The Clinical Value of Detection of TNF-α、IL-6 and IL-17 in Premature Ruptureof Membranes with Adverse Pregnancy Outcomes Associated with Maternal and Fetal Infection
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摘要:
目的 探讨母血、脐血血清中TNF-α、IL-6、IL-17表达水平在胎膜早破(premature rupture of membranes,PROM)合并绒毛膜羊膜炎(chorioamnionitis,CS)及PROM新生儿围产期感染中的临床意义。 方法 51例因胎膜早破至昆明医科大学第一附属医院产科住院的孕妇为PROM组,同期20例正常分娩孕妇为对照组。采用ELISA法检测母血、脐血血清TNF-α、IL-6、IL-17水平。再次将PROM组分为PROM无CS组和PROM合并CS组,PROM无新生儿围产期感染组(A1)和PROM新生儿围产期感染组(A2);比较母血、脐血中3项指标在不同分组中的表达水平,ROC曲线分析三项指标预测胎膜早破母儿感染相关不良妊娠结局的价值。 结果 (1)PROM合并CS组母血、脐血血清TNF-α、IL-6表达水平显著高于PROM无CS组和对照组(P < 0.05);PROM无CS组母血TNF-α、脐血IL-6的表达水平显著高于对照组(P < 0.05);(2)A2组母血、脐血血清TNF-α、IL-6和IL-17表达水平均显著高于A1组和对照组(P < 0.05);A1组母血TNF-α、脐血IL-6的表达水平显著高于对照组(P < 0.05);(3)母血、脐血血清TNF-α、IL-6、IL-17表达水平互呈显著正相关(P < 0.001);(4)诊断PROM合并CS时,单项检测母血TNF-α的曲线下面积(Area under the curve,AUC)最大(0.763),母血TNF-α的AUC高于脐血TNF-α(0.614)(P < 0.05);联合母血+脐血TNF-α+IL-6 4项指标诊断PROM合并CS的AUC(0.820)显著高于脐血TNF-α单项指标的AUC值(0.614)(P < 0.05);(5)诊断PROM新生儿围产期感染时,单项检测时母血中IL-6的AUC最大(0.800),脐血中IL-17的AUC最大(0.829),脐血IL-17的AUC高于母血IL-17(0.735)(P < 0.05);联合脐血IL-6+IL-17 2项指标或联合脐血TNF-α+ IL-6+ IL-17 3项指标诊断PROM发生新生儿围产期感染的诊断效果较好(AUC:0.863、0.866)。 结论 母血、脐血TNF-α、IL-6、IL-17是预测PROM母儿感染相关不良妊娠结局的重要指标,联合检测效果较好。临床工作中若考虑脐血检测的局限性,仅检测母血以上细因子也有较好的临床运用价值。 Abstract:Objective To investigate the clinical value of expression levels of TNF- α、IL-6、IL-17 in the maternal serum and umbilical cord serum in the premature rupture of membranes (PROM) with chorioamnionitis (CS) and PROM with the neonatal infection during the perinatal period. Methods 51 patients with the premature rupture of membrane who had been admitted to the Obstetrics Department of the First Affiliated Hospital of Kunming Medical University were enrolled as PROM group. At the same time, 20 normal maternities delivered in this hospital were adopted to the control group. Double antibody sandwich ELISA was used to detect the expression levels of TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum. After that, the PROM group was regrouped into PROM with CS group and PROM without CS group, PROM without the neonatal infection during the perinatal (group A1) and PROM with the neonatal infection during perinatal (group A2). Comparing the expression levels of these three indicators in the maternal serum and umbilical cord serum of different groups and using ROC curve to analyze the value of