组蛋白修饰在破骨细胞分化中的作用

破骨细胞(osteoclast,OC)是来源于造血干细胞的多核巨细胞,是机体内唯一具有骨吸收功能的细胞。OC功能失衡与多种骨代谢疾病的发生发展密切相关,如骨质疏松症、骨关节炎和Paget's病等,常作为骨代谢疾病临床治疗和药物研发的靶细胞。组蛋白(histone,H)是细胞核内序列高度保守的蛋白质,组蛋白修饰是指组蛋白在酶作用下发生甲基化、乙酰化、磷酸化、腺苷酸化和泛素化等修饰的过程,组蛋白修饰通过影响染色质的结构和松弛程度,调控基因转录和翻译,从而影响相关疾病的发展。近年来,越来越多的研究表明组蛋白修饰对于破骨细胞的分化具有重要的调节作用。本文对组蛋白修饰在破骨细胞分化中的作用进行综述,为组蛋白修饰抑制剂在骨代谢相关疾病中的研发和临床运用提供指导。     

氧化应激在急性肾损伤中的研究进展

急性肾损伤(AKI)是多种发病机制所致的疾病。氧化应激是AKI发病机制中的重要一环,与AKI的其他发病机制间相互作用,影响AKI的发生发展。现将氧化应激与AKI其他机制间的作用及抗氧化剂在AKI中的研究进展做一综述。     

Wnt/β-catenin信号通路与骨关节炎

近年大量研究证实Wnt/β-catenin信号通路通过调节胚胎期软骨发育及出生后软骨发生、成骨细胞和破骨细胞生成、软骨内成骨、骨重塑、骨折修复等过程,调控骨骼系统相关疾病和骨代谢,对骨关节炎(OA)发生发展、骨软骨组织诱导和修复起着至关重要的作用。基因敲除小鼠模型常用于Wnt/β-catenin信号通路与OA关系研究,全基因组扫描已发现一些与OA密切相关的单核苷酸多态性位点。目前在多个水平进行Wnt/β-catenin信号通路靶向治疗OA研究,重点考虑药物安全性。该文就Wnt/β-catenin与OA关系的研究进展作一综述。     

白藜芦醇在绝经后骨质疏松症中抗氧化机制的研究进展

绝经后骨质疏松症(PO)是一种全身性骨骼疾病,由雌激素缺乏和衰老引起,其特征是低骨密度(BMD)和骨组织的微结构恶化,并导致骨质疏松性骨折的风险增高。在PO的发生发展过程中,潜在的致病机制是复杂和多方面的,雌激素缺乏是骨吸收增加和骨质流失加速的重要原因。同时,由于雌激素的缺乏和机体的衰老导致氧化应激(OS)水平的升高,是PO发生的主要机制之一。针对老年绝经后骨质疏松患者的治疗目前较为有效的是采用雌激素替代疗法,但也增加了患乳腺癌、子宫癌和心血管事件发生的风险。因此,寻找有效的抗氧化应激药物以治疗PO受到了越来越多研究者的关注。其中以白藜芦醇(RES)为代表的天然植物化合物,是一种具有抗氧化和抗衰老作用的天然抗氧化剂。它能通过多种通路抑制体内氧化应激,促进成骨分化和减少骨量丢失,并调节骨转换的能力,从而有效治疗PO。本文就白藜芦醇在PO中的抗氧化机制及其研究进展做一综述。     

线粒体动力学与骨相关疾病关系的研究进展

线粒体是高度动态的细胞器，经历生物发生、分裂、融合和线粒体自噬的过程，这些事件统称为线粒体动力学。诸多研究证据表明，线粒体动力学的失衡与骨相关疾病的发生发展密切相关，调控线粒体动力学可为骨相关疾病的防治策略提供新途径。因此，笔者综述了线粒体动力学与骨相关疾病的最新研究进展，希望有助于在线粒体动力学维度上提供治疗骨相关疾病的新思路。     

