肾性骨病发病机制研究及进展

肾性骨病（renal osteopathy）,泛指继发于肾脏疾病的代谢性骨病,是慢性肾脏病晚期与血液透析患者的重要并发症。广义的肾性骨病是指一切和肾脏有关的骨病;狭义的肾病骨病也称肾性骨营养不良（ROD),即慢性肾脏病矿物质和骨代谢紊乱（CKD-MBD）,是慢性肾功能衰竭（CRF）时由于钙、磷及维生素D代谢障碍,继发甲状旁腺机能亢进,酸碱平衡紊乱等因素而引起的骨病。严重影响患者的生活质量。本文论述了肾性骨病的概念、肾性骨病的发病机制、肾性骨病的分型、与肾性骨病相关的分子通路、肾性骨病的治疗原则。旨在为临床肾性骨病的诊断、治疗提供参考。     

Wnt/β-catenin信号通路与肾性骨病

大量研究显示Wnt/β-catenin信号通路在肾性骨病发生发展中具有重要作用。本文从生理、病理两个层面综述了Wnt/β-catenin信号通路在肾骨调控中的作用。在生理状态下,Wnt/β-catenin信号通路不仅具有调节肾形成祖细胞自我更新与分化,进而形成足量的肾单位的作用,而且可以促进多能间充质干细胞分化成成骨细胞系,抑制其向软骨以及脂肪细胞系分化的同时抑制成骨细胞凋亡,延长其生命,促进骨形成,还可以通过调节OPG的表达抑制破骨细胞分化和骨吸收。当肾脏受损后,在SOST、DKK1、Vitamin D/VDR、FGF23/α-Klotho、PTH/PTH1R、TGF-β/BMPs等诸多因素直接或间接影响下,一方面骨细胞中Wnt/β-catenin信号表达异常,影响正常的骨形成与骨吸收,引起骨稳态失衡进而发生骨病,另一方面肾脏中Wnt/β-catenin信号的异常表达或加速或修复自身损伤,并进一步影响骨稳态。     

肾性骨病的研究进展

肾性骨病(renal osteodystrophy，ROD)可分为狭义肾性骨病与广义肾性骨病两类。前者又称肾性骨营养不良，是慢性肾衰竭伴随的代谢性疾病；后者是指一切和肾脏有关的骨病或病因与肾脏有关的骨病，如肾小管酸中毒伴发的软骨病、肾病综合征时发生的骨病、Fanconi综合征时的骨病等。本文主要介绍慢性肾衰竭时发生的骨病。该病以骨质疏松、骨软化、纤维性骨炎、软组织钙化、骨性佝偻病、骨硬化、骨滑脱、骨畸形、骨再生障碍和病理性骨折为临床特征，可以在慢性肾衰竭的任何阶段发生。     

miＲ 对骨质疏松骨代谢信号通路影响的研究进展

miＲ 在骨骼发育、代谢过程中具有重要的生物学功能,能够调控骨细胞生长、分化和功能表达。正常机体中,骨代谢相关信号通路对维持骨骼正常生物学功能意义重大,miＲ 通过与骨代谢相关的多种信号通路调节成骨细胞/破骨细胞代谢,达到有利于机体的平衡状态,如果 miＲ 表达失调这种稳态就会失衡,相关信号通路被激活,导致相应的骨代谢疾病,如骨质疏松症。信号通路作为调控骨代谢的重要途径,不同信号通路机制之间存在一定的联系,但是大多数信号通路的确切机制还不明了,各通路之间的相互联系研究较少,随着表观遗传学的发展,miＲ 通过相关信号通路精密调控骨代谢的机制被逐步阐明。miＲ 与多种骨质疏松多种信号通路存在密切的关系,成为潜在的检测标志物和治疗靶向点。研究 miＲ 参与调控骨质疏松骨代谢相关信号通路的机制,在骨质疏松的预防、诊治及预后意义重大。本文将从三个方面对近年来 miＲ 对骨质疏松症骨代谢相关信号通路的研究作以概述。     

