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

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

Antibodies to Serine Proteases in the Antiphospholipid Syndrome

It is generally accepted that the major autoantigen for antiphospholipid antibodies (aPL) in the antiphospholipid syndrome (APS) is β2-glycoprotein I (β2GPI). However, a recent study has revealed that some aPL bind to certain conformational epitope(s) on β2GPI shared by the homologous enzymatic domains of several serine proteases involved in hemostasis and fibrinolysis. Importantly, some serine protease–reactive aPL correspondingly hinder anticoagulant regulation and resolution of clots. These results extend several early findings of aPL binding to other coagulation factors and provide a new perspective about some aPL in terms of binding specificities and related functional properties in promoting thrombosis. Moreover, a recent immunological and pathological study of a panel of human IgG monoclonal aPL showed that aPL with strong binding to thrombin promote in vivo venous thrombosis and leukocyte adherence, suggesting that aPL reactivity with thrombin may be a good predictor for pathogenic potentials of aPL

Inhibition of sphingosine 1-phosphate protects mice against chondrocyte catabolism and osteoarthritis

Summary Objective Cartilage loss observed in osteoarthritis (OA) is prevented when osteoclasts in the subchondral bone are inhibited in mice. Here, we investigated the role of the osteoclast secretome and of the lipid mediator sphingosine 1-phosphate (S1P) in chondrocyte metabolism and OA. Materials and methods We used SphK1LysMCre and wild type mice to assess the effect of murine osteoclast secretome in chondrocyte metabolism. Gene and protein expressions of matrix metalloproteinase (Mmp) were quantified in chondrocytes and explants by RT-qPCR and Western blots. SphK1LysMCre mice or wild type mice treated with S1P2 receptor inhibitor JTE013 or anti-S1P neutralizing antibody sphingomab are analyzed by OA score and immunohistochemistry. Results The osteoclast secretome increased the expression of Mmp3 and Mmp13 in murine chondrocytes and cartilage explants and activated the JNK signaling pathway, which led to matrix degradation. JTE013 reversed the osteoclast-mediated chondrocyte catabolism and protected mice against OA, suggesting that osteoclastic S1P contributes to cartilage damage in OA via S1P/S1P2 signaling. The activity of sphingosine kinase 1 (SphK1) increased with osteoclast differentiation, and its expression was enhanced in subchondral bone of mice with OA. The expression of Mmp3 and Mmp13 in chondrocytes was low upon stimulation with the secretome of Sphk1-lacking osteoclasts. Cartilage damage was significantly reduced in SphK1LysMCre mice, but not the synovial inflammation. Finally, intra-articular administration of sphingomab inhibited the cartilage damage and synovial inflammation. Conclusions Lack of S1P in myeloid cells and local S1P neutralization alleviates from osteoarthritis in mice. These data identify S1P as a therapeutic target in OA.The authors thank Alexandre Garcia for measurements of S1P. The work was supported by the Sybil SP7 European project and the “Fondation de l’Avenir”. JT and SV received grants from the Deutsche Forschungsgemeinschaft within the collaborative research center SFB1149.Peer reviewe

A single amino acid substitution in ORF1 dramatically decreases L1 retrotransposition and provides insight into nucleic acid chaperone activity

L1 is a ubiquitous interspersed repeated sequence in mammals that achieved its high copy number by autonomous retrotransposition. Individual L1 elements within a genome differ in sequence and retrotransposition activity. Retrotransposition requires two L1-encoded proteins, ORF1p and ORF2p. Chimeric elements were used to map a 15-fold difference in retrotransposition efficiency between two L1 variants from the mouse genome, TFC and TFspa, to a single amino acid substitution in ORF1p, D159H. The steady-state levels of L1 RNA and protein do not differ significantly between these two elements, yet new insertions are detected earlier and at higher frequency in TFC, indicating that it converts expressed L1 intermediates more effectively into new insertions. The two ORF1 proteins were purified and their nucleic acid binding and chaperone activities were examined in vitro. Although the RNA and DNA oligonucleotide binding affinities of these two ORF1 proteins were largely indistinguishable, D159 was significantly more effective as a nucleic acid chaperone than H159. These findings support a requirement for ORF1p nucleic acid chaperone activity at a late step during L1 retrotransposition, extend the region of ORF1p that is known to be critical for its functional interactions with nucleic acids, and enhance understanding of nucleic acid chaperone activity

Tribological performance of Graphene/Carbon nanotube hybrid reinforced Al2O3 composites