these indexes above in predicting the premature ruptured of membranes with adverse pregnancy outcomes associated with maternal and fetal infection. Result (1) The levels of TNF-α and IL-6 in the maternal serum and umbilical cord serum in PROM with CS group were statistically higher than those in PROM without CS group and the control group (P < 0.05). The levels of TNF-α in the maternal serum and the levels of IL-6 in the umbilical cord serum in the PROM without CS group were statistically higher than those in the control group (P < 0.05). (2) Expression levels of TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum of A2 group were statistically higher than those of A1 group and the control group (P < 0.05). The levels of TNF-α in the maternal serum and the levels of IL-6 in the umbilical cord serum of A1 group were significantly higher than those of the control group (P < 0.05). (3) The expression level of TNF-α、IL-6 and IL-17 in the maternal serum and in the umbilical cord serum were significantly positively correlated (P < 0.001). (4) In the diagnosis of PROM with CS, TNF-α in the maternal serum was of the biggest area under the curve (AUC) among all single index (0.763). The AUC of TNF-α in the maternal serum was bigger than that in the umbilical cord serum (0.614)(P < 0.05). When four indexes were used in combination, the AUC of TNF-α+IL-6 in the maternal serum combined with TNF-α+IL-6 in the umbilical cord serum (0.820) was bigger than that of single detection of TNF-α in the umbilical cord serum (0.614)(P < 0.05). (5) In the diagnosis of PROM with the neonatal infection during perinatal, IL-6 was of the biggest AUC among all single index in the maternal serum (0.800) and IL-17 was of the biggest AUC among all single index in the umbilical cord serum (0.829). The AUC of IL-17 in the umbilical cord serum was bigger than that in the maternal serum (0.735)(P < 0.05). Two indexes combined of IL-6+ IL-17 or Three indexes combined of TNF-α+ IL-6+ IL-17 in the umbilical cord serum was of great diagnostic value (AUC: 0.863、0.866). Conclusion TNF-α, IL-6 and IL-17 in the maternal serum and umbilical cord serum are of great predictive value for predicting PROM with CS and PROM with the neonatal infection during the perinatal period. The diagnostic value of joint detection is better. In clinical work, detection of the three indexes in the maternal serum also has a good value of the clinical application when collecting of the umbilical cord serum is limited. -