氧化应激与糖尿病肾病

糖尿病肾病是糖尿病的重要微血管并发症之一，氧化应激即活性氧簇、糖氧化应激产物、抗氧化物酶等在糖尿病肾病发生发展中起到了重要的作用。抗氧化剂可以通过减少ROS的产生，增强机体的抗氧化能力等途径来减少氧化损伤，尽早应用抗氧化剂有望更好的预防和治疗糖尿病肾病。     

氧化应激与糖尿病肾病

糖尿病肾病是糖尿病的重要微血管并发症之一,氧化应激即活性氧簇、糖氧化应激产物、抗氧化物酶等在糖尿病肾病发生发展中起到了重要的作用.抗氧化剂可以通过减少ROS的产生,增强机体的抗氧化能力等途径来减少氧化损伤,尽早应用抗氧化剂有望更好的预防和治疗糖尿病肾病.     

免疫微环境对绝经后骨质疏松症的影响

绝经后骨质疏松症(postmenopausal osteoporosis, PMOP)是由于雌激素缺乏导致的、以骨量减少和骨组织微结构破坏为特征的的疾病。近年来，越来越多的观点认为免疫微环境与该病的发生发展密切相关，多种免疫细胞及其分泌的细胞因子通过RANK/RANKL/OPG等信号途径调控成骨细胞和破骨细胞的生物学功能，从而影响骨稳态失衡。因此，基于骨免疫学的免疫微环境逐渐成为PMOP防治研究的主要靶标之一。笔者综述了骨代谢相关的免疫细胞如T细胞、B细胞、巨噬细胞、肥大细胞和单核细胞对PMOP的发生发展以及对骨折愈合的影响，并总结基于骨免疫学的PMOP治疗靶点，以期为未来PMOP的药物开发及临床应用提供新的思路。     

MiRNA对成骨分化调控及骨质疏松发生的研究进展

微小RNA(microRNA,miRNA)是一类具有调控功能的非编码RNA,其主要起转录后的调控作用,在生物信号调节网络中扮演着重要的角色。miRNA与成骨分化,骨质新生,骨改建等过程密切相关,miRNA表达异常可导致骨质疏松等一系列骨代谢相关疾病。鉴于miRNA在骨代谢调控中的重要作用,本文就miRNA在细胞成骨分化及其与骨质疏松发病机制的研究进行综述,以期为骨代谢相关疾病的治疗提供新的方向。     

肠道菌群：绝经后骨质疏松防治新靶点

绝经后骨质疏松是一类由雌激素缺乏引起的,以骨量减少和骨微结构破坏为特点的骨骼疾病,可诱发脆性骨折的发生率增加。绝经后骨质疏松因其较高的发病率和严重的并发症受到越来越多的关注。目前绝经后骨质疏松的治疗药物存在诸多副作用,部分药物甚至对器官、系统造成严重损害,因此亟待寻求一条新的安全有效的治疗途径。肠道菌群是定植在人体肠道内的微生物总集,而益生菌是由肠道有益菌组成的膳食或药物补剂。近年来多项研究表明,肠道菌群和机体正常骨改建与骨代谢疾病的发生息息相关,并且益生菌在部分骨代谢疾病治疗中已初步展现了较好疗效,提示肠道菌群可作为绝经后骨质疏松防治的潜在靶点并且益生菌的应用作为绝经后骨质疏松新治疗方法的可能性。本文通过对肠道菌群与绝经后骨质疏松的相关研究进行综述,归纳总结了肠道菌群与绝经后骨质疏松发生发展的相关性以及益生菌对其的治疗效果,并从肠道菌群多样性、肠道上皮屏障功能以及机体免疫系统调控3方面探讨肠道菌群、雌激素和益生菌在绝经后骨质疏松的致病与治疗过程中的相关作用机制。     

Vasopressor hormone response following mesenteric traction during major abdominal surgery

