维生素D研究的新趋势——维生素D免疫学

本文作者概述了维生素D免疫学的三个发展阶段。发现免疫细胞存在维生素D受体和活化的巨噬细胞可以将25(OH)D，羟化为1，25(OH)2D3；在整体动物身上证明维生素D缺乏和药理剂量的维生素D激素抑制T细胞调节免疫；用维生素D激素预防和治疗自身免疫性疾病和抑制器官移植排斥反应。本文作者特别介绍了维生素D激素及其类似物在预防和治疗实验性自身免疫性脑脊髓炎(EAE)，胰岛素依赖性糖尿病(IDDM)和类风湿性关节炎(RA)等自身免疫性疾病和抑制器官移植排斥反应方面的进展，以及1，25(OH)2D3对细胞因子生成的调控。最后简述了自身免疫性疾病光免疫流行病学的启示。     

G蛋白偶联雌激素受体在免疫调节中作用的研究进展

近年来研究发现,G蛋白偶联雌激素受体（GPER）不同于传统的核受体,是第三种独立作用的雌激素受体,它属于七次跨膜的G蛋白偶联受体（GPCR）家族成员。雌激素通过GPER介导G蛋白信号通路活化从而在正常生理及多种异常疾病中扮演重要角色,包括癌症、心血管疾病和炎症性疾病等。GPER表达于多种免疫细胞中,通过增强免疫细胞活性或调节免疫细胞之间的互动从而在免疫反应中发挥作用。同样,GPER还可参与炎症因子相关基因的表达从而抑制炎症反应。近期研究进一步揭示GPER不仅参与正常免疫系统的维持、异常免疫性疾病及炎症性病变,而且在肿瘤免疫调节中或有重要价值。笔者研究团队前期在多种恶性肿瘤中证实GPER介导的下游信号通路及其生物学功能,并发现GPER在乳腺癌和肝癌的肿瘤微环境中可能通过能量代谢重塑调节肿瘤免疫,以及血液肿瘤免疫治疗中靶向GPER有协同抗肿瘤药物的正向作用。综合现有研究发现,GPER可通过多样化的调节方式参与多种癌症的肿瘤免疫过程,包括乳腺癌中GPER通过调节免疫检查点分子的表达影响肿瘤免疫逃逸;肝癌中GPER调节免疫微环境和免疫细胞浸润,增加细胞因子和趋化因子的产生影响肿瘤免疫调节;结直肠癌中GPER增强免疫细胞的抗肿瘤活性和促进免疫细胞的细胞毒杀伤能力;血液肿瘤中GPER影响不同免疫细胞之间的“交叉对话”增强抗肿瘤免疫治疗等。因此,GPER为免疫相关疾病的治疗发展提供了新的途径,尽管目前尚处于探索阶段,但GPER作为新靶点联合免疫检查点抑制剂等药物的研发充满了临床潜力。本文综述当前GPER相关免疫调节作用的研究进展,为相关的基础与临床研究提供参考。     

1,25-二羟维生素D3的免疫调节作用与肾脏病的研究进展

1,25-二羟维生素D3[1,25-dihydmxyvitamin D3,1,25-(OH)2D3]是维生素D3的活性形式,是第二甾体类激素,它除了调节机体的钙和骨代谢外,还参与免疫系统的分化与调节.1,25-(OH)2D3是通过与它的特定受体-维生素D受体(vitamin D receptor,VDR)相互作用来实现它的大部分基因效应的,抗原提呈细胞和T细胞是它作用的靶细胞,它的作用主要是诱导产生基因耐受性树突状细胞,抑制具有致病作用的T淋巴细胞,促进调节性T细胞(regulatory T cells,Treg)的增生.研究证实,1,25-( OH)2D3对多种自身免疫性疾病均有免疫调节作用,本文着重探讨其在肾脏病中的免疫调节作用.     

1，25-二羟基维生素D3对炎性肠病的免疫调节作用

1，25-二羟基维生素D3[1，25-（OH）2D3]是维生素D（Vitamin D，VD）的活性形式，除了具有调节钙和骨新陈代谢的功能外．还对许多类型细胞的生长和分化有重要的影响。1，25-（OH）2D3的生物学效应是VD受体（VD recepton，VDR）介导的。该受体是核受体家族成员之一，1，25-（OH）2D3作为配体与之结合导致VDR构象的改变，     