Tribological performance of the hot-pressed pure Al2O3 and its composites containing various hybrid contents of graphene nanoplatelets (GNPs) and carbon nanotubes (CNTs) were investigated under different loading conditions using the ball-on-disc method. Benchmarked against the pure Al2O3, the composite reinforced with a 0.5 wt% GNP exhibited a 23% reduction in the friction coefficient along with a promising 70% wear rate reduction, and a hybrid reinforcement consisting of 0.3 wt.% GNPs + 1 wt.% CNTs resulted in even better performance, with a 86% reduction in the wear rate. The extent of damage to the reinforcement phases caused during wear was studied using Raman spectroscopy. The wear mechanisms for the composites were analysed based on the mechanical properties, brittleness index and microstructural characterizations. The excellent coordination between GNPs and CNTs contributed to the excellent wear resistance property in the hybrid GNT-reinforced composites. GNPs played the important role in the formation of a tribofilm on the worn surface by exfoliation; whereas CNTs contributed to the improvement in fracture toughness and prevented the grains from being pulled out during the tribological test

Differential distribution of a SINE element in the Entamoeba histolytica and Entamoeba dispar genomes: Role of the LINE-encoded endonuclease

<p>Abstract</p> <p>Background</p> <p><it>Entamoeba histolytica </it>and <it>Entamoeba dispar </it>are closely related protistan parasites but while <it>E. histolytica </it>can be invasive, <it>E. dispar </it>is completely non pathogenic. Transposable elements constitute a significant portion of the genome in these species; there being three families of LINEs and SINEs. These elements can profoundly influence the expression of neighboring genes. Thus their genomic location can have important phenotypic consequences. A genome-wide comparison of the location of these elements in the <it>E. histolytica </it>and <it>E. dispar </it>genomes has not been carried out. It is also not known whether the retrotransposition machinery works similarly in both species. The present study was undertaken to address these issues.</p> <p>Results</p> <p>Here we extracted all genomic occurrences of full-length copies of EhSINE1 in the <it>E. histolytica </it>genome and matched them with the homologous regions in <it>E. dispar</it>, and vice versa, wherever it was possible to establish synteny. We found that only about 20% of syntenic sites were occupied by SINE1 in both species. We checked whether the different genomic location in the two species was due to differences in the activity of the LINE-encoded endonuclease which is required for nicking the target site. We found that the endonucleases of both species were essentially very similar, both in their kinetic properties and in their substrate sequence specificity. Hence the differential distribution of SINEs in these species is not likely to be influenced by the endonuclease. Further we found that the physical properties of the DNA sequences adjoining the insertion sites were similar in both species.</p> <p>Conclusions</p> <p>Our data shows that the basic retrotransposition machinery is conserved in these sibling species. SINEs may indeed have occupied all of the insertion sites in the genome of the common ancestor of <it>E. histolytica </it>and <it>E. dispar </it>but these may have been subsequently lost from some locations. Alternatively, SINE expansion took place after the divergence of the two species. The absence of SINE1 in 80% of syntenic loci could affect the phenotype of the two species, including their pathogenic properties, which needs to be explored.</p

The implementation and first insights of the French-speaking Swiss programme for monitoring self-harm.

Self-harm is a major risk factor for suicide but remains poorly documented. No data on self-harm in French-speaking Switzerland exist. To address this deficiency, the Swiss Federal Office of Public Health commissioned a specific self-harm monitoring programme. We present and discuss its implementation and first findings. Every patient aged 18&amp;ndash;65 years presenting for self-harm to the emergency departments of the Lausanne and Neuch&amp;acirc;tel general hospitals were included in the monitoring programme over a 10-month period (December 2016 to September 2017). Clinicians collected anonymous sociodemographic and clinical data. The sample included 490 patients (54.9% female and 45.1% male) for 554 episodes of self-harm, showing a higher proportion of patients aged 18&amp;ndash;34 (49.2%) than older age groups (35&amp;ndash;49, 33.7% and 50&amp;ndash;65, 17.1%). Patients were mostly single (56.1%) and in problematic socioeconomic situations (65.7%). Self-poisoning was the most commonly used method (58.2%) and was preferred by women (71% of females and 42.5% of males, Fisher&amp;rsquo;s exact test, p &amp;lt;0.001) and the majority of patients (53.3%) had experienced at least one previous episode of self-harm. The self-harm rate was 220 per 100,000 inhabitants in Lausanne and 140 in Neuch&amp;acirc;tel. Suicidal intent was clear for 50.6% of the overall sample, unclear for 25.1% and absent for 24.3%. It differed significantly between sites (&amp;chi;2(2) = 9.068, p = 0.011) as Lausanne reported more incidents of unclear intent (27.7% versus 17.4% in Neuch&amp;acirc;tel) and Neuch&amp;acirc;tel more incidents with absence of intent (33.1% versus 21.3% in Lausanne). In Lausanne, patients more frequently resorted to methods such as jumping from a height (11.4%) and hanging (9%) than in Neuch&amp;acirc;tel (1.6% and 4.9%, Fisher&amp;rsquo;s exact test, p = 0.006). Our results are globally consistent with previous research on self-harm. We found significant inter-site differences in methods, suicidal intent and self-harm rates. Our findings highlight the importance of implementing local self-harm monitoring to identify specific at-risk groups and develop targeted preventive intervention