Outflow Graft Obstruction due to Local Aortic Dissection After Implantation of Left Ventricle Assist Device (HeartMate 3).

Left ventricular assist devices (LVADs) improve symptoms and outcomes in patients with advanced heart failure. We report the case of a patient with a freshly implanted HeartMate 3 LVAD, suffering abruptly on postoperative day 55 from pejoration of his heart failure with multiple episodes of low-flow alarm. Outflow graft obstruction (OGO) due to local aortic dissection was diagnosed with multimodality imaging. After a multidisciplinary discussion, a surgical approach was decided, and the patient benefited from a revision of his outflow graft.

Effects of Extracellular Vesicles from Osteogenic Differentiated Human BMSCs on Osteogenic and Adipogenic Differentiation Capacity of Naïve Human BMSCs.

Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland.

[Extended medical preparticipation screening as a useful option for injury prevention in professional sports]. / Erweiterte medizinische Eingangsuntersuchungen als sinnvolle Instrumentarien zur Verletzungsprävention im Hochleistungssport am Beispiel eines Basketball-Bundesligisten.

BACKGROUND: Preparticipation screening is important in order to make a statement about an athlete's health. The evaluation includes both an internal medicine/cardiology and an orthopaedic section. In professional team sports, players have to undergo medical screening on an annual basis to obtain their license and be cleared for play. Screening delivers information about the acute health condition of the athlete but only gives an indirect statement on his/her functional status and performance. This gap has been tried to be closed with functional, sports-specific performance testing in the past few years. In the event of future injury, the collected data can be used as a baseline level to monitor the progress in an athlete's rehabilitation process. This provides a huge advantage in the return-to-play diagnosis. MATERIAL & METHODS: Based on the assumption that only a healthy player can perform to the best of his or her ability, we have extended our medical screening for a professional basketball team. Since the 2012/2013 season, a test battery was added with a view to basketball-specific conditioning. The collected data was prospectively correlated to injury occurrence. RESULTS: Seventy-one players were tested in 5 different categories. We have documented 142 injuries which lead to a downtime of 23 days (range 1-347 days). The injuries mainly involved the lower extremity, in particular the ankle, the knee and the thigh muscles. There was a clear trend indicating that players performing weaker in the agility tests sustained more injuries (r = 0.34, p = 0.029). Athletes who performed worse in the Yo-Yo test suffered from significantly more thigh muscle injuries (r = 0.266, p = 0.012). CONCLUSION: Pre-participation screening is a useful tool in injury prevention, which helps to detect injuries or chronic stress complaints, especially in, but not limited to professional sports. Adding sports-specific performance testing may reveal potential deficits in agility and endurance which could lead to an increased injury risk. In addition, it allows to obtain baseline data which could be used to show the progress in rehabilitation in the event of an injury.

Curcumin-primed human BMSC-derived extracellular vesicles reverse IL-1ß-induced catabolic responses of OA chondrocytes by upregulating miR-126-3p.

