Background/Aims: Growth hormone (GH) deficiency in pediatric patients results in short stature and osteopenia. We postulated that the GH and parathyroid hormone (PTH) combination would result in improvement in bone growth and bone formation. Methods: Forty hypophysectomized female rats at age 8 weeks were divided into hypophysectomy (HX), HX + PTH (62.5 µg/kg, s.c. daily), HX + GH (3.33 mg/kg, s.c. daily), and HX + PTH + GH for a 4-week study. Results: GH increased body weight, bone growth, bone mineral content (BMC) and bone mineral density (BMD), whereas PTH increased BMC and BMD without a significant effect on bone size. GH increased both periosteal and endocortical bone formation and cortical size, while PTH increased only endocortical bone formation. GH mitigated the trabecular bone loss by increasing bone formation, while PTH increased bone mass by increasing bone formation and suppressing osteoclast number per bone area. The result of combined intervention shows an increase in trabecular, periosteal and endocortical bone formation and suppression of bone resorption resulting in a synergistic effect on increasing trabecular and cortical bone volume and BMD. Conclusion: The combination treatment of PTH and GH increases bone growth, bone formation, decreases bone resorption and has a synergistic effect on increasing bone density and bone mass.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The purpose of the present study was to clarify the differences in the alterations of cellular activities of osteoblasts and osteoclasts, mineralization, and bone mass in cortical and cancellous bones of young growing rats with mild calcium deficiency. Twenty female Sprague-Dawley rats, 6 weeks of age, were randomized by the stratified method into two groups with 10 rats in each group: 0.5% (normal) calcium diet group and 0.1% (low) calcium diet group. After 10 weeks of feeding, bone histomorphometric analysis was performed on cancellous bone of the proximal tibia as well as cortical bone of the tibial shaft. Calcium deficiency increased eroded surface (ES/bone surface [BS]) and the number of osteoclast (N.Oc/BS) with an increase in osteoblast surface (ObS/BS), but decreased bone formation rate (BFR/BS) in cancellous bone. However, cancellous bone volume was preserved, while cortical bone area was decreased as a result of decreased periosteal bone gain and enlargement of the marrow cavity. These results suggest that short-term mild calcium deficiency in young growing female rats increased bone resorption by increasing osteoclastic recruitment, and suppressed mineralization followed by increased osteoblastic recruitment in cancellous bone, but cancellous bone loss was counteracted through redistribution of calcium from cortical bone to cancellous bone.

The following articles have been retracted by the Editorial Board of Experimental Animals, because some parts of their contents were published elsewhere.

The following articles have been retracted by the Editorial Board of Experimental Animals, because some parts of their contents were published elsewhere.

Vitamin D is involved in a range of physiological processes and its active form and analogs have been used to treat diseases such as osteoporosis. Yet how vitamin D executes its function remains unsolved. Here we show that the active form of vitamin D calcitriol increases the peak bone mass in mice by inhibiting osteoclastogenesis and bone resorption. Although calcitriol modestly promoted osteoclast maturation, it strongly inhibited osteoclast lineage commitment from its progenitor monocyte by increasing Smad1 transcription via the vitamin D receptor and enhancing BMP-Smad1 activation, which in turn led to increased IκBα expression and decreased NF-κB activation and NFATc1 expression, with IκBα being a Smad1 target gene. Inhibition of BMP type I receptor or ablation of Bmpr1a in monocytes alleviated the inhibitory effects of calcitriol on osteoclast commitment, bone resorption, and bone mass augmentation. These findings uncover crosstalk between the BMP-Smad1 and RANKL-NF-κB pathways during osteoclastogenesis that underlies the action of active vitamin D on bone health. © 2017 American Society for Bone and Mineral Research.