计算机辅助设计(computer aided design,CAD)和计算机辅助制造(computer aided manufacturing,CAM)是20世纪60年代快速发展起来的新生的综合性计算机应用技术,它是以计算机作为主要技术手段,处理各种数字信息和图形信息,辅助完成产品设计和制造中的各项活动。20世纪80年代,CAD/CAM技术引入口腔领域,促进了口腔医学的发展和进步,在就诊便捷性和流程规范性等方面有明显优势[1-2]。
口腔数字化技术的进步也不断改变着口腔医生的工作方式[3]。数字化技术在口腔科中最显着的好处之一是能够简化复杂的流程,减少患者预约,以及临床手术和实验室时间,并在不影响临床结果的情况下减少制造步骤[4−6],优化工作流程、提高工作效率[7−8]。同时CAD/CAM修复材料具有许多优点,如材料质量稳定,成本较低和节省时间等[9] ,这使得CAD/CAM修复材料得到广泛使用。本文将从CAD/CAM在嵌体、全冠、活动义齿、种植义齿及固定桥5种修复方式中的应用进行描述,从而概述CAD/CAM在口腔修复中的应用进展。
1. 嵌体
嵌体(Inlay)是1种嵌入患牙内部,用以恢复缺损牙体形态和功能的修复体。如果嵌体部分嵌入牙冠内、部分高于牙面则命名为高嵌体(Onlay)。研究表明[10],高嵌体可良好的修复牙齿缺损,得到极佳的修复效果。Metiner等[11]对数字印模制造嵌体和传统印模制造的嵌体进行了长达12个月的研究,随访结果表明用数字印模制造的嵌体修复体是传统嵌体修复的可靠替代品。嵌体修复后5 a,嵌体和牙冠的平均保存率分别为93.50%和95.38%[12−13]。 Tunac等[14−15]在经过2 a评估后得出结论:CAD/CAM树脂复合嵌体可以成功用于后牙II类洞修复,且失败率极低,随访结果也显示出高保存率。CAD/CAM高嵌体在修复根管治疗后磨牙大面积缺损的临床应用中各方面表现良好,患者满意度高,值得临床推广[16−17]。用CAD/CAM进行嵌体修复时,对医生技术有较高要求,收费也偏高。
2. 全冠
在口腔修复中最多见的1种修复体是全冠,它包绕了整个牙冠,修复缺损牙体,恢复牙齿功能。良好的边缘密合度是全冠修复的基础,修复体与自身牙体的紧密贴合也是我们希望达到的效果。研究表明[18],通过口内扫描仪(intraoral scanners,IOS)获得的CAD/CAM制造修复体比通过传统印模和随后实验室扫描获得的修复体显示出更好的边缘和内部贴合。直接数字工作流程是间接数字工作流程的有效替代方案,用于生产CAD/CAM全陶瓷修复体。口外扫描仪的类型也会影响CAD/CAM制造的牙冠的边缘密合,但它对牙冠与牙体的内部契合度没有显著影响[19]。CAD/CAM 技术可以增强陶瓷材料在口腔中应用,从而提高修复体的生物相容性,满足患者的美学需求[20]。另有研究表明[21],通过CAD/CAM制造的陶瓷全冠寿命低于传统制造的全冠。这可能与陶瓷的类型及其特性有关,关于CAD/CAM在全冠中的应用还有待进一步研究。此外,CAD/CAM行全冠修复对口腔技师有较高要求[22],经验不足、缺乏对材料的了解、数字技术等原因都能造成修复体临床并发症[23]。
3. 可摘局部义齿
可摘局部义齿(removable partial dentures,RPD)是1种患者可以自行摘戴的用于部分牙缺失(牙列缺损)的修复体。由于预期寿命的增加以及人口老龄化,无牙颌种群正在增加。越来越多的老年人要求保留更多牙齿。因此,对RPD治疗的需求将升高,这样的需求还将持续到将来[24]。
传统制造RPD是1个复杂、容易出错、耗时且昂贵的过程。使用CAD/CAM技术,可以快速原型制作,有望成为制造RPD支架的更有效方法[25]。1994年,首次尝试开发CAD/CAM系统来制造完整的RPD修复体[26]。随着当前数字化口腔的创新和发展,CAD/CAM技术制造已能成功地运用于RPD的修复[27]。传统制造的RPD可能非常耗时,并且它们的不贴合已被确定为RPD使用者的主要诉求之一[28]。与传统RPD相比,使用CAD/CAM支架和聚甲基丙烯酸甲酯(polymethyl methacrylate,PMMA)光盘进行数字RPD具有许多优势,它可以进行更准确的RPD支架设计,从而提高贴合度。RPD的贴合度越好,RPD就越舒适和实用。此外,使用计算机化技术可以减少RPD的制作时间,使其比传统技术更快地给患者使用[29]。与传统制造的RPD支架相比,通过CAD/CAM和快速原型技术制造的RPD支架具有临床可接受的拟合度,更高的精度和更好的准确性。但是支架和义齿基底之间粘合的准确性和耐用性的技术仍有待解决。在数字化制造中,人为因素也会影响支架的质量[30]。全数字化RPD可以在没有石膏确定铸件的情况下制造,但全数字RPD的指征仅限于肯氏III/IV类部分牙列缺失的病例[31]。数字印模采集和上颌骨关系记录的困难仍有待解决,需要扩展修复的适应症[32]。
4. 种植义齿
种植义齿(implant denture)是由牙种植体及其支持的上部结构组成的修复体。