Background : We investigated the vasopressor hormone response following mesenteric traction (MT) with hypotension due to prostacyclin (PGI₂) release in patients undergoing abdominal surgery with a combined general and epidural anesthesia. Methods : In a prospective, randomized, placebo-controlled study we administered 400 mg ibuprofen (i.v.) in 42 patients scheduled for abdominal surgery. General anesthesia was combined with epidural anesthesia (T4-L1). Before as well as 5, 15, 30, 45, and 90 min after MT we recorded plasma osmolality, hemodynamics and measured 6-keto-PGFlα (stabile metabolite of PGI₂), TXB₂ (stabile metabolite of thromboxane A₂) active renin, and arginine vasopressin (AVP) plasma concentrations by radioimmunoassay. Catecholamine levels were assessed by high-pressure liquid chromatography (HPLC) with electrochemical detection. Results : Following MT, arterial hypotension occurred along with a substantial PGI₂ release. This was completely abolished by ibuprofen administration. Although plasma levels of 6-keto-PGF_1α (1133 (708) vs. 60 (3) ng/L, median (median absolute deviation), P=0.0001, placebo vs. ibuprofen) remained significantly elevated, blood pressure was restored within 30 min after MT in the placebo group. At the same point in time plasma concentrations of TXB² (164 (87) vs. 58 (1) ng/L, P=0.0001), epinephrine (46 (33) vs. 14 (6) ng/L, P=0.001), AVP (41 ± (18) vs. 12 (7) ng/L, P=0.0004), and active renin (27 (12) vs. 12 (4) ng/L, P = 0.001) were significantly higher in placebo-treated patients. Conclusion : Under combined general and epidural anesthesia arterial hypotension following MT due to endogenous PGI₂ release is associated with enhanced release of AVP, active renin, epinephrine and thromboxane A₂, presumably contributing to hemodynamic stability within 30 min after MT.     

A comparison of the inhibitory effects of four volatile anaesthetics on the metabolism of chlorzoxazone, a substrate for CYP2E1, in rabbits

Background: Halothane inhibits in vitro and in vivo activity of cytochrome P-450 (CYP) 2E1. There are several fluorinated volatile anaesthetics besides halothane, and most of them are defluorinated by CYP2E1. It is unclear whether other fluorinated anaesthetics inhibit the in vivo activity of CYP2E1.
Methods: We compared the inhibitory effects of therapeutic concentrations of four inhalational anaesthetics, halothane, enflurane, isoflurane, and sevoflurane, on chlorzoxazone metabolism in rabbits receiving artificial ventilation.
Results: All four inhalational anaesthetics decreased arterial blood pressure and increased plasma chlorzoxazone concentration. However, no significant differences in the plasma chlorzoxazone concentration were found between the four anaesthetics. The estimated chlorzoxazone clearance increased after beginning inhalation with all four agents, but no significant difference in clearance was noted between agents.
Conclusions: At therapeutic concentrations, the in vivo inhibitory effect on chlorzoxazone metabolism was similar for all four inhalational anaesthetics examined, even though their chemical characteristics and extent of hepatic metabolism differ considerably.     

A Teaspoon Pump for Pumping Blood with High Hydraulic Efficiency and Low Hemolysis Potential

Abstract: Virtually all blood pumps contain some kind of rubbing, sliding, closely moving machinery surfaces that are exposed to the blood being pumped. These valves, internal bearings, magnetic bearing position sensors, and shaft seals cause most of the problems with blood pumps. The original teaspoon pump design prevented the rubbing, sliding machinery surfaces from contacting the blood. However, the hydraulic efficiency was low because the blood was able to "slip around" the rotating impeller so that the blood itself never rotated fast enough to develop adequate pressure. An improved teaspoon blood pump has been designed and tested and has shown acceptable hydraulic performance and low hemolysis potential. The new pump uses a nonrotating "swinging" hose as the pump impeller. The fluid enters the pump through the center of the swinging hose; therefore, there can be no fluid slip between the revolving blood and the revolving impeller. The new pump uses an impeller that is comparable to a flexible garden hose. If the free end of the hose were swung around in a circle like half of a jump rope, the fluid inside the hose would rotate and develop pressure even though the hose impeller itself did not "rotate"; therefore, no rotating shaft seal or internal bearings are required.     

