Razor-thin dust layers in protoplanetary disks:Limits on the vertical shear instability

Context. Recent observations with the Atacama Large Millimeter Array (ALMA) have shown that the large dust aggregates observed at millimeter wavelengths settle to the midplane into a remarkably thin layer. This sets strong limits on the strength of the turbulence and other gas motions in these disks. Aims. We intend to find out if the geometric thinness of these layers is evidence against the vertical shear instability (VSI) operating in these disks. We aim to verify if a dust layer consisting of large enough dust aggregates could remain geometrically thin enough to be consistent with the latest observations of these dust layers, even if the disk is unstable to the VSI. If this is falsified, then the observed flatness of these dust layers proves that these disks are stable against the VSI, even out to the large radii at which these dust layers are observed. Methods. We performed hydrodynamic simulations of a protoplanetary disk with a locally isothermal equation of state, and let the VSI fully develop. We sprinkled dust particles with a given grain size at random positions near the midplane and followed their motion as they got stirred up by the VSI, assuming no feedback onto the gas. We repeated the experiment for different grain sizes and determined for which grain size the layer becomes thin enough to be consistent with ALMA observations. We then verified if, with these grain sizes, it is still possible (given the constraints of dust opacity and gravitational stability) to generate a moderately optically thick layer at millimeter wavelengths, as observations appear to indicate. Results. We found that even very large dust aggregates with Stokes numbers close to unity get stirred up to relatively large heights above the midplane by the VSI, which is in conflict with the observed geometric thinness. For grains so large that the Stokes number exceeds unity, the layer can be made to remain thin, but we show that it is hard to make dust layers optically thick at ALMA wavelengths (e.g., τ1.3mm ≳ 1) with such large dust aggregates. Conclusions. We conclude that protoplanetary disks with geometrically thin midplane dust layers cannot be VSI unstable, at least not down to the disk midplane. Explanations for the inhibition of the VSI out to several hundreds of au include a high dust-to-gas ratio of the midplane layer, a modest background turbulence, and/or a reduced dust-to-gas ratio of the small dust grains that are responsible for the radiative cooling of the disk. A reduction of small grains by a factor of between 10 and 100 is sufficient to quench the VSI. Such a reduction is plausible in dust growth models, and still consistent with observations at optical and infrared wavelengths

Strontium ranelate decreases the incidence of new caudal vertebral fractures in a growing mouse model with spontaneous fractures by improving bone microarchitecture

Summary Young mice over-expressing Runx2 fail to gain bone relative to wild type mice with growth and present spontaneous fractures. It allows, for the first time in rodents, direct assessment of anti-fracture efficacy of strontium ranelate which was able to decrease caudal vertebrae fracture incidence through an improvement of trabecular and cortical architecture. Introduction The aim was to investigate whether strontium ranelate was able to decrease fracture incidence in mice over-expressing Runx2, model of severe developmental osteopenia associated with spontaneous vertebral fractures. Methods Transgenic mice and their wild type littermates were treated by oral route with strontium ranelate or vehicle for 9 weeks. Caudal fracture incidence was assessed by repeated X-rays, resistance to compressive loading by biochemical tests, and bone microarchitecture by histomorphometry. Results Transgenic mice receiving strontium ranelate had significantly fewer new fractures occurring during the 9 weeks of the study (−60%, p < 0.05). In lumbar vertebrae, strontium ranelate improves resistance to compressive loading (higher ultimate force to failure, +120%, p < 0.05) and trabecular microarchitecture (higher bone volume and trabecular number, lower trabecular separation, +60%, +50%, −39%, p < 0.05) as well as cortical thickness (+17%, p < 0.05). In tibiae, marrow cavity cross-section area and equivalent diameter were lower (−39%, −21%, p < 0.05). The strontium level in plasma and bone was in the same range as the values measured in treated postmenopausal women. Conclusions This model allows, for the first time, direct assessment of anti-fracture efficacy of strontium ranelate treatment in rodents. In these transgenic mice, strontium ranelate was able to decrease caudal vertebral fracture incidence through an improvement of trabecular and cortical architecture

Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.

BackgroundProdrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.MethodsHere we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.ResultsIn both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.ConclusionThese results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity

Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis

In men, vertebral fractures are poorly associated with bone density, and both cortical and trabecular micro-architectural changes could contribute to bone fragility. Bone histomorphometry makes it possible to investigate both the thickness and porosity of cortical bone, which has been reported to have a major impact on the biomechanical properties of bone. We therefore conducted a cross sectional study using iliac crest biopsies to investigate the trabecular and cortical bone structure in men with or without vertebral fractures.We selected 93 bone biopsies from men with idiopathic osteoporosis (defined as a T-score <− 2.5), between 40 and 70 years of age. Patients were divided into two groups on the basis of the presence (n = 46) or absence (n = 47) of prevalent vertebral fracture (VFX). We measured micro-architectural indices in trabecular and cortical bone by histomorphometry at the iliac crest. Patients with VFX had lower trabecular bone volume (BV/TV: 12.4 ± 3.8 versus 14.7 ± 3.1 % (m ± SD)), p < 0.01), higher trabecular separation (Tb.Sp: 871 ± 279 versus 719 ± 151 μm, p < 0.01), and higher marrow star volume (V*m.space: 1.617 ± 1.257 versus 0.945 ± 0.466 mm3, p < 0.01). Cortical thickness (Ct.Th) was the same in patients with or without VFX, whereas cortical porosity (Ct.Po) was higher in patients with VFX (6.5 ± 2.6 versus 5.0 ± 2.0 %, p < 0.01), because their Haversian canals had higher mean areas (8291 ± 4135 versus 5438 ± 2809 μm2, p < 0.001). There was no correlation between any trabecular and cortical micro-architectural parameters. Using a logistic regression model, we evaluated the VFX as a function of the V⁎m.space and Ct.Po, adjusted for age. The odds-ratio of having a VFX was 3.89 (95% CI 1.19–12.7, p = 0.02) for the third tertile of V*m.space (adjusted on age and Ct.Po), and 4.07 (95% CI 1.25–13.3, p = 0.02) for the third tertile of Ct.Po (adjusted on age and V*m.space). Our data show that both trabecular and cortical bone microarchitecture contribute independently to vertebral fractures in men with idiopathic osteoporosis. In contrast to data reported in women, in men it is cortical porosity, and not cortical width, that is associated with vertebral fractures. This suggests that the cortical deficit is different in men and in women with fragility fractures

Effects of Risedronate in Runx2 Overexpressing Mice, an Animal Model for Evaluation of Treatment Effects on Bone Quality and Fractures

Young mice overexpressing Runx2 specifically in cells of the osteoblastic lineage failed to gain bone mass and exhibited a dramatic increase in bone resorption, leading to severe osteopenia and spontaneous vertebral fractures. The objective of the current study was to determine whether treatment with a bisphosphonate (risedronate, Ris), which reduces fractures in postmenopausal as well as in juvenile osteoporosis, was able to improve bone quality and reduce vertebral fractures in mice overexpressing Runx2. Four-week-old female Runx2 mice received Ris at 2 and 10 μg/kg subcutaneously twice a week for 12 weeks. Runx2 and wild-type mice received vehicle (Veh) as control. We measured the number of new fractures by X-ray and bone mineral density (BMD) by DEXA. We evaluated bone quality by histomorphometry, micro-CT, and Fourier transform infrared imaging (FTIRI). Ris at 20 μg/kg weekly significantly reduced the average number of new vertebral fractures compared to controls. This was accompanied by significantly increased BMD, increased trabecular bone volume, and reduced bone remodeling (seen in indices of bone resorption and formation) in the vertebrae and femoral metaphysis compared to Runx2 Veh. At the femur, Ris also increased cortical thickness. Changes in collagen cross-linking seen on FTIRI confirmed that Runx2 mice have accelerated bone turnover and showed that Ris affects the collagen cross-link ratio at both forming and resorbing sites. In conclusion, young mice overexpressing Runx2 have high bone turnover-induced osteopenia and spontaneous fractures. Ris at 20 μg/kg weekly induced an increase in bone mass, changes in bone microarchitecture, and decreased vertebral fractures

When to discharge and when to voluntary or compulsory hospitalize? Factors associated with treatment decision after self-harm.

Clinicians assessing suicidal patients in emergency departments (EDs) must decide whether to admit the person to a psychiatric ward with voluntary or compulsory hospitalization or to discharge him/her as an outpatient. This cross-sectional study aimed to identify independent predictors of this decision among a large sample of self-harm (SH) patients. It used data from all patients admitted to four Swiss EDs between 2016 and 2019. Socio-demographic, clinical, and suicidal process-related characteristics data were evaluated against the decision for voluntary or compulsory hospitalization using t-tests, Chi-Square tests and logistic multiple regression. 2142 episodes from 1832 unique patients were evaluated. Independent predictors of decision to hospitalize included: male gender, advanced age, hospital location, depression and personality disorders, substance use, a difficult socio-economic condition, a clear intent to die, and a serious suicide attempt. Significant variables that emerged as independent predictors of compulsory hospitalization were hospital location, not having anxiety and personality disorders, being retired, having a clear intent to die, and making a serious suicide attempt. Hospital EDs had different rates of compulsory psychiatric admission. However, the decision to admit a patient for hospitalization, either voluntary or compulsory, was mainly based on clinical factors

Longitudinal Bone Loss Occurs at the Radius in CKD.

