Deletion of the Sequence Encoding the Tail Domain of the Bone Morphogenetic Protein type 2 Receptor Reveals a Bone Morphogenetic Protein 7-Specific Gain of Function

The bone morphogenetic protein (BMP) type II receptor (BMPR2) has a long cytoplasmic tail domain whose function is incompletely elucidated. Mutations in the tail domain of BMPR2 are found in familial cases of pulmonary arterial hypertension. To investigate the role of the tail domain of BMPR2 in BMP signaling, we generated a mouse carrying a Bmpr2 allele encoding a non-sense mediated decay-resistant mutant receptor lacking the tail domain of Bmpr2. We found that homozygous mutant mice died during gastrulation, whereas heterozygous mice grew normally without developing pulmonary arterial hypertension. Using pulmonary artery smooth muscle cells (PaSMC) from heterozygous mice, we determined that the mutant receptor was expressed and retained its ability to transduce BMP signaling. Heterozygous PaSMCs exhibited a BMP7‑specific gain of function, which was transduced via the mutant receptor. Using siRNA knockdown and cells from conditional knockout mice to selectively deplete BMP receptors, we observed that the tail domain of Bmpr2 inhibits Alk2‑mediated BMP7 signaling. These findings suggest that the tail domain of Bmpr2 is essential for normal embryogenesis and inhibits Alk2‑mediated BMP7 signaling in PaSMCs

Разработка информационной системы планирования энергоресурсов производственного предприятия OOO "Завод ТехноНИКОЛЬ-Сибирь"

OBJECTIVE: The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. While genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes. METHODS AND RESULTS: We tested the impact of pharmacologic BMP inhibition upon atherosclerosis and calcification in low density lipoprotein receptor-deficient (LDLR(−/−)) mice. LDLR(−/−) mice fed a high-fat diet developed abundant vascular calcification within twenty weeks. Prolonged treatment of LDLR(−/−) mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the anti-atherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species (ROS) induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis. CONCLUSIONS: These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification

«ЩОБ ХОЧ НЕ СИДЯЧОГО ТАТАРИ БРАЛИ…»

Одним із вагомих (не в останню чергу з точки зору суспільної ваги) напрямків в колі наукових зацікавлень Ганни Кирилівни є краєзнавство, до якого не завжди «прихильно» ставиться академічна наука. Саме з краєзнавчої актуальності виводить Автор у передмові потребу у написанні роботи, присвяченої досить знаковій постаті на загальноукраїнському тлі і абсолютно виключній особистості на регіональному рівні – Михайлові Федоровичу Комарову (1844-1913) (с.4-5

Minimal instructions improve the performance of laypersons in the use of semiautomatic and automatic external defibrillators

INTRODUCTION: There is evidence that use of automated external defibrillators (AEDs) by laypersons improves rates of survival from cardiac arrest, but there is no consensus on the optimal content and duration of training for this purpose. In this study we examined the use of semiautomatic or automatic AEDs by laypersons who had received no training (intuitive use) and the effects of minimal general theoretical instructions on their performance. METHODS: In a mock cardiac arrest scenario, 236 first year medical students who had not previously attended any preclinical courses were evaluated in their first study week, before and after receiving prespecified instructions (15 min) once. The primary end-point was the time to first shock for each time point; secondary end-points were correct electrode pad positioning, safety of the procedure and the subjective feelings of the students. RESULTS: The mean time to shock for both AED types was 81.2 ± 19.2 s (range 45–178 s). Correct pad placement was observed in 85.6% and adequate safety in 94.1%. The time to shock after instruction decreased significantly to 56.8 ± 9.9 s (range 35–95 s; P ≤ 0.01), with correct electrode placement in 92.8% and adequate safety in 97%. The students were significantly quicker at both evaluations using the semiautomatic device than with the automatic AED (first evaluation: 77.5 ± 20.5 s versus 85.2 ± 17 s, P ≤ 0.01; second evaluation: 55 ± 10.3 s versus 59.6 ± 9.6 s, P ≤ 0.01). CONCLUSION: Untrained laypersons can use semiautomatic and automatic AEDs sufficiently quickly and without instruction. After one use and minimal instructions, improvements in practical performance were significant. All tested laypersons were able to deliver the first shock in under 1 min

