Use of Denosumab in Children With Osteoclast Bone Dysplasias: Report of Three Cases.

Denosumab has been used successfully to treat disease-associated osteoclast overactivity, including giant cell tumor of bone. Given its mechanism of action, denosumab is a potent potential treatment of other osteoclast bone dysplasias including central giant cell granuloma (CGCG), aneurysmal bone cyst (ABC), and cherubism. Relatively little is known about the safety and efficacy of denosumab in patients with these conditions, especially in children. We report on 3 pediatric patients treated with denosumab over a 3-year period at UCLA Medical Center (Los Angeles and Santa Monica, CA, USA): a 12-year-old with recurrent ABC of the pelvis, a 14-year-old with CGCG of the mandible, and a 12-year-old with cherubism. All were started on a 1-year course of 15 doses 120 mg s.c., given monthly with two loading doses on day 8 and 15. All patients demonstrated rapid and pronounced clinical improvement while on denosumab, including a significant reduction in pain and sclerosis of lytic lesions on radiographs. Within 1 month of initiating therapy, 2 patients experienced hypocalcemia (Common Terminology Criteria for Adverse Events [CTCAE] grade 2) and hypophosphatemia, with 1 patient experiencing symptoms. One patient went on to experience symptomatic rebound hypercalcemia (CTCAE grade 4) 5 months after completing therapy, requiring bisphosphonates and calcitonin. For the second patient, we developed a schedule to wean denosumab involving the progressive lengthening of time between doses from 1 to 4 months in 1-month increments before cessation. We found that denosumab therapy results in significant clinical and radiographic improvement for pediatric patients with nonresectable ABC, CGCG, and cherubism. Problems with serum calcium may be more common in younger patients, with symptomatic and protracted rebound hypercalcemia after cessation of therapy the most significant. We present a potential solution to this problem with progressive spacing of doses. Potential serious adverse events from alterations in calcium homeostasis should be explored in prospective clinical trials. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research

Acoustic, psychophysical, and neuroimaging measurements of the effectiveness of active cancellation during auditory functional magnetic resonance imaging

Functional magnetic resonance imaging (fMRI) is one of the principal neuroimaging techniques for studying human audition, but it generates an intense background sound which hinders listening performance and confounds measures of the auditory response. This paper reports the perceptual effects of an active noise control (ANC) system that operates in the electromagnetically hostile and physically compact neuroimaging environment to provide significant noise reduction, without interfering with image quality. Cancellation was first evaluated at 600 Hz, corresponding to the dominant peak in the power spectrum of the background sound and at which cancellation is maximally effective. Microphone measurements at the ear demonstrated 35 dB of acoustic attenuation [from 93 to 58 dB sound pressure level (SPL)], while masked detection thresholds improved by 20 dB (from 74 to 54 dB SPL). Considerable perceptual benefits were also obtained across other frequencies, including those corresponding to dips in the spectrum of the background sound. Cancellation also improved the statistical detection of sound-related cortical activation, especially for sounds presented at low intensities. These results confirm that ANC offers substantial benefits for fMRI research

RNA-Seq identifies genes whose proteins are upregulated during syncytia development in murine C2C12 myoblasts and human BeWo trophoblasts

The fusion of villous cytotrophoblasts into the multinucleated syncytiotrophoblast is critical for the essential functions of the mammalian placenta. Using RNA-Seq gene expression, quantitative protein expression, and siRNA knockdown we identified genes and their cognate proteins which are similarly upregulated in two cellular models of mammalian syncytia development (human BeWo cytotrophoblast to syncytiotrophoblast and murine C2C12 myoblast to myotube). These include DYSF, PDE4DIP, SPIRE2, NDRG1, PLEC, GPR146, HSPB8, DHCR7, and HDAC5. These findings provide avenues for further understanding of the mechanisms underlying mammalian placental syncytiotrophoblast development

DISCOVERY OF TWO NEW THERMALLY BLOATED LOW-MASS WHITE DWARFS AMONG THE KEPLER BINARIES

We report the discovery of two new low-mass, thermally bloated, hot white dwarfs among the Kepler sample of eclipsing binaries. These are KIC 9164561 and KIC 10727668 with orbital periods of 1.2670 and 2.3058 days, respectively. The current primary in both systems is an A star of about 2 M[subscript ʘ]. This brings the number of similar binaries among the Kepler sample to six, and the two new systems have the shortest orbital periods among them. The white dwarf (WD) in KIC 9164561 has the largest thermal bloating, compared to its cold degenerate radius, of about a factor of 14. We utilize radial velocity measurements of the A star in KIC 9164561 to determine the WD mass rather accurately: 0.197 ± 0.005 M[subscript ʘ]. The mass of the WD in KIC 10727668 is based on the Doppler boosting signal in the Kepler photometry and is less accurately determined to be 0.266 ± 0.035 M[subscript ʘ]. Based on the inferred radii and effective temperatures of these two white dwarfs, we are able to make an independent theoretical estimate of their masses to within ~0.01 M[subscript ʘ] based on evolutionary models of their cooling history after they lose their hydrogen-rich envelopes. We also present evidence that there is a third body in the KIC 9164561 system with an orbital period of 8–14 yr.Spain. Ministerio de Economia y Competitividad (Grant ESP2013-48391-C4-2 R)National Aeronautics and Space Administration (Kepler Participating Scientist Program