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

Aims: Transcatheter mitral valve replacement (TMVR) is a novel technique for treating mitral regurgitation. We report 18-month/two-year outcomes of the five first-in-man patients undergoing chronic TMVR with the Tendvne device.Methods and results: Five patients (STS score range 14%-23%) underwent TMVR using the Tendvne system under compassionate use at a single centre. One patient (who was non-compliant with anticoagulation) died nine months after TMVR following a cerebrovascular accident. Whilst sonic of the remaining patients experienced recognised post-TMVR complications (left ventricular outflow tract obstruction, para-valvular leak, stent thrombosis), all patients alive at 18 mouths/two years after TMVR reported significant reduction in NYIIA class and increase in exercise capacity compared to baseline. Transthoracic echocardiography demonstrated valve stability, absent transvalvular mitral regurgitation, and significant reductions in tricuspid regurgitation severity and systolic pulmonary arterial pressure.Conclusions: Eighteen months/two years after compassionate use of the Tendvne system in a high-risk surgical group, the majority of patients were alive, patient symptoms improved, and the device was stable with good haemodynamic function, no late migration and no new paravalvular leak. Continued follow-up of patients treated with the Tendvne system is required in order to describe its safety and efficacy further.

Exercise enhances bone growth and increases peak bone mass. The aim of this study was to determine whether or not 4 weeks of deconditioning after 8 weeks of exercise in growing rats would result in a decrease in bone gain or reverse the benefits of exercise. Fifty 4-week-old female Sprague-Dawley rats were randomized by a stratified weight method into 5 groups with 10 rats in each group: 8 weeks exercise (8EX), 8 weeks sedentary control (8S), 12 weeks exercise (12EX), 8 weeks exercise followed by 4 weeks sedentary (8EX4S), and 12 weeks sedentary control (12S). The exercise consisted of running on a treadmill with a 5 degrees slope at 24 m/minute for 1 h/day and 5 days/week. After each period of exercise, cancellous and cortical bone histomorphometry were performed on double fluorescent labeled 5-microm-thick sections of the proximal tibia and 40-microm-thick sections of the tibial shaft, respectively. Eight and 12 weeks of exercise resulted in a significant increase in the body weight and gastrocnemius muscle weight by two-way analysis of variance (ANOVA). The femoral wet weight (mg; mean +/- SD; 8EX, 781 +/- 45.1 vs. 8S, 713 +/- 40.5; p < 0.05; 12EX, 892 +/- 41.6 vs. 12S, 807 +/- 19.8; p < 0.05) was significantly higher in the exercise group than that in the respective control groups. The femoral wet weight and bone volume (BV) of the 8EX4S group (818 +/- 46.2 mg and 531 +/- 31.2 microl, respectively) were significantly lower than those of the 12EX group (p < 0.05) and did not differ significantly from those of the 12S groups. The cancellous BV was significantly higher in the 8EX and 12EX groups than that in the respective sedentary groups (p < 0.05). The cortical bone area of the tibial shaft was also significantly higher in the 12EX than that in the 12S group (p < 0.05). The increase in the cancellous BV or cortical bone area was caused by an increase in the mineral apposition rate (MAR), without a significant effect in the labeled perimeter. The bone formation rate (BFR; microm3/microm2 per day) in the cancellous bone (12EX, 27.9 +/- 7.74 vs. 12S, 15.4 +/- 4.56; p < 0.05) or periosteal surface (12EX, 127.6 +/- 27.7 vs. 12S, 79.5 +/- 18.6; p < 0.05) was significantly higher in the exercised groups than that in the respective control group (p < 0.05). Again, deconditioning resulted in a decrease in the cancellous BFR, BV, periosteal BFR, and cortical bone area to levels not significantly different from the 12S group. In conclusion, our findings showed that exercised growing rats, when deconditioned, lost the benefits gained through exercise and their bone parameters were reduced to levels not different from the sedentary control. Thus, continued exercise is required to maintain high bone mass.