Chronic kidney disease (CKD) exposes to an increased incidence of fragility fractures. International guidelines recommend performing bone mineral density (BMD) if the results will impact treatment decisions. It remains unknown where bone loss occurs and what would preclude the longitudinal loss in patients with CKD. Here, we aimed to investigate factors influencing BMD and to analyze the longitudinal BMD changes. In the NephroTest cohort, we measured BMD at the femoral neck, total hip, lumbar spine, and proximal radius, together with circulating biomarkers and standardized measured glomerular filtration rate (mGFR) by <sup>51</sup> Cr-EDTA in a subset of patients with CKD stage 1 to 5 followed during 4.3 ± 2.0 years. A linear mixed model explored the longitudinal bone loss and the relationship of associated factors with BMD changes. A total of 858 patients (mean age 58.9 ± 15.2 years) had at least 1 and 477 had at least 2 BMD measures. At baseline, cross-sectional analysis showed a significantly lower BMD at femoral neck and total hip and a significant higher serum parathyroid hormone (PTH) along with CKD stages. Baseline age, gender, tobacco, low body mass index (BMI), and high PTH levels were significantly associated with low BMD. Longitudinal analysis during the mean 4.3 years revealed a significant bone loss at the radius only. BMD changes at the femoral neck were associated with BMI, but not CKD stages or basal PTH levels. CKD is associated with low BMD and high PTH in the cross-sectional analysis. Longitudinal bone loss occurred at the proximal radius after 4.3 years

Acute Consumption of Flavan-3-ol-Enriched Dark Chocolate Affects Human Endogenous Metabolism

Flavan-3-ols and methylxanthines have potential beneficial effects on human health including reducing cardiovascular risk. We performed a randomized controlled crossover intervention trial to assess the acute effects of consumption of flavan-3-ol-enriched dark chocolate, compared with standard dark chocolate and white chocolate, on the human metabolome. We assessed the metabolome in urine and blood plasma samples collected before and at 2 and 6 h after consumption of chocolates in 42 healthy volunteers using a nontargeted metabolomics approach. Plasma samples were assessed and showed differentiation between time points with no further separation among the three chocolate treatments. Multivariate statistics applied to urine samples could readily separate the postprandial time points and distinguish between the treatments. Most of the markers responsible for the multivariate discrimination between the chocolates were of dietary origin. Interestingly, small but significant level changes were also observed for a subset of endogenous metabolites. H-1 NMR revealed that flavan-3-ol-enriched dark chocolate and standard dark chocolate reduced urinary levels of creatinine, lactate, some amino acids, and related degradation products and increased the levels of pyruvate and 4-hydroxyphenylacetate, a phenolic compound of bacterial origin. This study demonstrates that an acute chocolate intervention can significantly affect human metabolism

Differential effect of polyphenol-rich dark chocolate on glucoregulatory and cardiovascular risk factors on healthy overweight and obese subjects: a randomized clinical trial

The association between excess cortisol and various parameters of metabolic syndrome including hypertension, insulin resistance and dyslipidaemia is increasingly recognised. The present single-blind randomised placebo-controlled cross-over study compared the effect of polyphenol-rich dark chocolate (DC) on biomarkers of glucose metabolism, lipid profile, and blood pressure (BP) in females with BMI 25 kg m-2 (n = 21) and females with BMI < 25 kg m-2 (n = 21). Volunteers consumed 20 g of DC containing 500 mg polyphenols or a placebo DC with negligible polyphenol-content daily for 4 weeks, separated by a 2-week washout period. Systolic BP and diastolic BP decreased after 4 weeks of polyphenol-rich DC. Placebo raised fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and salivary cortisol, an effect that was significantly different from polyphenol-rich DC which had a negligible effect on fasting insulin, HOMA-IR and salivary cortisol. Females with BMI 25 kg m-2 responded less favourably to placebo than lean females and consequently had higher fasting insulin and HOMA-IR, in addition to a lower quantitative sensitivity check index (QUICKI) after ingestion of placebo compared to polyphenol-rich DC. No significant changes in lipid profile were observed. This study provides evidence for the metabolic benefits of consuming polyphenol-rich dark chocolate while demonstrating the possibility of adverse effects occurring with polyphenol-poor chocolate placebo.Paper adds to the growing body of evidence that children can acquire phonological systems before they are able to master the phonetic skills needed to convey the contrasts in that systemsch_die3pub2420pub1