Multi-scale Investigation of Weight-bearing Exercise on Bone Biomechanical Integrity in the Osteogenesis Imperfecta Model (oim) Mouse

Comparative Medicine - OneHealth and Comparative Medicine Poster SessionOsteogenesis imperfecta (OI), a heritable connective tissue disorder generally due to type I collagen defects, is characterized by small stature, reduced bone mineral density, and frequent fractures. Bone is inherently mechanosensitive, responding and adapting to its mechanical environment. Bone formation occurs in response to high mechanical loads; often changing its geometry to strengthen the skeleton. In humans, during the normal 2 year prepubertal/pubertal growth period normal children attain 26% of their peak bone mass, and children which are physically active accrue 10-40% more bone (region specific) than inactive children. This suggests that sedentary lifestyle choices of children with OI are particularly detrimental to their bone health. We postulate that even though the OI bone material is biomechanically weaker, the OI bone will respond to exercise (muscle loading and/or gravitational ground force), especially during pubertal growth by altering bone geometry, architecture, and/or mineral:matrix physiochemistry to generate an inherently stronger bone. The potential benefits of therapeutic exercise to OI patients are significant, but the risks are real. It is critical that we first demonstrate the feasibility and potential success of an exercise therapy in a mouse model of OI for it to be considered a viable therapy for patients. To address this need we combined the unique strengths of two University of Missouri Campuses (Columbia and Kansas City) to create a collaborative research team from the Departments of Biochemistry (UMC) and Veterinary Pathobiology (UMC) and Oral Biology (UMKC School of Dentistry) to determine if weight bearing exercise will improve bone biomechanical integrity in a mouse model of osteogenesis imperfecta (oim), and to investigate the molecular, biochemical, physiochemical, structural and biomechanical impact of exercise on bone at the macro-, ultra- and nano-structural levels. The relationship of whole bone biomechanical integrity and geometry to the mineral:matrix composition, architecture, crystal geometry, and the matrix:mineral interactions of bone is poorly understood. Therefore, we examined femurs of wildtype and oim mice by multi-scale analyses characterizing geometry (muCT) and biomechanics (torsional loading to failure) in relation to the bone mineral and matrix, physicochemical and mechanical properties (FTIR, Raman and scanning acoustic microscopy). By muCT and torsional loading to failure we defined the geometric structural properties and the whole bone biomechanical properties (torsional ultimate strength, torsional stiffness, and strain energy until failure), which are a function of both the geometry and bone biomechanical material properties (tensile strength and shear modulus of elasticity). We used FTIR and Raman microscopy in conjunction with scanning acoustic microscopy to correlate the chemical structure and composition with mechanical integrity. We then performed the same analyses on femoral bones from wildtype and oim mice that underwent moderate weight bearing exercise (running on a treadmill) to determine if weight bearing exercise could alter the molecular structure of bone mineral:matrix and improve bone physicochemical and biomechanical properties. Our preliminary findings support the hypothesis that weight bearing exercise induces an adaptive response in oim mouse bone to alter its matrix/mineral composition, physiochemical structure/ property, and geometry to increase bone quality and biomechanical strength

Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models.

Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11-cis retinal, were exam- ined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat, genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina

Shape of the concentration–response association between fine particulate matter pollution and human mortality in Beijing, China, and its implications for health impact assessment, The