Assessment of the usefulness of a diagnostic test: A survey of patient preference for diagnostic techniques in the evaluation of intestinal inflammation

BACKGROUND: In order to assess the usefulness of radiolabeled white cell scanning in the diagnosis of intestinal inflammation, subjects were asked to rank several dimensions of preference for white cell scanning in relation to other diagnostic tests. Two groups were surveyed: one known to have inflammatory bowel disease and the second not familiar in most cases with the tests. Subjects were asked to rank preference for each of seven tests: radiolabeled white cell scan, colonoscopy, barium enema, sigmoidoscopy, enteroclysis, stool analysis and laparotomy for the diagnosis of IBD and impressions of discomfort, embarrassment, inconvenience and danger related to each test. Mean rank scores were calculated, test ranks compared within groups and significance determined by the Wilcoxon rank test. RESULTS: Significant differences were seen in overall preference for white cell scan over barium enema and colonoscopy (p < 0.01) in both survey groups. Perceived discomfort and embarrassment demonstrated similar rankings. CONCLUSION: This patient preference combined with the reported accuracy of white cell scanning further establishes the usefulness of this means of IBD diagnosis

Trajectories of Body Mass Index Among Active-Duty U.S. Army Soldiers

Establishing the shape and determinants of trajectories of body mass index (BMI) among Soldiers is critical given the importance of weight management to military service requirements. To establish the shape and determinants of BMI trajectories among Soldiers, we aimed to (1) model the overall BMI trajectory of Soldiers, (2) find the most common trajectory groups among Soldiers, (3) investigate the relationship between BMI trajectories and sociodemographic and military-specific characteristics, and (4) determine if there were Soldiers with large fluctuations in BMI. The study population included all US Army Soldiers on active-duty between 2011 and 2014 who were age 17–62 (n = 827,126). With longitudinal data from the Stanford Military Data Repository, we used group-based trajectory modeling to identify the BMI trajectories of Soldiers and multinomial logistic regression to estimate associations between Soldier characteristics and trajectory membership. Four distinct BMI trajectory groups were found: increasing, decreasing, constant, and inconstant. The constant, increasing, and decreasing trajectories were similar in shape and percentage between men and women. The constant trajectory had the fewest Soldiers who exceeded weight standards or had duty limitations. The increasing trajectory was associated with marriage and fewer service years. The decreasing trajectory was associated with more service years and higher educational attainment. The inconstant trajectory differed in shape between men and women. Over 6% of men and 12% of women had fluctuations in BMI indicative of weight cycling. Understanding the characteristics associated with BMI trends may assist the Army in targeting resources aimed to improve Soldier health and combat readiness

Modern foraminifera, δ\u3csup\u3e13\u3c/sup\u3eC, and bulk geochemistry of central Oregon tidal marshes and their application in paleoseismology

We assessed the utility of δ13C and bulk geochemistry (total organic content and C:N) to reconstruct relative sea-level changes on the Cascadia subduction zone through comparison with an established sea-level indicator (benthic foraminifera). Four modern transects collected from three tidal environments at Siletz Bay, Oregon, USA, produced three elevation-dependent groups in both the foraminiferal and δ13C/bulk geochemistry datasets. Foraminiferal samples from the tidal flat and low marsh are identified by Miliammina fusca abundances of \u3e 45%, middle and high marsh by M. fusca abundances of \u3c 45% and the highest marsh by Trochamminita irregularis abundances \u3e 25%. The δ13C values from the groups defined with δ13C/bulk geochemistry analyses decrease with an increasing elevation; − 24.1 ± 1.7‰ in the tidal flat and low marsh; − 27.3 ± 1.4‰ in the middle and high marsh; and − 29.6 ± 0.8‰ in the highest marsh samples. We applied the modern foraminiferal and δ13C distributions to a core that contained a stratigraphic contact marking the great Cascadia earthquake of AD 1700. Both techniques gave similar values for coseismic subsidence across the contact (0.88 ± 0.39 m and 0.71 ± 0.56 m) suggesting that δ13C has potential for identifying amounts of relative sea-level change due to tectonics

