Comparison of long‐period surface wave amplitude and phase anomalies for two models of global lateral heterogeneity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95459/1/grl2883.pd

Asperity distribution and earthquake occurrence in the southern Kurile Islands arc

The seismicity in the southern Kurile Islands arc is characterized by a complex overlapping of aftershock zones of a few great and many large earthquakes (Ms [greater, double equals] 7.0). The spatial relationships of these aftershock zones can be explained in terms of a simple pattern of fault plane heterogeneity. The four largest earthquakes in this region are, from north to south, the 1963 Kurile Islands (Mw = 8.5), the 1958 Etorofu (Mw = 8.3), the 1969 Kurile Islands (Mw = 8.2) and the 1973 Nemuro-Oki (Mw = 7.8) events. Detailed body wave studies indicate that the moment release associated with each event is concentrated in a small portion of the aftershock area, with scale lengths Ms [greater, double equals] 7.0) earthquakes both before and after the great events. The second mode involves either rupture of relatively weak regions which results in low-stress-drop events, or rupture of smaller asperities. The earthquakes produced by failure of small asperities tend to repeatedly rupture the same regions, and they have impulsive source time functions indicating rupture of highly stressed regions of the fault surface. By analysis of all Ms [greater, double equals] 7.0 events since 1946 in this region we find a segmentation of the southern Kurile Islands thrust zone into strongly coupled regions with two scale lengths (dominant and secondary asperities) and weakly coupled regions (the surrounding areas generating the low-stress-drop events). The largest earthquakes and the smaller asperity earthquakes occur at the down-dip portion of the lithospheric interface, while the low-stress-drop events occur much closer to the trench axis. This implies a difference in the degree of mechanical coupling between the subducting and overriding plates, with the deeper portions having greater strength than the shallower parts.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26509/1/0000047.pd

Contralateral Cruciate Survival in Dogs with Unilateral Non-Contact Cranial Cruciate Ligament Rupture

BACKGROUND: Non-contact cranial cruciate ligament rupture (CrCLR) is an important cause of lameness in client-owned dogs and typically occurs without obvious injury. There is a high incidence of bilateral rupture at presentation or subsequent contralateral rupture in affected dogs. Although stifle synovitis increases risk of contralateral CrCLR, relatively little is known about risk factors for subsequent contralateral rupture, or whether therapeutic intervention may modify this risk. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a longitudinal study examining survival of the contralateral CrCL in client-owned dogs with unilateral CrCLR in a large baseline control population (n = 380), and a group of dogs that received disease-modifying therapy with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline (n = 16), and were followed for one year. Follow-up in treated dogs included analysis of mobility, radiographic evaluation of stifle effusion and arthritis, and quantification of biomarkers of synovial inflammation. We found that median survival of the contralateral CrCL was 947 days. Increasing tibial plateau angle decreased contralateral ligament survival, whereas increasing age at diagnosis increased survival. Contralateral ligament survival was reduced in neutered dogs. Our disease-modifying therapy did not significantly influence contralateral ligament survival. Correlative analysis of clinical and biomarker variables with development of subsequent contralateral rupture revealed few significant results. However, increased expression of T lymphocyte-associated genes in the index unstable stifle at diagnosis was significantly related to development of subsequent non-contact contralateral CrCLR. CONCLUSION: Subsequent contralateral CrCLR is common in client-owned dogs, with a median ligament survival time of 947 days. In this naturally occurring model of non-contact cruciate ligament rupture, cranial tibial translation is preceded by development of synovial inflammation. However, treatment with arthroscopic lavage, intra-articular hyaluronic acid and oral doxycycline does not significantly influence contralateral CrCL survival

Effects of off great-circle propagation on the phase of long-period surface waves

Surface wave phase corrections for departures from great-circle propagation are computed using two-point ray-tracing through the aspherical earth model M84C of Woodhouse & Dziewonski (1984). For Rayleigh and Love waves with periods in the range 100–250 s, we determine whether these corrections provide significant variance reductions in source determinations compared with corrections calculated assuming great-circle propagation through the heterogeneous structure. For most source-receiver geometries, the off great-circle travel-time effects are small (< 10 s) for second and third orbits (e.g. R2 and R3), and their application in source determinations does not significantly reduce the data variance. This suggests that for the loworder heterogeneous models currently available the geometrical optics approximation is valid for long-period low orbit surface waves. Off great-circle phase anomalies increase quasi-linearly with increasing orbit number, indicating that the geometrical optics approximation degrades for higher orbits, which emphasizes the importance of developing higher order approximations for free-oscillation studies.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73147/1/j.1365-246X.1987.tb05217.x.pd

Lung Inflammation, Injury, and Proliferative Response after Repetitive Particulate Hexavalent Chromium Exposure

