FP601DECREASED OSTEOCALCIN LEVELS AND INCREASED MORTALITY IN HEMODIALYSIS PATIENTS WITH DIABETES MELLITUS

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Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function

Background: Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification. Methods: Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically. Results: Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries. Conclusions: These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients.This study was supported by a grant form Boehringer-Ingelheim Pharma, Germany (manufacturer of Dabigatran). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Selective Functional Movement Assessment (SFMA) Reliability and Proposal of Its Use in Sports

Introduction: The Selective Functional Movement Assessment (SFMA) is a functional movement assessment method to observe movement restrictions in individuals with known musculoskeletal disorders, although it has also been used to evaluate healthy athletes of different sports. Aim: The present paper aimed to evaluate the applicability of SFMA in a clinical setting and to verify whether a student can correctly perform it. Methods: An introductory and explanatory email was sent to the subjects, containing the instructions needed to produce a video with SFMA evaluation movements. SFMA methodology was then used to analyze the received videos. The results between interobserver and intraobserver agreement were compared to the literature, considered the gold standard methods. Results: Twenty-eight subjects (17.71 ± 1.96 years aged) were rated. The functional non-painful scenario (FN) has been assigned more frequently by all raters. The student's intra-rater reliability proved to be moderate (Kappa coefficient 0.49). Results for inter-rater reliability showed that the reliability degree between the senior physiotherapist and student before and after their educational path is good (Kappa coefficient 0.60 and 0.62, respectively). Conclusions: The results of this study showed SFMA intra-rater reliability to be moderate, while inter-rater reliability can be considered good. These characteristics make it a valuable tool for sport's needs, even when used by students

Viral-mediated oncolysis is the most critical factor in the late-phase of the tumor regression process upon vaccinia virus infection

<p>Abstract</p> <p>Background</p> <p>In principle, the elimination of malignancies by oncolytic virotherapy could proceed by different mechanisms - e.g. tumor cell specific oncolysis, destruction of the tumor vasculature or an anti-tumoral immunological response. In this study, we analyzed the contribution of these factors to elucidate the responsible mechanism for regression of human breast tumor xenografts upon colonization with an attenuated vaccinia virus (VACV).</p> <p>Methods</p> <p>Breast tumor xenografts were analyzed 6 weeks post VACV infection (p.i.; regression phase) by immunohistochemistry and mouse-specific expression arrays. Viral-mediated oncolysis was determined by tumor growth analysis combined with microscopic studies of intratumoral virus distribution. The tumor vasculature was morphologically characterized by diameter and density measurements and vessel functionality was analyzed by lectin perfusion and extravasation studies. Immunological aspects of viral-mediated tumor regression were studied in either immune-deficient mouse strains (T-, B-, NK-cell-deficient) or upon cyclophosphamide-induced immunosuppression (MHCII⁺-cell depletion) in nude mice.</p> <p>Results</p> <p>Late stage VACV-infected breast tumors showed extensive necrosis, which was highly specific to cancer cells. The tumor vasculature in infected tumor areas remained functional and the endothelial cells were not infected. However, viral colonization triggers hyperpermeability and dilatation of the tumor vessels, which resembled the activated endothelium in wounded tissue. Moreover, we demonstrated an increased expression of genes involved in leukocyte-endothelial cell interaction in VACV-infected tumors, which orchestrate perivascular inflammatory cell infiltration. The immunohistochemical analysis of infected tumors displayed intense infiltration of MHCII-positive cells and colocalization of tumor vessels with MHCII⁺/CD31⁺vascular leukocytes. However, GI-101A tumor growth analysis upon VACV-infection in either immunosuppressed nude mice (MHCII⁺-cell depleted) or in immune-deficient mouse strains (T-, B-, NK-cell-deficient) revealed that neither MHCII-positive immune cells nor T-, B-, or NK cells contributed significantly to VACV-mediated tumor regression. In contrast, tumors of immunosuppressed mice showed enhanced viral spreading and tumor necrosis.</p> <p>Conclusions</p> <p>Taken together, these results indicate that VACV-mediated oncolysis is the primary mechanism of tumor shrinkage in the late regression phase. Neither the destruction of the tumor vasculature nor the massive VACV-mediated intratumoral inflammation was a prerequisite for tumor regression. We propose that approaches to enhance viral replication and spread within the tumor microenvironment should improve therapeutical outcome.</p

The impact of the COVID-19 pandemic on functional capacity in a population of young athletes: should we expect long-time consequences?

