extended radio continuum halo at 20 cm and see for the first time the radio continuum feature associated with the western Halpha arm at wavelengths shorter than 20cm. The spectral index trends in this galaxy support the theory that there is a convective wind at work in this galaxy. We derive a total magnetic field strength of 38 microG in the central regions and 10-15 microG in the halo. The magnetic field is largely random in the center of the galaxy; the uniform field is ~3-9 microG and is strongest in the halo. We find that the magnetic pressure is the same order of magnitude but, in general, a factor of a few less than the other components of the interstellar medium in this galaxy. The uniform magnetic field in NGC 1569 is closely associated with the Halpha bubbles and filaments. We suggest that a supernova-driven dynamo may be operating in this galaxy. The outflow of hot gas from NGC 1569 is clearly shaping the magnetic field, but the magnetic field in turn may be aiding the outflow by channeling gas out of the disk of the galaxy. Dwarf galaxies with extended radio continuum halos like that of NGC 1569 may play an important role in magnetizing the intergalactic medium.Comment: ApJ accepted. 56 pages, 14 figures (low resolution), 8 tables. Version with high resolution figures at http://www.astro.virginia.edu/~aak8t/data/n1569/ms.pd

Behavioral deficits, early gliosis, dysmyelination and synaptic dysfunction in a mouse model of mucolipidosis IV

Mucolipidosis IV (MLIV) is caused by mutations in the gene MCOLN1. Patients with MLIV have severe neurologic deficits and very little is known about the brain pathology in this lysosomal disease. Using an accurate mouse model of mucolipidosis IV, we observed early behavioral deficits which were accompanied by activation of microglia and astrocytes. The glial activation that persisted during the course of disease was not accompanied by neuronal loss even at the late stage. In vivo [Ca2+]-imaging revealed no changes in resting [Ca2+] levels in Mcoln1−/− cortical neurons, implying their physiological health. Despite the absence of neuron loss, we observed alterations in synaptic plasticity, as indicated by elevated paired-pulse facilitation and enhanced long-term potentiation. Myelination deficits and severely dysmorphic corpus callosum were present early and resembled white matter pathology in mucolipidosis IV patients. These results indicate the early involvement of glia, and challenge the traditional view of mucolipidosis IV as an overtly neurodegenerative condition. Electronic supplementary material The online version of this article (doi:10.1186/s40478-014-0133-7) contains supplementary material, which is available to authorized users