After bone injury, developmental processes such as endochondral and intramembranous ossification are recapitulated as the skeleton regenerates. In contrast to development, skeletal healing involves inflammation. During the early stages of healing a variety of inflammatory cells infiltrate the injured site, debride the wound, and stimulate the repair process. Little is known about the inflammatory process during bone repair. In this work, we examined the effect of a pro-inflammatory cytokine, Interleukin-1 beta (IL-1b), on osteoblast and stem cell differentiation and on intramembranous and endochondral ossification, because IL-1b exerts effects on skeletal homeostasis and is upregulated in response to fracture. We determined that IL-1b stimulated proliferation of osteoblasts and production of mineralized bone matrix, but suppressed proliferation and inhibited differentiation of bone marrow derived MSCs. We next performed loss-and gain-offunction experiments to determine if altering IL-1b signaling affects fracture healing. We did not detect any differences in callus, cartilage, and bone matrix production during healing of nonstabilized or stabilized fractures in mice that lacked the IL-1b receptor compared to wildtype animals. We observed subtle alterations in the healing process after administering IL-1b during the early phases of repair. At day 10 after injury, the ratio of cartilage to callus was increased, and by day 14, the proportion of cartilage to total callus and to bone was reduced. These changes could reflect a slight acceleration of endochondral ossification, or direct effects on cartilage and bone formation.

Age affects fracture repair; however, the underlying mechanisms are not well understood. The goal of this study was to assess the effects that age has on vascularization during fracture healing. Tibial fractures were created in juvenile (4-week-old), middle-aged (6-month-old), and elderly (18-month-old) mice. The length density and surface density of blood vessels within fracture calluses were analyzed using stereology at 7 days after fracture. The expression of molecules that regulate vascular invasion of the fracture callus was also compared among the three age groups by immunohistochemistry and in situ hybridization. At 7 days after fracture, juvenile mice had a higher surface density of blood vessels compared to the middle-aged and elderly. Hypoxia-inducible factor-1a protein and transcripts of vascular endothelial growth factor were detected at 3 days postinjury in juvenile but not middle-aged and elderly mice. Stronger Mmp-9 and -13 expression was detected in fracture calluses at day 7 in the juvenile compared to the middle-aged and elderly mice. At 21 days postfracture, expression of both Mmps was more robust in the elderly than juvenile and middle-aged animals. These data indicate that age affects vascularization during fracture repair, and the changes we observed are directly correlated with altered expression of biochemical factors that regulate the process of angiogenesis. However, whether the increased vascularization is the cause or result of accelerated bone repair in juvenile animals remains unknown. Nonetheless, our results indicate that enhancing vascularization during fracture repair in the elderly may provide unique therapeutic opportunities. ß

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Integrins are heterodimeric transmembrane proteins that mediate cell-matrix interactions and modulate cell behavior. Beta3 subunit is a component of aIIb3 and aVb3 integrins. In this study, we first determined that b3 transcripts are expressed by cells within fracture calluses at 7 and 10 days after injury in a mouse model. We then analyzed fracture healing in mice deficient of b3 integrin with molecular, histomorphometric, and biomechanical techniques. We found that lack of b3 integrin results in an extended bleeding time and leads to more bone formation and accelerated cartilage maturation at 7 days after injury. However, b3 deficiency does not appear to affect later fracture healing. At days 14 and 21, histological appearance or biomechanical properties of fracture calluses are similar between wild type and mutant mice. We also found that altered fracture healing in b3-null mice is not associated with accelerated angiogenesis, because no significant difference of length density and surface density of blood vessels in fracture limbs was detected at 3 days after injury between wild type and b3-null mice. In conclusion, our findings demonstrate that b3 integrin plays an important role during early fracture healing. Further research is required to determine the underlying mechanisms. ß