Microspheres Based Detoxification System: A New Method in Convective Blood Purification

Abstract: A variety of protein-bound or hydrophobic substances, accumulating as a result of pathologic conditions such as exogenous or endogenous intoxications, are removed poorly by conventional detoxification methods because of low accessibility (hemodialysis), insufficient adsorption capabilities (hemosorption), low efficiency (peritoneal dialysis), or economic limitations (high-volume plasmapheresis). Combining advantages of existing methods with microspheric technology, a module-based system was designed. Major operating parameters of the latter can be modified to allow for adjustment to individual clinical situations. An extracorporeal blood circuit including a plasmafilter is combined with a secondary high-velocity plasma circuit driven by a centrifugal pump. Different microspheric adsorbers can be combined in one circuit or applied in sequence. Thus, a prolonged treatment can be tailored using specially designed selective adsorber materials. Comparing this system with existing methods (high-flux hemodialysis, molecular adsorbent recycling system), results from our in vitro studies and animal experiments demonstrate the superior efficiency of substance removal.     

Tissue perfusion in relation to cardiac output during continuous positive-pressure ventilation and administration of propranolol or verapamil

Background : Our objective was to determine whether administration of propranolol or verapamil modifies the hemodynamic adaptation to continuous positive-pressure ventilation (CPPV), in particular the regional distribution of cardiac output (CO).
Methods : General hemodynamics and regional blood flows assessed by microsphere technique (15 (μm) were recorded in 16 anesthetized pigs during spontaneous breathing (SB) and CPPV with 8 cm H₂O end-expiratory pressure (CPPV8) before and after intravenous administration of propranolol (0.3 mg · kg⁻¹ followed by 0.15 mg · kg⁻¹ · h⁻¹, n=8) or verapamil (0.1 mg · kg⁻¹ followed by 0.3 mg · kg⁻¹ · h⁻¹, n=8).
Results : CPPV8 depressed CO by 25% without shifts in its relative distribution with the exception of a noteworthy increase in adrenal perfusion. Propranolol increased arterial blood pressure, and due to a fall in heart rate, CO dropped by 25%. The kidneys and, to a lesser extent, the splanchic region and central nervous system received increased fractions of the remaining CO at the expense of skeletal muscle flow. Similar patterns were seen during SB and CPPV8 such that the combination of propranolol and CPPV8 depressed CO by 50%. The circulatory effects of verapamil were less evident but myocardial perfusion tended to increase.
Conclusions : The combination of propranolol or verapamil with CPPV does not result in any specific hemodynamic interaction in anesthetized pigs, except that the combined effect of propranolol and CPPV may severely reduce CO.     

Volatile anaesthetics reduce adhesion of blood platelets under low-flow conditions in the coronary system of isolated guinea pig hearts

Background : Inhibitory effects of volatile anaesthetics on platelet aggregation have been demonstrated in several studies. However, the influence of volatile anaesthetics on intracoronary platelet adhesion has not been elucidated so far.
Methods : Isolated hearts of guinea pigs were perfused with buffer in the absence or presence of volatile anaesthetics (0.5 and 1 MAC) at constant coronary flow rates of 5 ml/min for 25 min, then 1 ml/min for 30 min and again 5 ml/min for 10 min. Before, during and after low-flow perfusion, a bolus of human platelets was applied into the coronary system. To simulate thrombogenic conditions, 0.3 U/ml human thrombin was infused during low-flow perfusion and reperfusion. The number of platelets sequestered to the endothelium was calculated from the difference between coronary in- and output of platelets. The myocardial production of lactate and consumption of pyruvate and coronary perfusion pressure were also determined.
Results : At a flow rate of 5 ml/min only about 3% of the applied platelets did not emerge from the coronary system, in any group. In contrast, 13.1±1.2% (mean±SEM) of infused platelets became adherent in low-flow perfusion in the control group without anaesthetic. The adherence was reduced with each 1 MAC isoflurane (to 6.2±1.2%), sevoflurane (to 4.4±0.9%) or halothane (to 3.2±1.5%) (each P <0.05 vs. control). Volatile anaesthetic, 0.5 MAC, did not inhibit platelet adhesion to a statistically significant extent in any case. Perfusion pressure and metabolic parameters were not statistically different between the control and the hearts exposed to anaesthetics.
Conclusion : Volatile anaesthetics in a concentration of 1 MAC can reduce the adhesion of platelets in the coronary system under reduced flow conditions. This action does not arise from vasodilation or inhibition of ischaemic stress.     

