Alendronate reduces bone toughness of ribs without significantly increasing microdamage accumulation in dogs following three years of daily treatment

Reduced bone toughness, the energy absorption capacity of the tissue, has been consistently documented in vertebrae of animals treated with a wide range of bisphosphonate doses. Data regarding toughness changes in the rib are conflicting, with one report showing no effect and another showing a significant reduction following treatment of beagle dogs with high doses of bisphosphonates. The goal of this study was to evaluate changes in bone toughness and various other tissue-level properties of the rib following 3 years of bisphosphonate treatment with doses at and above those used to treat osteoporosis. Skeletally mature intact beagle dogs were treated daily for 3 years with vehicle (VEH), alendronate 0.2 mg/kg (ALN0.2), or alendronate 1.0 mg/kg (ALN1.0). The lower ALN dose approximates, on a milligram per kilogram basis, that used for treatment of postmenopausal osteoporosis, with the higher dose being five times higher. Ribs were assessed for biomechanical properties, bone turnover rate, microdamage, density, and geometry. Toughness was significantly lower with ALN1.0 (−33%) but not ALN0.2 (−19%) compared to VEH, while neither ultimate stress nor modulus differed among the groups. Bone density, geometry, and structural biomechanical properties were similar among the three groups. There was no significant difference in overall microdamage accumulation among the groups. Intracortical bone formation rate was significantly lower than VEH in both ALN groups (−69% to −90%). These data show that while rib cortical bone experiences significant reductions in turnover following bisphosphonate treatment, it is only in animals treated with doses above those used to treat osteoporosis that toughness is significantly compromised

Time-resolved charge detection with cross-correlation techniques

We present time-resolved charge sensing measurements on a GaAs double quantum dot with two proximal quantum point contact (QPC) detectors. The QPC currents are analyzed with cross-correlation techniques, which enables us to measure dot charging and discharging rates for significantly smaller signal-to-noise ratios than required for charge detection with a single QPC. This allows to reduce the current level in the detector and therefore the invasiveness of the detection process and may help to increase the available measurement bandwidth in noise-limited setups.Comment: 6 pages, 4 figure

Non-invasive detection of charge-rearrangement in a quantum dot in high magnetic fields

We demonstrate electron redistribution caused by magnetic field on a single quantum dot measured by means of a quantum point contact as non-invasive detector. Our device which is fabricated by local anodic oxidation allows to control independently the quantum point contact and all tunnelling barriers of the quantum dot. Thus we are able to measure both the change of the quantum dot charge and also changes of the electron configuration at constant number of electrons on the quantum dot. We use these features to exploit the quantum dot in a high magnetic field where transport through the quantum dot displays the effects of Landau shells and spin blockade. We confirm the internal rearrangement of electrons as function of the magnetic field for a fixed number of electrons on the quantum dot.Comment: 4 pages, 5 figure

Phase coherent transport in (Ga,Mn)As

Quantum interference effects and resulting quantum corrections of the conductivity have been intensively studied in disordered conductors over the last decades. The knowledge of phase coherence lengths and underlying dephasing mechanisms are crucial to understand quantum corrections to the resistivity in the different material systems. Due to the internal magnetic field and the associated breaking of time-reversal symmetry quantum interference effects in ferromagnetic materials have been scarcely explored. Below we describe the investigation of phase coherent transport phenomena in the newly discovered ferromagnetic semiconductor (Ga,Mn)As. We explore universal conductance fluctuations in mesoscopic (Ga,Mn)As wires and rings, the Aharonov-Bohm effect in nanoscale rings and weak localization in arrays of wires, made of the ferromagnetic semiconductor material. The experiments allow to probe the phase coherence length L_phi and the spin flip length L_SO as well as the temperature dependence of dephasing.Comment: 22 pages, 10 figure

A Longitudinal Study of the Effect of Genistein on Bone in Two Different Murine Models of Diminished Estrogen-Producing Capacity

This experiment was designed to assess the capacity of dietary genistein (GEN), to attenuate bone loss in ovariectomized (OVX) and ovary-intact VCD-treated mice. Pretreatment of mice with 4-vinylcyclohexene diepoxide (VCD) gradually and selectively destroys ovarian follicles whilst leaving ovarian androgen-producing cells largely intact. VCD induces a perimenopause-like condition prior to the onset of reproductive acyclicity. Sixteen-week-old C57BL/6J mice were randomized to five treatment groups: sham(SHM), OVX, SHM + VCD, OVX + GEN, and SHM + VCD + GEN. In vivo, blood samples were drawn for hormone and isoflavone analyses, estrous cycles were monitored, and X-ray imaging was performed to assess changes in bone parameters. Following sacrifice, ovaries were assessed histologically, bone microarchitecture was evaluated via microcomputed tomography, and bone mechanical properties were measured. Some effects of GEN were observed in OVX mice, but GEN effects were not able to be evaluated in VCD-treated mice due to the subtle diminution of bone during the 4 months of this experiment

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients.

Published onlineClinical TrialJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tINTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. METHODS: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. CONCLUSION: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. TRIAL REGISTRATION: ClinicalTrials.gov NCT02058316. Registered 20 January 2014.PfizerOesterreichische Nationalbank (Anniversary Fund, project number 15346)

Increased strontium uptake in trabecular bone of ovariectomized calcium-deficient rats treated with strontium ranelate or strontium chloride

Based on clinical trials showing the efficacy to reduce vertebral and non-vertebral fractures, strontium ranelate (SrR) has been approved in several countries for the treatment of postmenopausal osteoporosis. Hence, it is of special clinical interest to elucidate how the Sr uptake is influenced by dietary Ca deficiency as well as by the formula of Sr administration, SrR versus strontium chloride (SrCl2). Three-month-old ovariectomized rats were treated for 90 days with doses of 25 mg kg-1 d-1 and 150 mg kg-1 d-1 of SrR or SrCl2 at low (0.1% Ca) or normal (1.19% Ca) Ca diet. Vertebral bone tissue was analysed by confocal synchrotron-radiation-induced micro X-ray fluorescence and by backscattered electron imaging. Principal component analysis and k-means clustering of the acquired elemental maps of Ca and Sr revealed that the newly formed bone exhibited the highest Sr fractions and that low Ca diet increased the Sr uptake by a factor of three to four. Furthermore, Sr uptake in bone of the SrCl2-treated animals was generally lower compared with SrR. The study clearly shows that inadequate nutritional calcium intake significantly increases uptake of Sr in serum as well as in trabecular bone matrix. This indicates that nutritional calcium intake as well as serum Ca levels are important regulators of any Sr treatment

Reset of inflammatory priming of joint tissue and reduction of the severity of arthritis flares by bromodomain inhibition

OBJECTIVE: We have recently shown that priming of synovial fibroblasts (SFs) drives arthritis flares. Pathogenic priming of SFs is essentially mediated by epigenetic reprogramming. Bromodomain and extra-terminal motif (BET) proteins translate epigenetic changes into transcription. Here we used a BET inhibitor to target inflammatory tissue priming and reduce flare severity in experimental arthritis. METHODS: BALB/c mice were treated intraperitoneally or locally into the paw with I-BET151, which blocks interaction of BET proteins with acetylated histones. Effect of I-BET151 on acute arthritis and/or inflammatory tissue priming was assessed in a model of repeated injections of monosodium urate crystals or zymosan into the paw. I-BET151 was given either from before arthritis induction, at peak inflammation, or after healing of the first arthritis bout. Transcriptomic (RNA-Seq), epigenomic (ATAC-Seq) and functional analysis (invasion, cytokine production, migration, senescence, metabolic flux) was performed on murine and human SFs treated with I-BET151 in vitro or in vivo. RESULTS: Systemic I-BET151 administration did not affect acute inflammation but abolished inflammatory tissue priming and diminished flare severity in both preventive and therapeutic treatment settings. I-BET151 was also effective when applied locally in the joint. BET inhibition also inhibited osteoclast differentiation, while macrophage activation in the joint was not affected. Flare reduction after BET inhibition was mediated, at least in part, by rolling back the primed transcriptional, metabolic and pathogenic phenotype of SFs. CONCLUSION: Inflammatory tissue priming is dependent on transcriptional regulation by BET proteins, which makes them promising therapeutic targets for preventing arthritis flares in previously affected joints

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

Introduction: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. Methods: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. Results: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. Conclusion: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. Trial registration: ClinicalTrials.gov NCT02058316. Registered 20 January 2014