BACKGROUND: Curcumin has anti-inflammatory effects and qualifies as a potential candidate for the treatment of osteoarthritis (OA). However, curcumin has limited bioavailability. Extracellular vesicles (EVs) are released by multiple cell types and act as molecule carrier during intercellular communication. We assume that EVs can maintain bioavailability and stability of curcumin after encapsulation. Here, we evaluated modulatory effects of curcumin-primed human (h)BMSC-derived EVs (Cur-EVs) on IL-1ß stimulated human osteoarthritic chondrocytes (OA-CH). METHODS: CellTiter-Blue Viability- (CTB), Caspase 3/7-, and live/dead assays were used to determine range of cytotoxic curcumin concentrations for hBMSC and OA-CH. Cur-EVs and control EVs were harvested from cell culture supernatants of hBMSC by ultracentrifugation. Western blotting (WB), transmission electron microscopy, and nanoparticle tracking analysis were performed to characterize the EVs. The intracellular incorporation of EVs derived from PHK26 labeled and curcumin-primed or control hBMSC was tested by adding the labeled EVs to OA-CH cultures. OA-CH were pre-stimulated with IL-1ß, followed by Cur-EV and control EV treatment for 24 h and subsequent analysis of viability, apoptosis, and migration (scratch assay). Relative expression of selected anabolic and catabolic genes was assessed with qRT-PCR. Furthermore, WB was performed to evaluate phosphorylation of Erk1/2, PI3K/Akt, and p38MAPK in OA-CH. The effect of hsa-miR-126-3p expression on IL-1ß-induced OA-CH was determined using CTB-, Caspase 3/7-, live/dead assays, and WB. RESULTS: Cur-EVs promoted viability and reduced apoptosis of IL-1ß-stimulated OA-CH and attenuated IL-1ß-induced inhibition of migration. Furthermore, Cur-EVs increased gene expression of BCL2, ACAN, SOX9, and COL2A1 and decreased gene expression of IL1B, IL6, MMP13, and COL10A1 in IL-1ß-stimulated OA-CH. In addition, phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK, induced by IL-1ß, is prevented by Cur-EVs. Cur-EVs increased IL-1ß-reduced expression of hsa-miR-126-3p and hsa-miR-126-3p mimic reversed the effects of IL-1ß. CONCLUSION: Cur-EVs alleviated IL-1ß-induced catabolic effects on OA-CH by promoting viability and migration, reducing apoptosis and phosphorylation of Erk1/2, PI3K/Akt, and p38 MAPK thereby modulating pro-inflammatory signaling pathways. Treatment of OA-CH with Cur-EVs is followed by upregulation of expression of hsa-miR-126-3p which is involved in modulation of anabolic response of OA-CH. EVs may be considered as promising drug delivery vehicles of curcumin helping to alleviate OA.

[Ligamentous ankle injury: an underestimated trauma?] / Die Bandverletzung des oberen Sprunggelenks ­ eine unterschätzte Verletzung?

Ligamentous injuries of the ankle joint are among the most common injuries in sports, with landing on the opponent's foot or direct contact counting among the most common injury mechanisms. Initial measures most notably include a clinical examination, supplemented by X-rays, sonography or MRI as required. In most cases, conservative treatment is the treatment of choice. At the beginning, pain and swelling have to be reduced. Then function must be regained before patients may return to sports after a return-to-play test. Some injury patterns are more complex with concomitant injuries, and despite all the success of conservative treatment, certain cases remain the preserve of surgery. Not only the downtime of athletes, the severity of long-term damage and chronic functional limitations, but also the associated costs for treatment suggest the recommendation that ankle joint injuries should not be underestimated and adequate treatment should be selected.

hBMSC-Derived Extracellular Vesicles Attenuate IL-1ß-Induced Catabolic Effects on OA-Chondrocytes by Regulating Pro-inflammatory Signaling Pathways.