国外期刊摘译

前列腺特异性抗原（PSA）速率阈值可用来预测年轻男性的前列腺癌；前列腺癌细胞N-myc下游基因1（NDRG1）及其与雄激素反应元件相互作用的蛋白质组学分析；肿瘤蛋白独立生长因子-1在抑制25-羟维生素D1α-羟化酶（CYP2781）中的作用：一项在前列腺癌和肾脏细胞的比较分析；前列腺衍生因子作为一种旁分泌和自分泌因子可促进雄激素受体阳性的人前列腺癌细胞增殖。     

1，25-二羟维生素D3及其类似物与慢性肾脏疾病

1,25-二羟维生素D3即活性维生素D3（1,25-dihydroxyvitamin D3,1,25-（OH）2D3）属于第二甾体类激素,其生物学作用主要包括调节钙磷代谢和骨的再建,调节细胞增生与分化以及免疫调节等。慢性肾脏疾病（chronic kidney disease,CKD）患者中广泛存在维生素D缺乏和继发性甲状旁腺机能亢进（secondary hyperparathyroidism,SHPT）,1,25-（OH）2D3及其类似物可以抑制甲状旁腺激素（parathyroid hormone,PTH）分泌,降低血PTH,改善心血管病变,增加CKD患者生存率。     

滑膜成纤维细胞与类风湿性关节炎相关研究的进展

类风湿性关节炎（rheumatoid arthritis，RA）是一种慢性起病的自身免疫性疾病，其病程最终转归往往导致关节破坏，其显著特点是由免疫细胞参与的自身免疫调节紊乱。长期以来，一直认为T细胞、巨嗜细胞及其各自的细胞因子在RA病程中起着关键作用，然而这一学说在近年来受到了强力的挑战，相当一部分学者认为在RA长期的病程中成纤维样细胞（fibroblast—like synoviocytes，FLS）起着主导的作用，这种作用甚至在疾病早期就已经体现出来，     

维生素D分子机制及其与成纤维生长因子23、Klotho 相关性的新进展

维生素D（ VD）的经典作用为调节钙磷和骨代谢,同时还与免疫系统、细胞增殖和分化等有重要联系。1α,25－羟基维生素D（1,25（OH）D）配体结合维生素D受体（VDR）引发VDR与维甲酸X受体（RXR）紧密结合,且配体结合的VDR－RXR异二聚体识别VD调控基因序列中的维生素D应答元件（VDREs）。虽然1,25（OH）D－VDR可通过非基因机制快速发挥作用,但1,25（OH）D－VDR主要通过基因机制实现功能。1,25（OH）D－VDR可控制基因转录,VD配体、VDRE的DNA序列以及招募的共激活因子／共阻遏因子都能影响基因表达。1,25（OH）D－VDR调节基因的VDREs具有重要功能。通过推测RANKL基因染色质成环模型表明DNA成环和染色质的结构在VD调节基因表达的作用中发挥主要作用。1,25（OH）D－VDR调节基因表达可以延缓衰老和老年性疾病,比如癌症、2型糖尿病和心血管疾病。针对VD在磷酸盐代谢与衰老方面的关系已有了新的认识,认为1,25（OH）D－VDR诱导的骨骼中FGF23和肾脏中Klotho蛋白在该代谢途径中发挥重要作用,VD调节磷酸盐稳态可能是延缓衰老及相关慢性疾病的机制。     

活性维生素D3及其类似物的足细胞保护作用研究进展

近年来研究发现1,25-二羟维生素D3（1,25-（OH）2D3）及其类似物具有独立于钙磷调节之外的许多功能,这些功能是结合细胞内维生素D受体（vitamin D receptor,VDR）后发挥作用的.而足细胞是维持肾小球功能的重要细胞,足细胞上表达VDR.因此1,25-（OH）2D3及其类似物与足细胞功能之间的相互关系值得探索.本文就近年来活性维生素D3及其类似物对足细胞的保护作用研究进展作一介绍.     

维生素D及其受体与雄性生殖

<正>一、维生素D及其受体(一)维生素D的来源及代谢维生素D主要来源于紫外线照射后皮肤中合成及食物摄取。维生素D在小肠吸收,经淋巴循环入血,循环至肝脏后,经25-羟化酶(由CYP2R1编码)作用变成25(OH)D。25(OH)D是循环中维生素D的主要形式,并认为是反映血清维生素D水平的可靠指标。25(OH)D再经肾脏1-α羟化酶(由CYP27B1编码)的作用生成有生物活性的代谢物1,25(OH)_2D_3,与外周靶细胞的维生素D受体结合,发挥多种生物活性作用。24-羟化酶(由CYP24A1编码)可使循环中各种     

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.     

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.     

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.     

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.