miR-146a介导TLR4/NF-κB信号通路延缓骨关节炎的作用及机制

骨关节炎（osteoarthritis, OA）作为慢性低度炎症性疾病，对它的研究一直是重点和难点，因此如何延缓OA的进展成为最主要的问题。miR-146a作为维持软骨稳态的关键调节因子，其表达的变化对软骨退变和炎症具有调节作用。Toll样受体4(toll-like receptor 4, TLR4)/核因子-κB(nuclear Factor-κB, NF-κB)信号通路通过调节免疫炎症反应，维持软骨代谢稳态。虽然miR-146a介导TLR4/NF-κB信号通路延缓OA已有研究，但是具体作用机制仍然不完善。本研究通过miR-146a介导TLR4/NF-κB信号通路对炎症及软骨细退变方面的综述，为OA的治疗提供理论依据和潜在分子靶标。     

HMGB1介导TLR4/NF⁃κB信号通路干预骨关节炎研究进展

骨关节炎(osteoarthritis, OA)作为临床常见老年退行性疾病，目前尚无有效治疗手段。研究发现OA是一种慢性低度炎性疾病。损伤相关分子模式HMGB1（high mobility group box-1）在OA病理过程中发挥中心分子作用。HMGB1与固有免疫模式识别受体TLR4(toll-like receptor 4, TLR4)结合后激活NF-κB信号通路导致OA软骨退变和滑膜炎等免疫炎症反应。通过综述HMGB1介导TLR4/NF-κB信号通路在OA发病机制中的作用，为靶向阻断HMGB1治疗OA提供理论依据和参考。     

线粒体质量控制在骨性关节炎软骨细胞的调控作用

软骨退变是骨性关节炎（osteoarthritis, OA）的核心特征，软骨细胞衰老及其介导的代谢失衡是软骨退变持续进展的重要原因。乙酰化/去乙酰化是线粒体质量控制（mitochondrial quality control, MQC）的关键机制之一，主要由去乙酰化酶（sirtuin, SIRT）介导。近年发现MQC失衡与OA软骨细胞衰老及软骨退变密切相关，而SIRT1/3在正常及OA软骨细胞中存在差异表达并参与OA软骨细胞MQC失衡及衰老调控。本文从SIRT1/3及细胞衰老角度对MQC在OA软骨细胞的调控作用做一综述，以期为后续OA发病机制及治疗策略探索整理思路和潜在靶点。     

氧化应激与骨关节炎

骨关节炎（osteoarthritis,OA）是一种在中老年人群中常见的缓慢进展的关节疾病,以关节软骨退变、磨损和骨赘生成为特征,与外伤、炎症、衰老、代谢和免疫等因素有关,但确切发病机制至今尚未明确。氧化应激（oxidative stress,OS）是自由基在体内产生的一种负面作用,并被认为是导致衰老和疾病的一个重要因素。最近研究表明,OS可能参与OA的病理过程,在其发生、发展中起重要作用。现就OS与OA的关系做综述。     

纤维连接蛋白降解产物对软骨破坏作用机制研究进展

软骨进行性破坏是骨关节炎(OA)和类风湿关节炎(RA)的重要特点之一,基质金属蛋白酶、一氧化氮、炎性细胞因子等均可造成软骨破坏。OA和RA中纤维连接蛋白降解产物(FN-f)在软骨破坏过程中发挥重要作用,其通过细胞表面特定受体如整合素、CD44等,结合至软骨细胞和滑膜成纤维细胞上,并通过这些受体激活丝裂原活化蛋白激酶、核因子-κB等细胞内的分解代谢信号传导通路,导致一系列软骨破坏性因素的出现。该文就FN-f引起的软骨破坏作用机制作一综述。     