Inhibition of Bone Morphogenetic Protein Signal Transduction Prevents the Medial Vascular Calcification Associated with Matrix Gla Protein Deficiency

Objective: Matrix Gla protein (MGP) is reported to inhibit bone morphogenetic protein (BMP) signal transduction. MGP deficiency is associated with medial calcification of the arterial wall, in a process that involves both osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) and mesenchymal transition of endothelial cells (EndMT). In this study, we investigated the contribution of BMP signal transduction to the medial calcification that develops in MGP-deficient mice. Approach and Results MGP-deficient mice (MGP-/-) were treated with one of two BMP signaling inhibitors, LDN-193189 or ALK3-Fc, beginning one day after birth. Aortic calcification was assessed in 28-day-old mice by measuring the uptake of a fluorescent bisphosphonate probe and by staining tissue sections with Alizarin red. Aortic calcification was 80% less in MGP-/- mice treated with LDN-193189 or ALK3-Fc compared with vehicle-treated control animals (P<0.001 for both). LDN-193189-treated MGP-/- mice survived longer than vehicle-treated MGP-/- mice. Levels of phosphorylated Smad1/5 and Id1 mRNA (markers of BMP signaling) did not differ in the aortas from MGP-/- and wild-type mice. Markers of EndMT and osteogenesis were increased in MGP-/- aortas, an effect that was prevented by LDN-193189. Calcification of isolated VSMCs was also inhibited by LDN-193189. Conclusions: Inhibition of BMP signaling leads to reduced vascular calcification and improved survival in MGP-/- mice. The EndMT and osteogenic transdifferentiation associated with MGP deficiency is dependent upon BMP signaling. These results suggest that BMP signal transduction has critical roles in the development of vascular calcification in MGP-deficient mice

Inhaled nitric oxide improves transpulmonary blood flow and clinical outcomes after prolonged cardiac arrest: a large animal study

Introduction: The probability to achieve a return of spontaneous circulation (ROSC) after cardiac arrest can be improved by optimizing circulation during cardiopulomonary resuscitation using a percutaneous left ventricular assist device (iCPR). Inhaled nitric oxide may facilitate transpulmonary blood flow during iCPR and may therefore improve organ perfusion and outcome. Methods: Ventricular fibrillation was electrically induced in 20 anesthetized male pigs. Animals were left untreated for 10 minutes before iCPR was attempted. Subjects received either 20 ppm of inhaled nitric oxide (iNO, n = 10) or 0 ppm iNO (Control, n = 10), simultaneously started with iCPR until 5 hours following ROSC. Animals were weaned from the respirator and followed up for five days using overall performance categories (OPC) and a spatial memory task. On day six, all animals were anesthetized again, and brains were harvested for neurohistopathologic evaluation. Results: All animals in both groups achieved ROSC. Administration of iNO markedly increased iCPR flow during CPR (iNO: 1.81 ± 0.30 vs Control: 1.64 ± 0.51 L/min, p < 0.001), leading to significantly higher coronary perfusion pressure (CPP) during the 6 minutes of CPR (25 ± 13 vs 16 ± 6 mmHg, p = 0.002). iNO-treated animals showed significantly lower S-100 serum levels thirty minutes post ROSC (0.26 ± 0.09 vs 0.38 ± 0.15 ng/mL, p = 0.048), as well as lower blood glucose levels 120–360 minutes following ROSC. Lower S-100 serum levels were reflected by superior clinical outcome of iNO-treated animals as estimated with OPC (3 ± 2 vs. 5 ± 1, p = 0.036 on days 3 to 5). Three out of ten iNO-treated, but none of the Control animals were able to successfully participate in the spatial memory task. Neurohistopathological examination of vulnerable cerebral structures revealed a trend towards less cerebral lesions in neocortex, archicortex, and striatum in iNO-treated animals compared to Controls. Conclusions: In pigs resuscitated with mechanically-assisted CPR from prolonged cardiac arrest, the administration of 20 ppm iNO during and following iCPR improved transpulmonary blood flow, leading to improved clinical neurological outcomes