Background: From 2020, most countries all over the world have implemented strategies aimed at limiting contagion of COVID-19. The pandemic caused a reduction in physical activity (PA) and sports at all levels. The aim of the present study was to analyze and quantify the related impact of imposed PA restrictions on functional capacity in young athletes. Methods: This observational cohort study evaluated annually the exercise capacity of a sample of young athletes (N.=344) referred for the pre-participation screening at our Sports and Exercise Medicine Division (2017-2021). Standardized maximal exercise testing was performed on treadmill and linear mixed models analyzed metabolic equivalent of tasks (METs) and exercise time as dependent variables. Results: METs and exercise time showed a reduction in the year 2020 and a subsequent increase in 2021, with males revealing a faster recovery in exercise capacity. Athletes who maintained >250 annual training hours were less affected by the pandemic. Conclusions: These data suggest a significant impact of forced physical inactivity on a cohort of apparently healthy young athletes. The COVID-19-related experience should lead to strategies to avoid negative effects and long-term consequences of containment measures

A Novel Quantitative Computer-Assisted Score Can Improve Repeatability in the Estimate of Vascular Calcifications at the Abdominal Aorta

In CKD and in the elderly, Vascular Calcifications (VC) are associated to cardiovascular events and bone fractures. VC scores at the abdominal aorta (AA) from lateral spine radiographs are widely applied (the 0&ndash;24 semiquantitative discrete visual score (SV) being the most used). We hypothesised that a novel continuum score based on quantitative computer-assisted tracking of calcifications (QC score) can improve the precision of the SV score. This study tested the repeatability and reproducibility of QC score and SV score. In forty-four patients with VC from an earlier study, five experts from four specialties evaluated the data twice using a dedicated software. Test&ndash;retest was performed on eight subjects. QC results were reported in a 0&ndash;24 scale to readily compare with SV. The QC score showed higher intra-operator repeatability: the 95% CI of Bland&ndash;Altman differences was almost halved in QC; intra-operator R2 improved from 0.67 for SV to 0.79 for QC. Inter-observer repeatability was higher for QC score in the first (Intraclass Correlation Coefficient 0.78 vs. 0.64), but not in the second evaluation (0.84 vs. 0.82), indicating a possible heavier learning artefact for SV. The Minimum Detectable Difference (MDD) was smaller for QC (2.98 vs. 4 for SV, in the 0&ndash;24 range). Both scores were insensitive to test&ndash;retest procedure. Notably, QC and SV scores were discordant: SV showed generally higher values, and an increasing trend of differences with VC severity. In summary, the new QC score improved the precision of lateral spine radiograph scores in estimating VC. We reported for the first time an estimate of MDD in VC assessment that was 25% lower for the new QC score with respect to the usual SV score. An ongoing study will determine whether this lower MDD may reduce follow-up times to check for VC progression

Histomorphometric parameters in femur and vertebra (S2 Dataset and S3 Dataset).

<p>*<b>p< 0.05 vs control and dabigatran groups;</b></p><p>** <b>p<0.001 vs control and dabigatran groups.</b></p><p>Histomorphometric parameters in femur and vertebra (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133847#pone.0133847.s002" target="_blank">S2 Dataset</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0133847#pone.0133847.s003" target="_blank">S3 Dataset</a>).</p

Significant histomorphometric results of cellular parameters in femur (upper panel) and vertebra (lower panel) analysis of rats.

<p>The main alteration of cellular parameters in warfarin treated rats was the increased osteoclast activity (ES/BS), although in femur a decreased osteoblast activity (OS/BS) was also detected. ES/BS: Erosion Surface / Bone Surface; OS/BS: Osteoid Surface / Bone Surface. *p< 0.01 vs control; #p<0.001 vs dabigatran; ##p< 0.005 vs dabigatran.</p