Background: Human bone marrow-derived mesenchymal stromal cells (hBMSCs) provide a promising therapeutic approach in the cell-based therapy of osteoarthritis (OA). However, several disadvantages evolved recently, including immune responses of the host and regulatory hurdles, making it necessary to search for alternative treatment options. Extracellular vesicles (EVs) are released by multiple cell types and tissues into the extracellular microenvironment, acting as message carriers during intercellular communication. Here, we investigate putative protective effects of hBMSC-derived EVs as a cell-free approach, on IL-1ß-stimulated chondrocytes obtained from OA-patients. Methods: EVs were harvested from the cell culture supernatant of hBMSCs by a sequential ultracentrifugation process. Western blot, scanning electron microscopy (SEM), and nanoparticle tracking analysis (NTA) were performed to characterize the purified particles as EVs. Intracellular incorporation of EVs, derived from PHK26-labeled hBMSCs, was tested by adding the labeled EVs to human OA chondrocytes (OA-CH), followed by fluorescence microscopy. Chondrocytes were pre-stimulated with IL-1ß for 24 h, followed by EVs treatment for 24 h. Subsequently, proliferation, apoptosis, and migration (wound healing) were analyzed via BrdU assay, caspase 3/7 assay, and scratch assay, respectively. With qRT-PCR, the relative expression level of anabolic and catabolic genes was determined. Furthermore, immunofluorescence microscopy and western blot were performed to evaluate the protein expression and phosphorylation levels of Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB as components of pro-inflammatory signaling pathways in OA-CH. Results: EVs from hBMSCs (hBMSC-EVs) promote proliferation and reduce apoptosis of OA-CH and IL-1ß-stimulated OA-CH. Moreover, hBMSC-EVs attenuate IL-1ß-induced reduction of chondrocyte migration. Furthermore, hBMSC-EVs increase gene expression of PRG4, BCL2, and ACAN (aggrecan) and decrease gene expression of MMP13, ALPL, and IL1ß in OA-CH. Notably, COL2A1, SOX9, BCL2, ACAN, and COMP gene expression levels were significantly increased in IL-1ß+ EV groups compared with those IL-1ß groups without EVs, whereas the gene expression levels of COLX, IL1B, MMP13, and ALPL were significantly decreased in IL-1ß+ EV groups compared to IL-1ß groups without EVs. In addition, the phosphorylation status of Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB signaling molecules, induced by IL-1ß, is prevented by hBMSC- EVs. Conclusion: EVs derived from hBMSCs alleviated IL-1ß-induced catabolic effects on OA-CH via promoting proliferation and migration and reducing apoptosis, probably via downregulation of IL-1ß-activated pro-inflammatory Erk1/2, PI3K/Akt, p38, TAK1, and NF-κB signaling pathways. EVs released from BMSCs may be considered as promising cell-free intervention strategy in cartilage regenerative medicine, avoiding several adverse effects of cell-based regenerative approaches.

Influence of Extracellular Vesicles Isolated From Osteoblasts of Patients With Cox-Arthrosis and/or Osteoporosis on Metabolism and Osteogenic Differentiation of BMSCs.

Background: Studies with extracellular vesicles (EVs), including exosomes, isolated from mesenchymal stem cells (MSC) indicate benefits for the treatment of musculoskeletal pathologies as osteoarthritis (OA) and osteoporosis (OP). However, little is known about intercellular effects of EVs derived from pathologically altered cells that might influence the outcome by counteracting effects from "healthy" MSC derived EVs. We hypothesize, that EVs isolated from osteoblasts of patients with hip OA (coxarthrosis/CA), osteoporosis (OP), or a combination of both (CA/OP) might negatively affect metabolism and osteogenic differentiation of bone-marrow derived (B)MSCs. Methods: Osteoblasts, isolated from bone explants of CA, OP, and CA/OP patients, were compared regarding growth, viability, and osteogenic differentiation capacity. Structural features of bone explants were analyzed via µCT. EVs were isolated from supernatant of naïve BMSCs and CA, OP, and CA/OP osteoblasts (osteogenic culture for 35 days). BMSC cultures were stimulated with EVs and subsequently, cell metabolism, osteogenic marker gene expression, and osteogenic differentiation were analyzed. Results: Trabecular bone structure was different between the three groups with lowest number and highest separation in the CA/OP group. Viability and Alizarin red staining increased over culture time in CA/OP osteoblasts whereas growth of osteoblasts was comparable. Alizarin red staining was by trend higher in CA compared to OP osteoblasts after 35 days and ALP activity was higher after 28 and 35 days. Stimulation of BMSC cultures with CA, OP, and CA/OP EVs did not affect proliferation but increased caspase 3/7-activity compared to unstimulated BMSCs. BMSC viability was reduced after stimulation with CA and CA/OP EVs compared to unstimulated BMSCs or stimulation with OP EVs. ALP gene expression and activity were reduced in BMSCs after stimulation with CA, OP, and CA/OP EVs. Stimulation of BMSCs with CA EVs reduced Alizarin Red staining by trend. Conclusion: Stimulation of BMSCs with EVs isolated from CA, OP, and CA/OP osteoblasts had mostly catabolic effects on cell metabolism and osteogenic differentiation irrespective of donor pathology and reflect the impact of tissue microenvironment on cell metabolism. These catabolic effects are important for understanding differences in effects of EVs on target tissues/cells when harnessing them as therapeutic drugs.