miR对骨质疏松骨代谢信号通路影响的研究进展

miR在骨骼发育、代谢过程中具有重要的生物学功能,能够调控骨细胞生长、分化和功能表达。正常机体中,骨代谢相关信号通路对维持骨骼正常生物学功能意义重大,miR通过与骨代谢相关的多种信号通路调节成骨细胞/破骨细胞代谢,达到有利于机体的平衡状态,如果miR表达失调这种稳态就会失衡,相关信号通路被激活,导致相应的骨代谢疾病,如骨质疏松症。信号通路作为调控骨代谢的重要途径,不同信号通路机制之间存在一定的联系,但是大多数信号通路的确切机制还不明了,各通路之间的相互联系研究较少,随着表观遗传学的发展,miR通过相关信号通路精密调控骨代谢的机制被逐步阐明。miR与多种骨质疏松多种信号通路存在密切的关系,成为潜在的检测标志物和治疗靶向点。研究miR参与调控骨质疏松骨代谢相关信号通路的机制,在骨质疏松的预防、诊治及预后意义重大。本文将从三个方面对近年来miR对骨质疏松症骨代谢相关信号通路的研究作以概述。     

激素性骨质疏松症发病机制的研究进展

激素性骨质疏松症是临床使用糖皮质激素后常见的副作用,对于激素性骨质疏松的发病机制,从信号通路的层面研究来看,糖皮质激素可以通过抑制骨形成的Wnt/β-catenin、BMPs等信号通路和促进骨吸收的OPG/RANKL/RANK等信号通路引起骨质疏松。近年来对自噬通路和非编码RNA等通路调节因子的研究发现其对激素性骨质疏松的形成有着重要的作用,而且部分通路间的交联反应也被证实是激素性骨质疏松发生的介导因素,这为激素性骨质疏松发病机制的研究提供了新的方向。但是,我们目前的研究层面很可能只是这个复杂的调控网络中的冰山一角,许多通路和调节因子的研究仍处于起步阶段,具体机制很多未完全阐明,仍需要更多的基础和临床实验去完善这个调控网络。本文拟对激素性骨质疏松的发病信号通路及相关通路调节因子研究现状进行综述,为该疾病的靶向治疗提供新的研究方向。     

慢性肾衰竭与肾性骨病

肾性骨病的定义分为狭义肾性骨病和广义肾性骨病。狭义肾性骨病是指慢性肾衰竭伴发代谢性骨病。广义肾性骨病是指和肾脏相关的疾病。近 30年来 ,由于血液净化技术的开展和发展 ,尿毒症患者的生命得到延长 ,但肾性骨病未有减少 ,且由于透析因素的参与 ,铝中毒而致的骨骼变化 ,透析膜生物相容性导致的骨、关节病变 ,使慢性肾衰竭肾病的概念更有扩大与深化 ,它已成为慢性肾衰竭和透析领域的主要问题之一。慢性肾衰竭尿毒症 (Ｓｃｒ >445 μｍｏｌ/Ｌ ,ＢＵＮ >2 0ｍｍｏｌ/Ｌ ,Ｃｃｒ >2 5ｍｌ/ｍｉｎ)骨病的发生率甚高 ,尤其是维持性透析患者…     

Hedgehog信号通路调控骨形成及BMSCs成骨分化的研究进展

目的综述Hedgehog信号通路对骨形成及BMSCs成骨分化的调控及其分子机制。方法查阅近年来Hedgehog通路在体内、体外及离体研究中对骨形成及BMSCs成骨分化调控的相关文献,并对其作用机制进行分析总结。结果 Hedgehog信号通路在体外研究中可通过激活下游关键分子Smoothened(Smo)及Gli1促进BMSCs成骨分化,并可通过IGF激活m TORC2-Akt信号产生类似作用;Hedgehog信号特殊结构鞭毛内运输蛋白80通过激活经典Hh-Smo-Ptch1-Gli信号、抑制非经典Hh-Gαi-Rho A应力纤维信号,调节成骨细胞的分化;应用新型Hedgehog信号激动剂Oxy133可激活Hedgehog信号。Hedgehog信号还可协同BMP及Wnt信号通路调控成骨关键分子Runx2促进细胞的成骨分化和基质矿化,并在体内研究及骨移植模型中促进骨形成及骨缺损修复愈合。结论 Hedgehog信号通路通过对自身或对其他信号及关键分子的调节对骨形成及BMSCs成骨分化进行调控,对Hedgehog信号进行靶向调控或可作为治疗某些骨相关疾病(如骨质疏松症和骨折愈合)的潜在研究方向及新靶点。     