OBJECTIVES The authors present the UK and Irish real-world learning curve experience of the Evolut R transcatheter heart valve.BACKGROUND The Evolut R is a self-expanding, repositionable, and fully recapturable second-generation transcatheter heart valve with several novel design features to improve outcomes and reduce complications.METHODS Clinical, procedural, and 30-day outcome data were prospectively collected for the first 264 patients to receive the Evolut R valve in the United Kingdom and Ireland.RESULTS A total of 264 consecutive Evolut R implantations were performed across 9 centers. The mean age was 81.1 +/- 7.8 years, and the mean logistic European System for Cardiac Operative Risk Evaluation score was 19.9 +/- 13.7%. Procedural indications included aortic stenosis (72.0%), mixed aortic valve disease (17.4%), and failing aortic valve bioprostheses (10.6%). Conscious sedation was used in 39.8% of patients and transfemoral access in 93.6%. The procedural success rate was 91.3%, and paravalvular leak immediately after implantation was mild or less in 92.3%. Major complications were rare: cardiac tamponade in 0.4%, conversion to sternotomy in 0.8%, annular rupture in 0.0%, coronary occlusion in 0.8%, major vascular in 5.3%, acute kidney injury in 6.1%, new permanent pacemaker implantation in 14.7%, and procedure-related death in 0.0%. At 30-day follow-up, survival was 97.7%, paravalvular leak was mild or less in 92.3%, and the stroke rate was 3.8%.CONCLUSIONS This registry represents the largest published real-world experience of the Evolut R valve. The procedural success rate was high and safety was excellent, comparable with previous studies of the Evolut R valve and other second-generation devices. The low rate of complications represents an improvement on first-generation devices. (C) 2017 by the American College of Cardiology Foundation.

BACKGROUNDCoronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide. Vorapaxar, a protease-activated receptor-1 (PAR-1) antagonist, is a novel antiplatelet agent that may provide us a new way in antithrombotic therapy. Several studies had been conducted to evaluate the efficacy of vorapaxar in the treatment of CAD, but the results were inconsistent. Here a meta-analysis was made to assess the efficacy and safety of vorapaxar in reducing adverse cardiac events in patients with CAD.METHODSA comprehensive literature search was conducted. The primary efficacy endpoint was the major adverse cardiac events, which was defined as a composite of cardiovascular death, myocardial infarction (MI), stroke, urgent coronary revascularization, or recurrent ischemia with rehospitalization. The primary safety endpoint was the composite of major or minor bleeding events. Pooled effects were measured by odds ratios (ORs) with 95% confidence intervals (CIs). A random-effect or fixed model was used in this meta-analysis.RESULTSTotally, 31,388 patients from four randomized controlled trials (RCTs) were included in this meta-analysis. Patients who took vorapaxar combined with standard dual anti-platelet therapy (aspirin and thienopyridine) showed a lower incidence in major adverse cardiac events (OR, 0.86, 95% CI: 0.75-0.99, P=0.03), MI (OR, 0.79, 95% CI: 0.67-0.95, P=0.01) and ischemic stroke (OR, 0.72, 95% CI: 0.58-0.89, P=0.003) than those who only took placebo instead. But there was no significant reduction in cardiovascular death (OR, 0.95, 95% CI: 0.82-1.09, P=0.45). Nevertheless, the vorapaxar group were associated with a higher risk of bleeding events (P<0.001).CONCLUSIONSThe result of this meta-analysis indicated that adding vorapaxar to the standard dual anti-platelet therapy may be efficient in reducing the incidence of major adverse cardiac events at the cost of increasing risk of bleeding events.

Background: The effect of triptolide (TPL) on cardiac fibroblasts (CFbs) and cardiac fibrosis remain unknown till now. This study was conducted to explore the effects of TPL on proliferation and apoptosis of angiotensin II (Ang II)-induced CFbs. Materials and Methods: Ang II was used to promote proliferation of CFbs. Two dosages of TPL (10ng/ml and 100ng/ml) were chosen. MTT assay was used to detect cell survival rate in vitro. Flow cytometer was performed to analyze apoptosis of CFbs. Hydroxyproline concentration was detected with hydroxyproline assay kit. Quantitative real-time PCR was used to detect the expression of TGF-β1 and Smad3 mRNA. Results: Ang II promoted CFbs proliferation significantly. Compared to Ang II group, TPL markedly reduced the viability of CFbs and its Hydroxyproline concentration (P<0.05). Besides, TPL can significantly promote apoptosis of CFbs (P<0.05). Furthermore, TPL reduced the expressions of TGF-βΙ and Smad3 mRNA in Ang II-induced CFbs (P<0.05). Conclusion: TPL can inhibit the proliferation of CFbs in rats by down-regulating TGF-β1/Smad3 signaling pathway. TPL might be a promising therapeutic drug for myocardial fibrosis.