Bariatric Surgery in Some "Central and East-European (former Eastern bloc)"Countries - Current Status and Prediction for the Next Millennium

Background: Obesity is increasing globallly, including in the formerly "Eastern Bloc" countries. Methods: A survey was made of obesity and bariatric surgery. Results: In the 8 East and Central European countries studied, with total population 300 million, roughly 43% of the population was overweight (BMI 25-30), 23% obese (BMI > 30), with about 15 million people morbidly obese (BMI > 40). From 0-10 morbidly obese individuals/100,000/year undergo bariatric surgery. Conclusion: Most countries were found to provide inadequate treatment for obesity.The majority of the morbidly obese are not treated effectively. However, health-care awareness of obesity and bariatric surgeons are slowly increasing.     

Is the recovery profile of mivacurium independent of the rate of decay of its plasma concentration in patients with normal plasma cholinesterase activity?

Background: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. Methods: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg . kg^?1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg . kg^?1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg . kg^?1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. Results: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). Conclusion: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.     

Membranes in Artificial Organs

Abstract: Membrane processes play a pivotal and enabling role in modern replacement therapy for acute and chronic organ failure and in the management of immunologic diseases. In fact, virtually all contemporary extracorporeal blood purification methods employ membrane devices, and the next generation of artificial organs and tissue engineering therapies are almost certain to be similarly grounded in membrane technology. In this short essay, we comment on the similarities and differences among synthetic membranes and their natural counterparts and also provide a critical overview of the demographics and technology of hemodialysis, hemofiltration, apheresis, oxygenation, and emerging membrane technologies and applications.     

Synergistic interaction between the effects of propofol and midazolam with fentanyl on phrenic nerve activity in rabbits

Background: It has been shown that the depressive effects of both propofol and midazolam on consciousness are synergistic with opioids, but the nature of their interactions on other physiological systems, e. g. respiration, has not been fully investigated. The present study examined the effect of propofol and midazolam alone and in combination with fentanyl on phrenic nerve activity (PNA) and whether such interactions are additive or synergistic. Methods: PNA was recorded in 27 anaesthetised and artificially ventilated rabbits. In three groups, propofol, fentanyl and midazolam were administered intravenously in incremental doses to construct dose-response curves for the depressant effects of each one on PNA. In another two groups, the effect of pretreatment with either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. on the effects of propofol and fentanyl respectively on PNA were studied. Results: Propofol and fentanyl caused a dose-dependent depression of PNA with complete abolition at the highest total doses of 16 mg · kg^?1 i. v. and 32 μg · kg^?1 i. v., respectively. In contrast, midazolam in incremental doses to a total of 0.8 mg · kg^?1 reduced mean PNA by 63%, but approximately 12% of PNA remained at a total dose as high as 6.4 mg · kg^?1. The mean ED₅₀s, calculated from dose-response curves, were 5.4 mg · kg^?1, 3.9 μg · kg^?1 and 0.4 mg · kg^?1 for propofol, fentanyl and midazolam, respectively. Initial doses of either fentanyl 1 μg · kg^?1 i. v. or midazolam 0.05 mg · kg^?1 i. v. acted synergistically with subsequent doses of either propofol or fentanyl to abolish PNA at total doses of 8 mg · kg^?1 and 8 μg · kg^?1, respectively. Conclusion: Fentanyl has a synergistic interaction with both propofol and midazolam on PNA and hence potentially on respiration.