基于Wnt／β-catenin信号通路的中医药干预骨关节炎的研究进展

骨关节炎是老年人最常见的骨病之一,该病的发病机制尚不明确,除手术外无有效治疗手段。目前Wnt/β-catenin信号通路与骨关节炎已成为研究热点,近年来中医药调控Wnt/β-catenin信号通路干预骨关节炎的研究取得较大进展。作者通过查阅CNKI、维普和PUBMED数据库近10年的国内外相关文献,总结了中医药调控Wnt/β-catenin信号通路干预骨关节炎的研究进展,分析这些研究中存在的问题,以期进一步阐明中医药如何通过调控Wnt/β-catenin信号通路干预骨关节炎的分子机制,发掘中医药防治骨关节炎的潜在价值。     

Notch和TGF信号通路对话在肾间质纤维化的研究

肾间质纤维化是许多慢性肾脏疾病发展过程中的必经阶段,信号通路调控多种功能基因的转录和参与许多重要的生理病理过程,信号通路在肾间质纤维化发生、发展过程中发挥着重要作用,其中TGF和Notch信号通路均参与肾纤维化的发生、发展,通过干预TGF和Notch信号通路可延缓肾间质纤维化的进展。研究表明,TGF信号通路与Notch信号通路既独立发挥作用,又存在对话间相互作用。既调控各信号通路组分的活性,又调控共同下游靶基因和表达产物,由此调节肾间质纤维化的发生、发展。因此,进一步研究两条通路的关系可能为抗肾纤维化研究提供新切入点。     

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 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.     

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.     

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.     

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.     

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.     

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.     

Influence of dopexamine hydrochloride on haemodynamics and regulators of circulation in patients undergoing major abdominal surgery

Background: Catecholaminergic support is often used to improve haemodynamics in patients undergoing major abdominal surgery. Dopexamine is a synthetic vasoactive catecholamine with beneficial microcirculatory properties. Methods: The influence of perioperative administration of dopexamine on cardiorespiratory data and important regulators of macro- and microcirculation were studied in 30 patients undergoing Whipple pancreaticduodenectomy. The patients received randomized and blinded either 2 μg · kg^?1 · min^?1 of dopexamine (n=15) or placebo (n=15, control group). The infusion was started after induction of anaesthesia and continued until the morning of the first postoperative day. Endothelin-1 (ET-1), vasopressin, atrial natriuretic peptide (ANP), and catecholamine plasma levels were measured from arterial blood samples. Measurements were carried out after induction of anaesthesia, 2 h after onset of surgery, at the end of surgery, 2 h after surgery, and on the morning of the first postoperative day. Results: Cardiac index (CI) increased significantly in the dopexamine group (from 2.61±0.41 to 4.57±0.78 1 · min^?1 · m^?2) and remained elevated until the morning of the first postoperative day. Oxygen delivery index (DO₂I) and oxygen consumption index (VO₂I) were also significantly increased in the dopexamine group (DO₂I: from 416±91 to 717±110 ml/m² · m²; VO₂I: from 98±25 to 157±22 ml/m² · m²), being significantly higher than in the control group. pHi remained stable only in the dopexamine patients, indicating adequate splanchnic perfusion. Vasopressive regulators of circulation increased significantly only in the untreated control patients (vasopressin: from 4.37±1.1 to 35.9±12.1 pg/ml; ET-1: from 2.88±0.91 to 6.91±1.20 pg/ml). Conclusion: Patients undergoing major abdominal surgery may profit from prophylactic perioperative administration of dopexamine hydrochloride in the form of improved haemodynamics and oxygenation as well as beneficial influence on important regulators of organ blood flow.     

Systemic analgesia adapted to the children's condition

A concept of balanced analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), opioids, and corticosteroids can also be used in patients with pre-existing illnesses. NSAIDs are the most effective treatment for acute pain of moderate intensity in children; however, these drugs should be avoided in patients at increased risk for serious side effects, e.g. patients with renal impairment, bleeding tendency, or extreme prematurity. NSAIDs can be given with minimal risks to the younger child with mild to moderate asthma, and, in these patients, the use of steroids can be encouraged; in addition to their antiemetic and analgesic action, a beneficial effect on asthma symptoms can be expected. In the non-intubated child with cerebral trauma, exaggerated sedation caused by opioids and increased bleeding tendency caused by NSAIDs must be avoided. In neonates and small infants, the oral administration of sucrose or glucose is helpful to minimize pain reaction during short uncomfortable interventions.