Includes bibliographical references (pages 107009-12-107009-14).Publisher version: https://doi.org/10.1289/EHP4464.Background: Studies found approximately linear short-term associations between particulate matter (PM) and mortality in Western communities. However, in China, where the urban PM levels are typically considerably higher than in Western communities, some studies suggest nonlinearity in this association. Health impact assessments (HIA) of PM in China have generally not incorporated nonlinearity in the concentration–response (C-R) association, which could result in large discrepancies in estimates of excess deaths if the true association is nonlinear. Objectives: We investigated nonlinearity in the C-R associations between with PM with aerodynamic diameter ≤2.5μm (PM2.5) and mortality in Beijing, China, and the sensitivity of HIA to linearity assumptions. Methods: We modeled the C-R association between PM2.5 and cause-specific mortality in Beijing, China (2009–2012), using generalized linear models (GLM). PM2.5 was included through either linear, piecewise-linear, or spline functions to investigate evidence of nonlinearity. To determine the sensitivity of HIA to linearity assumptions, we estimated PM2.5-attributable deaths using both linear- and nonlinear-based C-R associations between PM2.5 and mortality. Results: We found some evidence that, for nonaccidental and circulatory mortality, the shape of the C-R association was relatively flat at lower concentrations of PM2.5, but then had a positive slope at higher concentrations, indicating nonlinearity. Conversely, the shape for respiratory mortality was positive and linear at lower concentrations of PM2.5, but then leveled off at the higher concentrations. Estimates of excess deaths attributable to short-term PM2.5 exposure were, in some cases, very sensitive to the linearity assumption in the association, but in other cases robust to this assumption. Conclusions: Our results demonstrate some evidence of nonlinearity in PM2.5–mortality associations and that an assumption of linearity in this association can influence HIAs, highlighting the importance of understanding potential nonlinearity in the PM2.5–mortality association at the high concentrations of PM2.5 in developing megacities like Beijing. https://doi.org/10.1289/EHP446

Longitudinal Observation of Treatment Patterns and Outcomes for Patients with Fibromyalgia: 12‐Month Findings from the REFLECTIONS Study

Objective To describe 12‐month treatment patterns and outcomes for patients starting a new medication for fibromyalgia in routine clinical practice. Design and Outcome Measures Data from 1,700 patients were collected at baseline and 1, 3, 6, and 12 months. Repeated measures and P oisson regression models controlling for demographic, clinical, and baseline outcomes were used to assess changes in health outcomes ( B rief P ain I nventory severity and interference, S heehan D isability S cale, F ibromyalgia I mpact Q uestionnaire), satisfaction, and economic factors for patients who initiated on pregabalin (214, 12.6%), duloxetine (264, 15.5%), milnacipran (134, 7.9%), or tricyclic antidepressants (66, 3.9%). Sensitivity analyses were run using propensity‐matched cohorts. Results Patients started on 145 unique drugs for fibromyalgia, and over 75% of patients took two or more medications concurrently for fibromyalgia at each time point assessed. Overall, patients showed improvement on the four health outcomes, with few differences across medication cohorts. At baseline, patients reported annual averages of 20.3 visits for outpatient care, 27.7 missed days of work, and 32.6 days of care by an unpaid caregiver. The duloxetine and milnacipran (vs pregabalin or tricyclic antidepressant) cohorts had fewer outpatient visits during the 12‐month study. Patients reported satisfaction with overall treatment and their fibromyalgia medication (46.0% and 42.8%, respectively). Conclusions In this real‐world setting, patients with fibromyalgia reported modest improvements, high resource, and medication use, and were satisfied with the care they received. Cohort differences were difficult to discern because of the high rates of drug discontinuation and concomitant medication use over the 12‐month study period.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100168/1/pme12168.pd

Detection of carbon monoxide and hydrogen with non-stoichiometric perovskites, and variation in transduction modes

Peer reviewed: YesNRC publication: Ye

Widely adaptable oil-in-water gel emulsions stabilized by an amphiphilic hydrogelator derived from dehydroabietic acid

A surfactant, R-6-AO, derived from dehydroabietic acid has been synthesized. It behaves as a highly efficient low-molecular-weight hydrogelator with an extremely low critical gelation concentration (CGC) of 0.18 wt % (4 mm). R-6-AO not only stabilizes oil-in-water (O/W) emulsions at concentrations above its critical micelle concentration (cmc) of 0.6 mm, but also forms gel emulsions at concentrations beyond the CGC with the oil volume fraction freely adjustable between 2 % and 95 %. Cryo-TEM images reveal that R-6-AO molecules self-assemble into left-handed helical fibers with cross-sectional diameters of about 10 nm in pure water, which can be turned to very stable hydrogels at concentrations above the CGC. The gel emulsions stabilized by R-6-AO can be prepared with different oils (n-dodecane, n-decane, n-octane, soybean oil, olive oil, tricaprylin) owing to the tricyclic diterpene hydrophobic structure in their molecules that enables them to adopt a unique arrangement in the fibers