CAD/CAM的引入使临床医生能够使用更便宜的材料和更快的制造程序,提高了义齿修复治疗的效率[33]。口内扫描在单种植体和多种植体修复体中都表现出很高的准确性[34]。IOS数字扫描的准确性与传统的印模技术相比,在单基台或双基台印模时,口内数字扫描具有更高的效率。患者对口内数字扫描的满意度和偏好优于接受传统印模手术的患者[35]。Pesce等[36]通过体外研究,提出数字印模可能可以成为1种可靠的方法,用于在存在倾斜植入物时制作具有良好被动配合的全牙弓植入物支架。李瑾等[37]通过比较上颌前牙缺失后行常规即刻种植修复术和联合应用CAD/CAM牙种植导板进行即刻种植修复术的术前术后咀嚼效率、言语功能及美学效果等指标,提出CAD/CAM牙种植导板联合应用在上颌前牙即刻种植术中能增强修复的精确性、提高咀嚼效率及改善牙周环境。种植导板良好的固位力是提高手术精确度的前提,这对技师的要求较高[38]。
通常情况下,为获得良好的骨支持,上颌窦底至牙槽嵴要有足够的距离,反之则会选择行上颌窦底提升术来处理骨量不足的问题,进行上颌窦底提升术时,应选择“最佳选择”—CAD/CAM引导的设计,因为它减少了组之间和组内所选参数的差异。这有助于没有足够的种植手术经验的口腔医生取得更好的种植效果[39]。Yeung等[40]还将现有的设计原则和CAD/CAM材料相结合,制作出1种金属丙烯酸树脂,最大限度地减少了单个牙齿断裂,并促进了磨损表面的有效表面修复。
CAD/CAM牙种植导板引导下的牙种植手术治疗效果高于常规牙种植手术,可有效改善咀嚼功能。CAD/CAM引入种植义齿修复,需要医生和技师的高度配合,以保证手术的精确性。
5. 固定桥
固定桥用于修复牙列中1个或几个缺失牙,通过粘接剂或固定装置与缺牙2侧预备好的基牙或种植体连接成一体,恢复缺失牙的形态和功能。将CAD/CAM技术整合到完整的义齿设计和制造中,简化了临床和加工厂的流程,并改善了义齿的物理特性,提高了义齿质量[41]。CAD/CAM 系统能够生产可重复制作且边缘间隙小的固定桥[42]。与传统方法和其他合金制成的结构相比,由CAD/CAM技术制成的锆基修复体在边缘贴合、减少炎症、良好维护以及牙周健康等方面展现了更好的临床效果[43]。
6. 小结
综上所述,CAD/CAM在嵌体、全冠、活动义齿、种植义齿及固定桥五种修复方式中应用广泛。CAD/CAM的应用增加了修复体的精密度、准确度,减少临床诊治时间和就诊次数,数字存档可显著提高数据保留率,更有利于以患者为中心的治疗和临床修复后随访。CAD/CAM制作的修复义齿在强度、刚度及耐腐蚀性等方面具有优势,提升了义齿与牙体之间的贴合度,增加了义齿的韧性、极限弯曲强度和更高的弹性模量等[44]。除此之外,CAD/CAM还可应用于过渡粘接中以恢复咬合[45]。虽然CAD/CAM技术还存在部分如初始成本高的局限性[46],但其给口腔修复带来的诸多优点不容小觑。未来,CAD/CAM将更加广泛的应用于口腔修复,促进口腔修复的迅猛发展。
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表 1 研究对象临床资料比较(
$ \bar{x}\pm s $ )Table 1. Comparation of clinical information between study objects (
$ \bar{x}\pm s $ )组别 例数 产妇
年龄(岁)孕次
(次)孕前BMI
[kg/m2]孕期增重
(kg)入院体温
(℃)Apgar评分($ \bar{x} $ ± s) 新生儿脐动脉PH值
($ \bar{x} $ ± s)1 min 5 min 对照组 20 29.20 ± 4.82 2.45 ± 1.39 20.71 ± 2.25 12.91 ± 3.97 36.78 ± 0.38 8.95 ± 0.22 10 7.25 ± 0.07 PROM组 51 30.28 ± 3.23 2.02 ± 1.12 21.84 ± 3.26 11.79 ± 3.93 36.61 ± 0.37 9.01 ± 0.45 9.98 ± 0.14 7.26 ± 0.09 t/Z −0.919 1.354 −1.419 1.069 −1.575 −1.819 −0.623 0.316 P 0.366 0.180 0.160 0.293 0.120 0.073 0.535 0.753 表 2 对照组、PROM无CS组、PROM合并CS组母血、脐血各因子表达水平比较
Table 2. Comparation of various cytokine expression levels in maternal serum and umbilical cord serum between the control group,PROM without CS group and PROM with CS group
指标
(ng/L)对照组
(n = 20)PROM无CS组(n = 33) PROM合并CS(n = 18) χ2 P 母血 TNF-α 17.43(14.32,20.24) 25.40(18.57,41.54)# 48.01(28.19,302.68)#& 24.834 < 0.001 IL-6 7.00(3.56,12.40) 8.61(5.73,11.91) 15.76(8.41,62.69) #& 10.844 0.004 IL-17 48.26(32.13,64.69) 52.63(34.93,133.56) 64.99(33.27,265.14) 2.756 0.252 脐血 TNF-α 17.04(14.02,19.99) 18.25(10.86,39.21) 25.12(14.59,123.18)#& 6.285 0.043 IL-6 5.35(4.17,8.21) 8.16(5.10,17.26)# 25.37(9.43,39.33)#& 17.908 < 0.001 IL-17 33.63(17.67,45.82) 38.47(24.09,56.12) 52.93(25.62,122.31) 3.946 0.139 与对照组相比,#P < 0.05;与PROM无CS组相比,&P < 0.05。 表 3 对照组、A1、A2组母血、脐血各因子表达水平比较