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Purpose:to assess the association between depression and all-cause mortality in patients with congestive heart failure (CHF) after cardiac resynchronization therapy (CRT).Materials and Methods.We enrolled in this study 156 patients (mean age 55.3±9.6 years) with CHF and implanted devices for CRT. Mean duration of follow-up was 51.6±33.4 months. The Beck Depression Inventory (BDI) was used to evaluate depressive symptoms (DS); DS were considered absent for a score 0–9, mild to moderate – 10–18, severe – ≥19. For assessment of association of DS and mortality we used multivariate Cox proportional hazards regression model with estimation of hazard ratios (HR) with 95 % confidence intervals (95 %CI).Results. Average Beck Depression Inventory score was 12.4±8.3. In 66 patients (42.3 %) there were no DS, 57 patients (36.5 %) had mild, and 33 (21.2 %) – severe DS. These groups did not differ by main clinical-functional and laboratory indicators. Among individuals without DS prevailed men (90.9 vs. 69.7 % among those with severe DS, p=0.007). Hypercholesterolemia was more frequent in patients with DS (63.3 vs. 43.9 % in patients without DS, p=0.02). During follow-up 33 patients died (21.2 %). Adjusted HR of death from all-causes for DS score as continuous parameter was 1.05, 95 % CI 1.01–1.09, p=0.02. Patients without DS were used as reference (HR=1.0) in analysis of categorical indicator. HR was 1.08, 95 % CI 0.46–2.54, p=0.9 in patients with mild, and 2.92, 95 % CI 1.17–7.32, p=0.02 – with severe DS.Conclusion:DS were associated with gender and hypercholesterolemia. Severe DS were independently associated with all-cause mortality in patients with CHF and implanted CRT devices.

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BACKGROUND: According  to the results of the ESSE-RF study, the frequency of obesity in the population  reached 29.7%. Obesity is one of the main risk factors for the development of cardiovascular diseases. Features of the course of COVID-19 in patients with obesity is a very urgent problem.AIM: The aim of the study was a comparative investigation of clinical and laboratory-instrumental parameters in AH patients with or without obesity who had COVID-19 associated pneumonia, to identify the role of obesity as a potential predictor of post-COVID cardiovascular complications 3 months after discharge from the hospital.MATERIALS AND METHODS: Materials and methods. The study included 174 patients with COVID-19-associated pneumonia. Group 1 included 78 patients with AH without obesity, group 2 — 96 patients with AH and obesity. All patients were tested with a blood sample at the time of admission and 3 months after discharge from the hospital. We assessed parameters of general blood test, biochemistry, hemostasis, inflammation biomarkers — concentration of C-reactive protein (CRP), highly sensitive CRP (hs-CRP), homocysteine, IL-6, etc. All patients initially underwent computed tomography  of the chest. In both groups, 24-hour blood pressure monitoring was performed using BPLaB device, according to the standard protocol; echocardiography using  an expert class ultrasound diagnostic  system Vivid S70. The study is registered with the Clinical Trials.gov database Identifier: NCT04501822.RESULTS: Results. The biomarker that significantly distinguished the both groups of patients, as well as subgroups according to the degree of obesity was the concentration of maxCRP and hs-CRP, which was significantly higher in group 2. In addition, the registered maximum values of MPO, NT-proBNP, IL-1,6, TNA-α and NRL parameters in group 2 of patients with 2–3 degrees of obesity, may indicate the highest probability of developing  delayed adverse cardiovascular complications  in this group of patients. Mean systolic blood pressure, variability of systolic and diastolic blood pressure, and heart rate at night were significantly  higher in AH patients with obesity. Numerous correlations of obesity with laboratory and instrumental parameters have been registered, which may indicate an increased likelihood of delayed unwanted cardiovascular complications in this particular group of patients. Multiple regression showed that obesity is an independent predictor of an increase in LDH, hs-CRP and right atrium.CONCLUSION: Dynamic control of the studied parameters in patients with AH and OB registered an increased concentration of CRP at the initial stage and 3 months after treatment, with a general trend towards a decrease in the increased initial structural parameters of ECHO CG. The logistic regression method showed that the presence of OB in patients with AH is an independent factor causing increased levels of immune inflammation (CRP), a marker of tissue destruction (LDH), and load on the right atrium.