Bryostatin enhancement of memory in Hermissenda

Author Posting. © Marine Biological Laboratory, 2006. This article is posted here by permission of Marine Biological Laboratory for personal use, not for redistribution. The definitive version was published in Biological Bulletin 210 (2006): 201-214.Bryostatin, a potent agonist of protein kinase C (PKC), when administered to Hermissenda was found to affect acquisition of an associative learning paradigm. Low bryostatin concentrations (0.1 to 0.5 ng/ml) enhanced memory acquisition, while concentrations higher than 1.0 ng/ml down-regulated the pathway and no recall of the associative training was exhibited. The extent of enhancement depended upon the conditioning regime used and the memory stage normally fostered by that regime. The effects of two training events (TEs) with paired conditioned and unconditioned stimuli, which standardly evoked only short-term memory (STM) lasting 7 min, were—when bryostatin was added concurrently—enhanced to a long-term memory (LTM) that lasted about 20 h. The effects of both 4- and 6-paired TEs (which by themselves did not generate LTM), were also enhanced by bryostatin to induce a consolidated memory (CM) that lasted at least 5 days. The standard positive 9-TE regime typically produced a CM lasting at least 6 days. Low concentrations of bryostatin (<0.5 ng/ml) elicited no demonstrable enhancement of CM from 9-TEs. However, animals exposed to bryostatin concentrations higher than 1.0 ng/ml exhibited no behavioral learning. Sharp-electrode intracellular recordings of type-B photoreceptors in the eyes from animals conditioned in vivo with bryostatin revealed changes in input resistance and an enhanced long-lasting depolarization (LLD) in response to light. Likewise, quantitative immunocytochemical measurements using an antibody specific for the PKC-activated Ca2+/GTP-binding protein calexcitin showed enhanced antibody labeling with bryostatin. Animals exposed to the PKC inhibitor bisindolylmaleimide-XI (Ro-32-0432) administered by immersion prior to 9-TE conditioning showed no training-induced changes with or without bryostatin exposure. However, if animals received bryostatin before Ro-32, the enhanced acquisition and demonstrated recall still occurred. Therefore, pathways responsible for the enhancement effects induced by bryostatin were putatively mediated by PKC. Overall, the data indicated that PKC activation occurred and calexcitin levels were raised during the acquisition phases of associative conditioning and memory initiation, and subsequently returned to baseline levels within 24 and 48 h, respectively. Therefore, the protracted recall measured by the testing regime used was probably due to bryostatin-induced changes during the acquisition and facilitated storage of memory, and not necessarily to enhanced recall of the stored memory when tested many days after training.AMK and HTE acknowledge the support of the Marine Biological Laboratory and Blanchette Rockefeller Neurosciences Institutes for these initial studies

The combined effects of coping and pain interference on army readiness

IntroductionChronic pain and associated interference with daily activities are common in the military and impact Force readiness. Chronic pain affects one-third of service members and is a leading cause of medical non-readiness (MNR) in the military. Research suggests that underlying psychological mechanisms related to trait coping styles and pain interference (PI) affect functional outcomes, but little research exists examining this relationship within an Army population. The purpose of this study was to examine the combined effects of PI and coping on U.S. Army soldier readiness by using annual well-being data from the Global Assessment Tool (GAT) and medical non-readiness (MNR) based on duty restriction records.MethodsThe sample comprised 866,379 soldiers who completed the GAT between 2014 and 2017 with no duty restrictions at the time of baseline GAT completion; subjects were observed through 2018 for duty restrictions. Parametric survival regression models with a Weibull distribution predicted demographic-adjusted hazards of MNR by dichotomized PI (no PI/PI) and beneficial/non-beneficial use of GAT coping components (good coping, bad coping, catastrophizing-flexibility, and catastrophizing-hopelessness). Incident MNR was evaluated for all duty restrictions, and stratified by selected body systems (upper extremity, lower extremity, psychiatric).ResultsAmong soldiers with PI, hazards were higher in those reporting non-beneficial coping styles (bad coping, hopelessness) and lower in those reporting beneficial coping styles (good coping, flexibility). Across all coping styles, PI/coping interactions were particularly strong for catastrophizing-hopelessness and when examining MNR from psychiatric conditions.DiscussionThese findings suggest some synergistic associations between pain and coping that may impact pain-related occupational disability. Coping skills may be an effective interventional target for chronic pain reduction/prevention within military programs, such as the Master Resilience Training Course offered to soldiers in the Army. Further research should assess whether early coping style interventions can reduce pain-related outcomes

Disclination Unbinding Transition in Quantum Hall Liquid Crystals

We derive the the long-wavelength elastic theory for the quantum Hall smectic state starting from the Hartree-Fock approximation. Dislocations in this state lead to an effective nematic model for $T>0$, which undergoes a disclination unbinding transition from a phase with algebraic orientational order into an isotropic phase. We obtain transition temperatures which are in qualitative agreement with recent experiments which have observed large anisotropies of the longitudinal resistivities in half-filled Landau levels, lending credence to the liquid crystal interpretation of experiments.Comment: Added explanation for spin dependence of anisotropic strength: The reason for this spin oscillation is simple: in the energetics of Eqs. (4-6), there is an energy scale $e^2/l_b$ that decreases with increasing filling factor $\nu$; simultaneously the matrix elements of the Coulomb interaction [Eq. (3)] increase with increasing LL index $L$, resulting in the observed spin dependenc