Table 3. Comparation of various cytokine expression levels in maternal serum and umbilical cord serum between the control group,A1 group and A1 group
指标(ng/L) 对照组(n = 20) A1组(n = 41) A2组(n = 10) χ2 P 母血 TNF-α 17.43(14.32,20.24) 25.40(18.57,41.54)# 48.01(28.19,302.68)#& 17.468 < 0.001 IL-6 7.00(3.56,12.40) 8.47(5.65,12.53) 47.56(10.13,148.23)#& 11.475 0.001 IL-17 48.26(32.13,64.69) 48.45(32.49,108.74) 227.41(45.31,436.34)#& 7.202 0.007 脐血 TNF-α 17.04(14.02,19.99) 18.98(11.05,32.21) 46.98(16.43,435.71)#& 6.244 0.044 IL-6 5.35(4.17,8.21) 9.14(5.38,21.64)# 33.51(17.91,94.00)#& 19.852 < 0.001 IL-17 33.63(17.67,45.82) 38.47(20.66,52.82) 91.02(50.54,365.29)#& 13.208 0.001 与对照组相比,#P < 0.05;与A1组相比,&P < 0.05。 表 4 各细胞因子在母血、脐血中的相关性分析
Table 4. Correlation analysis of each cytokine in maternal serum with it in umbilical cord serum
项目 相关系数r P TNF-α(母血/脐血) 0.626 < 0.001* IL-6(母血/脐血) 0.646 < 0.001* IL-17(母血/脐血) 0.789 < 0.001* *P < 0.05。 表 5 母血、脐血TNF-α、IL-6诊断PROM合并CS的ROC曲线
Table 5. ROC curve of TNF-α and IL-6 in maternal serum and umbilical cord serum in the diagnosis of PROM with CS
指标(pg/mL) 临界点 AUC 灵敏度(%) 特异度(%) 95%置信区间 P 母血 TNF-α 26.19 0.763 83.3 66.7 0.624~0.871 < 0.001 IL-6 12.32 0.702 61.1 81.8 0.558~0.822 0.013 TNF-α+ IL-6 − 0.747 77.8 66.7 0.606~0.859 0.005 脐血 TNF-α 13.52 0.614 83.3 39.4 0.468~0.747 0.1697 IL-6 11.59 0.673 72.2 66.7 0.528~0.798 0.027 TNF-α+ IL-6 − 0.628 96.4 36.4 0.481~0.759 0.115 母血+脐血 TNF-α+ IL-6 − 0.820 72.2 87.9 0.687~0.913 0.005 表 6 母血、脐血TNF-α、IL-6和IL-17诊断PROM发生新生儿围产期感染的ROC曲线
Table 6. ROC curve of TNF-α,IL-6 and IL-17 in maternal serum and umbilical cord serum in the diagnosis of PROM with CS
指标(pg/mL) 临界点 AUC 灵敏度(%) 特异度(%) 95%置信区间 P 母血 TNF-α 26.19 0.787 90.0 56.1 0.649~0.889 < 0.001 IL-6 8.75 0.800 100 51.2 0.664~0.899 < 0.001 IL-17 179.57 0.735 60.0 85.4 0.593~0.849 0.014 TNF-α+ IL-6 − 0.810 100.0 51.2 0.675~0.906 < 0.001 TNF-α+ IL-6+ IL-17 − 0.766 90.0 61.0 0.626~0.873 0.007 脐血 TNF-α 13.52 0.722 100.0 39.0 0.579~0.838 0.015 IL-6 14.18 0.795 90 65.9 0.659~0.895 < 0.001 IL-17 53.00 0.829 80.0 78.0 0.698~0.920 < 0.001 IL-6+ IL-17 − 0.863 100.0 65.9 0.738~0.943 < 0.001 TNF-α+ IL-6+ IL-17 − 0.866 90.00 80.49 0.741~0.945 < 0.001 母血 + 脐血 TNF-α+ IL-6 +IL-17 − 0.822 90.0 75.6 0.689~0.915 < 0.001 -
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