Brief inhalation of nitric oxide increases resuscitation success and improves 7-day-survival after cardiac arrest in rats: a randomized controlled animal study

Introduction: Inhaled nitric oxide (iNO) improves outcomes when given post systemic ischemia/reperfusion injury. iNO given during cardiopulmonary resuscitation (CPR) may therefore improve return of spontaneous circulation (ROSC) rates and functional outcome after cardiac arrest (CA). Methods: Thirty male Sprague-Dawley rats were subjected to 10 minutes of CA and at least 3 minutes of CPR. Animals were randomized to receive either 0 (n = 10, Control), 20 (n = 10, 20 ppm), or 40 (n = 10, 40 ppm) ppm iNO during CPR until 30 minutes after ROSC. A neurological deficit score was assessed daily for seven days following the experiment. On day 7, brains, hearts, and blood were sampled for histological and biochemical evaluation. Results: During CPR, 20 ppm iNO significantly increased diastolic arterial pressure (Control: 57 ± 5.04 mmHg; 20 ppm: 71.57 ± 57.3 mmHg, p < 0.046) and decreased time to ROSC (Control: 842 ± 21 s; 20 ppm: 792 ± 5 s, (p = 0.02)). Thirty minutes following ROSC, 20 ppm iNO resulted in an increase in mean arterial pressure (Control: 83 ± 4 mmHg; 20 ppm: 98 ± 4 mmHg, p = 0.035), a less pronounced rise in lactate and inflammatory cytokine levels, and attenuated cardiac damage. Inhalation of NO at 20 ppm improved neurological outcomes in rats 2 to 7 days after CA and CPR. This translated into increases in 7 day survival (Control: 4; 20 ppm: 10; 40 ppm 6, (p ≤ 0.05 20 ppm vs Control and 40 ppm). Conclusions: Our study revealed that breathing NO during CPR markedly improved resuscitation success, 7-day neurological outcomes and survival in a rat model of VF-induced cardiac arrest and CPR. These results support the beneficial effects of NO inhalation after cardiac arrest and CPR

The intuitive use of laryngeal airway tools by first year medical students

Abstract Background Providing a secured airway is of paramount importance in cardiopulmonary resuscitation. Although intubating the trachea is yet seen as gold standard, this technique is still reserved to experienced healthcare professionals. Compared to bag-valve facemask ventilation, however, the insertion of a laryngeal mask airway offers the opportunity to ventilate the patient effectively and can also be placed easily by lay responders. Obviously, it might be inserted without detailed background knowledge. The purpose of the study was to investigate the intuitive use of airway devices by first-year medical students as well as the effect of a simple, but well-directed training programme. Retention of skills was re-evaluated six months thereafter. Methods The insertion of a LMA-Classic and a LMA-Fastrach performed by inexperienced medical students was compared in an airway model. The improvement on their performance after a training programme of overall two hours was examined afterwards. Results Prior to any instruction, mean time to correct placement was 55.5 ± 29.6 s for the LMA-Classic and 38.1 ± 24.9 s for the LMA-Fastrach. Following training, time to correct placement decreased significantly with 22.9 ± 13.5 s for the LMA-Classic and 22.9 ± 19.0 s for the LMA-Fastrach, respectively (p Conclusion Untrained laypersons are able to use different airway devices in a manikin and may therefore provide a secured airway even without having any detailed background knowledge about the tool. Minimal theoretical instruction and practical skill training can improve their performance significantly. However, refreshment of knowledge seems justified after six months.</p