BACKGROUND: Chronic inflammation is implicated in the development of several human cancers, including lung cancer. Certain particulate hexavalent chromium [Cr(VI)] compounds are well-documented human respiratory carcinogens that release genotoxic soluble chromate and are associated with fibrosis, fibrosarcomas, adenocarcinomas, and squamous cell carcinomas of the lung. Despite this, little is known about the pathologic injury and immune responses after repetitive exposure to particulate chromates. OBJECTIVES: In this study we investigated the lung injury, inflammation, proliferation, and survival signaling responses after repetitive exposure to particulate chromate. METHODS: BALB/c mice were repetitively treated with particulate basic zinc chromate or saline using an intranasal exposure regimen. We assessed lungs for Cr(VI)-induced changes by bronchoalveolar lavage, histologic examination, and immunohistochemistry. RESULTS: Single exposure to Cr(VI) resulted in inflammation of lung tissue that persists for up to 21 days. Repetitive Cr(VI) exposure induced a neutrophilic inflammatory airway response 24 hr after each treatment. Neutrophils were subsequently replaced by increasing numbers of macrophages by 5 days after treatment. Repetitive Cr(VI) exposure induced chronic peribronchial inflammation with alveolar and interstitial pneumonitis dominated by lymphocytes and macrophages. Moreover, chronic toxic mucosal injury was observed and accompanied by increased airway pro-matrix metalloprotease-9. Injury and inflammation correlated with airways becoming immuno reactive for phosphorylation of the survival signaling protein Akt and the proliferation marker Ki-67. We observed a reactive proliferative response in epithelial cells lining airways of chromate-exposed animals. CONCLUSIONS: These data illustrate that repetitive exposure to particulate chromate induces chronic injury and an inflammatory microenvironment that may promote Cr(VI) carcinogenesis

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

Safety in Nonhuman Primates of Ocular AAV2-\u3cem\u3eRPE65\u3c/em\u3e, a Candidate Treatment for Blindness in Leber Congenital Amaurosis

Leber congenital amaurosis (LCA) is a molecularly heterogeneous disease group that leads to blindness. LCA caused by RPE65 mutations has been studied in animal models and vision has been restored by subretinal delivery of AAV- RPE65 vector. Human ocular gene transfer trials are being considered. Our safety studies of subretinal AAV-2/2. RPE65 in RPE65 -mutant dogs showed evidence of modest photoreceptor loss in the injection region in some animals at higher vector doses. We now test the hypothesis that there can be vector-related toxicity to the normal monkey, with its human-like retina. Good Laboratory Practice safety studies following single intraocular injections of AAV-2/2. RPE65 in normal cynomolgus monkeys were performed for 1-week and 3-month durations. Systemic toxicity was not identified. Ocular-specific studies included clinical examinations, electroretinography, and retinal histopathology. Signs of ocular inflammation postinjection had almost disappeared by 1 week. At 3 months, electroretinography in vector-injected eyes was no different than in vehicle-injected control eyes or compared with presurgical recordings. Healed sites of retinal perforation from subretinal injections were noted clinically and by histopathology. Foveal architecture in subretinally injected eyes, vector or vehicle, could be abnormal. Morphometry of central retina showed no photoreceptor layer thickness abnormalities occurring in a dose-dependent manner. Vector sequences were present in the injected retina, vitreous, and optic nerve at 1 week but not consistently in the brain. At 3 months, there were no vector sequences in optic nerve and brain. The results allow for consideration of an upper range for no observed adverse effect level in future human trials of subretinal AAV-2/2. RPE65. The potential value of foveal treatment for LCA and other retinal degenerations warrants further research into how to achieve gene transfer without retinal injury from surgical detachment of the retina

The Cascadia Initiative : a sea change In seismological studies of subduction zones

Author Posting. © The Oceanography Society, 2014. This article is posted here by permission of The Oceanography Society for personal use, not for redistribution. The definitive version was published in Oceanography 27, no. 2 (2014): 138-150, doi:10.5670/oceanog.2014.49.Increasing public awareness that the Cascadia subduction zone in the Pacific Northwest is capable of great earthquakes (magnitude 9 and greater) motivates the Cascadia Initiative, an ambitious onshore/offshore seismic and geodetic experiment that takes advantage of an amphibious array to study questions ranging from megathrust earthquakes, to volcanic arc structure, to the formation, deformation and hydration of the Juan De Fuca and Gorda Plates. Here, we provide an overview of the Cascadia Initiative, including its primary science objectives, its experimental design and implementation, and a preview of how the resulting data are being used by a diverse and growing scientific community. The Cascadia Initiative also exemplifies how new technology and community-based experiments are opening up frontiers for marine science. The new technology—shielded ocean bottom seismometers—is allowing more routine investigation of the source zone of megathrust earthquakes, which almost exclusively lies offshore and in shallow water. The Cascadia Initiative offers opportunities and accompanying challenges to a rapidly expanding community of those who use ocean bottom seismic data.The Cascadia Initiative is supported by the National Science Foundation; the CIET is supported under grants OCE- 1139701, OCE-1238023, OCE‐1342503, OCE-1407821, and OCE-1427663 to the University of Oregon

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD