Mechanical Competence and Bone Quality Develop During Skeletal Growth.

Bone fracture risk is influenced by bone quality, which encompasses bone's composition as well as its multiscale organization and architecture. Aging and disease deteriorate bone quality, leading to reduced mechanical properties and higher fracture incidence. Largely unexplored is how bone quality and mechanical competence progress during longitudinal bone growth. Human femoral cortical bone was acquired from fetal (n = 1), infantile (n = 3), and 2- to 14-year-old cases (n = 4) at the mid-diaphysis. Bone quality was assessed in terms of bone structure, osteocyte characteristics, mineralization, and collagen orientation. The mechanical properties were investigated by measuring tensile deformation at multiple length scales via synchrotron X-ray diffraction. We find dramatic differences in mechanical resistance with age. Specifically, cortical bone in 2- to 14-year-old cases exhibits a 160% greater stiffness and 83% higher strength than fetal/infantile cases. The higher mechanical resistance of the 2- to 14-year-old cases is associated with advantageous bone quality, specifically higher bone volume fraction, better micronscale organization (woven versus lamellar), and higher mean mineralization compared with fetal/infantile cases. Our study reveals that bone quality is superior after remodeling/modeling processes convert the primary woven bone structure to lamellar bone. In this cohort of female children, the microstructural differences at the femoral diaphysis were apparent between the 1- to 2-year-old cases. Indeed, the lamellar bone in 2- to 14-year-old cases had a superior structural organization (collagen and osteocyte characteristics) and composition for resisting deformation and fracture than fetal/infantile bone. Mechanistically, the changes in bone quality during longitudinal bone growth lead to higher fracture resistance because collagen fibrils are better aligned to resist tensile forces, while elevated mean mineralization reinforces the collagen scaffold. Thus, our results reveal inherent weaknesses of the fetal/infantile skeleton signifying its inferior bone quality. These results have implications for pediatric fracture risk, as bone produced at ossification centers during children's longitudinal bone growth could display similarly weak points. © 2019 American Society for Bone and Mineral Research

Synthesis and Complexation Study of New Aminoalkynyl−amidinate Ligands

Abstract The current library of amidinate ligands has been extended by the synthesis of two novel dimethylamino‐substituted alkynylamidinate anions of the composition [Me 2 N−CH 2 −C≡C−C(NR) 2 ] − (R = i Pr, cyclohexyl (Cy)). The unsolvated lithium derivatives Li[Me 2 N−CH 2 −C≡C−C(NR) 2 ] ( 1 : R = i Pr, 2 : R = Cy) were obtained in good yields by treatment of in situ‐ prepared Me 2 N−CH 2 −C≡C−Li with the respective carbodiimides, R−N=C=N−R. Recrystallization of 1 and 2 from THF afforded the crystalline THF adducts Li[Me 2 N−CH 2 −C≡C−C(NR) 2 ] ⋅  n THF ( 1 a : R = i Pr, n =1; 2 a : R = Cy, n =1.5). Precursor 2 was subsequently used to study initial complexation reactions with selected di‐ and trivalent transition metals. The dark red homoleptic vanadium(III) tris(alkynylamidinate) complex V[Me 2 N−CH 2 −C≡C−C(NCy) 2 ] 3 ( 3 ) was prepared by reaction of VCl 3 (THF) 3 with 3 equiv. of 2 (75 % yield). A salt‐metathesis reaction of 2 with anhydrous FeCl 2 in a molar ratio of 2 : 1 afforded the dinuclear homoleptic iron(II) alkynylamidinate complex Fe 2 [Me 2 N−CH 2 −C≡C−C(NCy) 2 ] 4 ( 4 ) in 69 % isolated yield. Similarly, treatment of Mo 2 (OAc) 4 with 3 or 4 equiv. of 2 provided the dinuclear, heteroleptic molybdenum(II) amidinate complex Mo 2 (OAc)[Me 2 N−CH 2 −C≡C−C(NCy) 2 ] 3 ( 5 ; yellow crystals, 50 % isolated yield). The cyclohexyl‐substituted title compounds 2 a , 4 , and 5 were structurally characterized through single‐crystal X‐ray diffraction studies.imag

Gauging the strength of the molecular halogen bond via experimental electron density and spectroscopy

Strong and weak halogen bonds (XBs) in discrete aggregates involving the same acceptor are addressed by experiments in solution and in the solid state. Unsubstituted and perfluorinated iodobenzenes act as halogen donors of tunable strength; in all cases, quinuclidine represents the acceptor. NMR titrations reliably identify the strong intermolecular interactions in solution, with experimental binding energies of approx. 7 kJ/mol. Interaction of the σ hole at the halogen donor iodine leads to a redshift in the symmetric C–I stretching vibration; this shift reflects the interaction energy in the halogen-bonded adducts and may be assessed by Raman spectroscopy in condensed phase even for weak XBs. An experimental picture of the electronic density for the XBs is achieved by high-resolution X-ray diffraction on suitable crystals. Quantum theory of atoms in molecules (QTAIM) analysis affords the electron densities and energy densities in the bond critical points of the halogen bonds and confirms stronger interaction for the shorter contacts. For the first time, the experimental electron density shows a significant effect on the atomic volumes and Bader charges of the quinuclidine N atoms, the halogen-bond acceptor: strong and weak XBs are reflected in the nature of their acceptor atom. Our experimental findings at the acceptor atom match the discussed effects of halogen bonding and thus the proposed concepts in XB activated organocatalysis

Corticothalamic feedback sculpts visual spatial integration in mouse thalamus

En route from retina to cortex, visual information travels through the dorsolateral geniculate nucleus of the thalamus (dLGN), where extensive cortico-thalamic (CT) feedback has been suggested to modulate spatial processing. How this modulation arises from direct excitatory and indirect inhibitory CT feedback components remains enigmatic. We show that in awake mice topographically organized cortical feedback modulates spatial integration in dLGN by sharpening receptive fields (RFs) and increasing surround suppression. Guided by a network model revealing wide-scale inhibitory CT feedback necessary to reproduce these effects, we targeted the visual sector of the thalamic reticular nucleus (visTRN) for recordings. We found that visTRN neurons have large receptive fields, show little surround suppression, and have strong feedback-dependent responses to large stimuli, making them an ideal candidate for mediating feedback-enhanced surround suppression in dLGN. We conclude that cortical feedback sculpts spatial integration in dLGN, likely via recruitment of neurons in visTRN

Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 +/- 11.2 kg/m(2)) and 15 non-obese (23.9 +/- 2.1 kg/m(2)) patients were analyzed. AUC(0-8) in ISF decreased by -1.69 mg*h/L (95% CI: -2.59 to -0.79, p = 1 mg/L in ISF and >= 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC >= 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients

CO Observations of the Interacting Galaxy Pair NGC 5394/95

BIMA CO 1-0 observations are presented of the spiral galaxies NGC 5394 and NGC 5395 that have undergone a recent, grazing encounter. In NGC 5394, 80% of the CO emission detected by BIMA is concentrated in the central 800 pc (FWHM) starburst region.In an encounter simulation that reproduces some of the main features of this galaxy pair, a considerable amount of gas in NGC 5394 falls into the central region early in the collision. The observed total gas distribution in the disk of NGC 5394 is lopsided, with more HI, CO, and H-alpha emission coming from the western or southwestern side. The innermost western arm of NGC 5394 is seen in CO and H-alpha emission, but the eastern inner-disk arm, which is very bright in the optical continuum, is not detected in CO or H-alpha emission. From a comparison of the radio continuum, H-alpha, 60 micron, and CO luminosities, we estimate that the average visual extinction of the starburst is 3 - 4 mag and the conversion factor N(H2)/I(CO) in the starburst is a factor of 3 - 4 below the standard value. Comparison of NGC 5394 with two other systems previously studied suggests that in prograde grazing encounters a central starburst may not develop until near the end of the ocular phase. Very little of the CO emission from NGC 5395 found in previous single-dish observations is detected by BIMA.Comment: AAS-Latex, v5.0, 45 pages including embedded .ps figures. AJ, in pres

Reproducibility and reuse of adaptive immune receptor repertoire data

High-throughput sequencing (HTS) of immunoglobulin (B-cell receptor, antibody) and T-cell receptor repertoires has increased dramatically since the technique was introduced in 2009 (1-3). This experimental approach explores the maturation of the adaptive immune system and its response to antigens, pathogens, and disease conditions in exquisite detail. It holds significant promise for diagnostic and therapy-guiding applications. New technology often spreads rapidly, sometimes more rapidly than the understanding of how to make the products of that technology reliable, reproducible, or usable by others. As complex technologies have developed, scientific communities have come together to adopt common standards, protocols, and policies for generating and sharing data sets, such as the MIAME protocols developed for microarray experiments. The Adaptive Immune Receptor Repertoire (AIRR) Community formed in 2015 to address similar issues for HTS data of immune repertoires. The purpose of this perspective is to provide an overview of the AIRR Community\u27s founding principles and present the progress that the AIRR Community has made in developing standards of practice and data sharing protocols. Finally, and most important, we invite all interested parties to join this effort to facilitate sharing and use of these powerful data sets ([email protected])

Negative Regulation of Bone Formation by the Transmembrane Wnt Antagonist Kremen-2

Wnt signalling is a key pathway controlling bone formation in mice and humans. One of the regulators of this pathway is Dkk1, which antagonizes Wnt signalling through the formation of a ternary complex with the transmembrane receptors Krm1/2 and Lrp5/6, thereby blocking the induction of Wnt signalling by the latter ones. Here we show that Kremen-2 (Krm2) is predominantly expressed in bone, and that its osteoblast-specific over-expression in transgenic mice (Col1a1-Krm2) results in severe osteoporosis. Histomorphometric analysis revealed that osteoblast maturation and bone formation are disturbed in Col1a1-Krm2 mice, whereas bone resorption is increased. In line with these findings, primary osteoblasts derived from Col1a1-Krm2 mice display a cell-autonomous differentiation defect, impaired canonical Wnt signalling and decreased production of the osteoclast inhibitory factor Opg. To determine whether the observed effects of Krm2 on bone remodeling are physiologically relevant, we analyzed the skeletal phenotype of 24 weeks old Krm2-deficient mice and observed high bone mass caused by a more than three-fold increase in bone formation. Taken together, these data identify Krm2 as a regulator of bone remodeling and raise the possibility that antagonizing KRM2 might prove beneficial in patients with bone loss disorders

Meropenem Plasma and Interstitial Soft Tissue Concentrations in Obese and Nonobese Patients—A Controlled Clinical Trial

Background: This controlled clinical study aimed to investigate the impact of obesity on plasma and tissue pharmacokinetics of meropenem. Methods: Obese (body mass index (BMI) >= 35 kg/m(2)) and age-/sex-matched nonobese (18.5 kg/m(2) >= BMI MIC) in the plasma and ISF did not differ significantly for MICs of 0.25-8 mg/L. Conclusions: In morbidly obese patients, meropenem has lower maximum concentrations and higher volumes of distribution. However, due to the slightly longer half-life, obesity has no influence on the T > MIC, so dose adjustments for obesity seem unnecessary

How does mental health care perform in respect to service users' expectations? Evaluating inpatient and outpatient care in Germany with the WHO responsiveness concept

<p>Abstract</p> <p>Background</p> <p>Health systems increasingly try to make their services more responsive to users' expectations. In the context of the World Health Report 2000, WHO developed the concept of health system <it>responsiveness </it>as a performance parameter. <it>Responsiveness </it>relates to the system's ability to respond to service users' legitimate expectations of non-medical aspects. We used this concept in an effort to evaluate the performance of mental health care in a catchment area in Germany.</p> <p>Methods</p> <p>In accordance with the method WHO used for its <it>responsiveness </it>survey, <it>responsiveness </it>for inpatient and outpatient mental health care was evaluated by a standardised questionnaire. <it>Responsiveness </it>was assessed in the following domains: <it>attention, dignity</it>, <it>clear communication</it>, <it>autonomy, confidentiality, basic amenities, choice </it>of health care provider, <it>continuity</it>, and <it>access to social support</it>. Users with complex mental health care needs (i.e., requiring social and medical services or inpatient care) were recruited consecutively within the mental health services provided in the catchment area of the Hanover Medical School.</p> <p>Results</p> <p>221 persons were recruited in outpatient care and 91 in inpatient care. Inpatient service users reported poor <it>responsiveness </it>(22%) more often than outpatients did (15%); however this was significant only for the domains <it>dignity </it>and <it>communication</it>. The best performing domains were <it>confidentiality </it>and <it>dignity</it>; the worst performing were <it>choice</it>, <it>autonomy </it>and <it>basic amenities </it>(only inpatient care). <it>Autonomy </it>was rated as the most important domain, followed by <it>attention </it>and <it>communication</it>. <it>Responsiveness </it>within outpatient care was rated worse by people who had less money and were less well educated. Inpatient <it>responsiveness </it>was rated better by those with a higher level of education and also by those who were not so well educated. 23% of participants reported having been discriminated against in mental health care during the past 6 months.</p> <p>The results are similar to prior <it>responsiveness </it>surveys with regard to the overall better performance of outpatient care. Where results differ, this can best be explained by certain characteristics that are applicable to mental health care and also by the users with complex needs. The expectations of <it>attention </it>and <it>autonomy</it>, including participation in the treatment process, are not met satisfactorily in inpatient and outpatient care.</p> <p>Conclusion</p> <p><it>Responsiveness </it>as a health system performance parameter provides a refined picture of inpatient and outpatient mental health care. Reforms to the services provided should be orientated around domains that are high in importance, but low in performance. Measuring <it>responsiveness </it>could provide well-grounded guidance for further development of mental health care systems towards becoming better patient-orientated and providing patients with more respect.</p