Wnt信号通路对软骨和软骨下骨双靶向调控及其在骨关节炎进展中的作用

目的综述Wnt信号通路在骨关节炎(osteoarthritis,OA)发生发展中的活性变化,及其对软骨、软骨下骨的双靶向调控和两者间信息交流对OA进程的影响和机制。方法查阅近年在体内外实验研究及临床研究中,OA和非OA状态下Wnt信号通路对关节软骨、软骨下骨调控作用及软骨与软骨下骨间信息交流的相关文献,并对其作用机制进行分析总结。结果 Wnt信号可通过依赖β-catenin的经典或不依赖β-catenin的非经典Wnt信号通路及其与其他信号通路的交联,调控软骨细胞、成骨细胞的分化和功能,进而影响软骨及骨的代谢。过度激活Wnt信号可加重软骨OA样退变,并且Wnt信号通路可激活下游蛋白Wnt1诱导的信号通路蛋白1调控OA进展,还可通过软骨及软骨下骨中不同细胞间建立的缝隙连接,直接进行分子交流调控OA的发生发展。关节腔内注射Wnt信号通路抑制剂SM04690可以抑制OA进程;在成骨细胞中过表达Wnt信号通路抑制剂Dickkopf可以拮抗VEGF对软骨细胞的作用,并抑制其基质的分解代谢。结论 Wnt信号通路及其与其他信号分子的交互作用,可调控软骨和软骨下骨的代谢和功能及两者间信息交流,因此在OA的发生发展中发挥重要作用,有望成为OA治疗的新靶点。     

NF-κB信号通路在骨性关节炎发生发展中作用机制的研究

NF-κB( Nuclear Factor-κB)是广泛存在于真核细胞内的一个信号通路,它通过MAPKKK (Mitogen Activated Protein Kinase Kinase Kinase)或细胞膜受体级联激活,导致NIK( NF-κB inducing kinase-1)激活,进而活化IKK( IκB Kinase),磷酸化IκB(Inhibitory κB proteins),最终导致NF-κB向细胞核内转位指导目的基因表达.NF-κB在OA( Osteoarthritis)炎症反应及疾病发生发展过程中起到了至关重要的作用,最终导致软骨降解和关节损伤.NF-κB信号参与并调控软骨细胞的增殖、分化、凋亡,而NF-κB信号的失调在骨关节炎的发生、发展中扮演着十分重要的角色,这提示深入研究NF-κB信号在骨性关节炎发病机制中的确切作用将有助于骨性关节炎的靶向治疗,从而为骨性关节炎的治疗开辟更加广阔的前景.     

软骨细胞线粒体功能异常对骨关节炎发病机制的研究

骨关节炎(osteoarthritis, OA)主要是关节软骨退变导致的慢性炎症性关节疾病，病因及发病机制复杂，最新研究发现，软骨细胞中的线粒体功能异常与OA发病机制密切相关。线粒体通过调控软骨细胞衰老、凋亡、氧化应激、炎症抑制，参与OA发病进程。此外，线粒体相关信号通路AMPK/SIRT3对于调节软骨细胞的代谢过程很重要，表明这些可能是OA治疗的目标。因此，该文论述软骨细胞线粒体功能异常与OA的发病机制的相关性。     

血管内皮生长因子与骨关节炎

骨关节炎（OA）是最常见的关节退行性疾病,主要病理表现为滑膜炎症、关节软骨退行性破坏、软骨下骨硬化及骨赘形成,而主要由血管内皮生长因子（VBGF）介导的血管生成,则在OA病理变化中有着重要作用。该文就VEGF在OA中的作用及其研究进展作一综述。     

丹参酮IIA对胃癌细胞的抑制作用及其与NF-κB信号通路的关系

目的：探讨丹参酮IIA（tanshinone IIA）体外对人胃癌SGC7901细胞的作用及其对NF-κB信号通路的影响。 方法：不同浓度丹参酮IIA（0.5、1、2、4 μg/mL）作用SGC7901细胞不同时间（24、48、72 h）后,用MTT法检测细胞增殖情况。丹参酮IIA（2 μg/mL）作用SGC7901细胞48 h后,用流式细胞术检测细胞凋亡率;Western blot法检测NF-κB p65亚单位、IκB-α、磷酸化IκB-α、IKK-α/β、磷酸化IKK-α/β的水平;ELISA法检测p65亚单位的DNA结合活性。 结果：MTT结果显示,丹参酮IIA（1、2、4 μg/mL）明显抑制SGC7901细胞的增殖,并呈明显的时间与浓度依赖性（均P<0.05）;凋亡分析显示,丹参酮IIA处理组细胞凋亡率明显高于对照组（P<0.05）;NF-κB信号通路相关分子检测显示,与对照组比较,丹参酮IIA处理组细胞p65、IKK-β及其磷酸化蛋白水平明显下降（均P<0.05）,IκB-α水平无明显改变（P>0.05）,但其磷酸化蛋白水平明显降低（P<0.05）,而IKK-α及其磷酸化蛋白表达水平表达变化均不明显（均P>0.05）;NF-κB亚单位p65的DNA结合活性明显下降。 结论：丹参酮IIA可抑制人胃癌SGC7901细胞增殖并促进其凋亡,其机制可能是降低NF-κB信号通路的活性有关。     

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.