【作者】 李洋；

【导师】 朱泽章；

【作者基本信息】 南京大学 ， 临床医学， 2021， 博士

【摘要】 第二章青少年特发性脊柱侧凸易感基因在中国汉族人群中验证性研究目的:在中国汉族人群中验证近期报道的14个易感位点与青少年特发性脊柱侧凸(adolescent idiopathic scoliosis,AIS)发病的相关性,并进一步分析相关基因与AIS患者临床特征之间的关系。方法:共纳入1210名女性AIS患者和2500名健康的青少年对照,收集其血样标本和影像资料。从全血中提取DNA,通过Taqman探针对rs141903557、rs11205303、rs12029076、rs1978060、rs2467146、rs11787412、rs188915802、rs658839、rs160335、rs482012、rs17011903、rs397948882、rs12149832、rs11341092位点进行基因分型,比较风险等位基因频率在AIS组和对照组之间的分布差异。手术取36例AIS患者近端的椎旁肌组织并记录侧凸角度、患者月经初潮年龄、身体质量指数(body mass index,BMI)等临床信息,同时收取36例青少年腰椎间盘突出症患者椎旁肌组织作为对照组,通过实时荧光定量PCR技术检测上述验证成功的易感位点对应的基因在椎旁肌组织表达情况以及该基因与AIS临床特征相关性。结果:多态性位点rs141903557(LOC101928978)、rs1978060(TBX1)、rs2467146(LINC02378/MIR3974)、rs658839(BCKDHB/FAM46A)和rs482012(NT5DC1)的风险等位基因频率分布在AIS患者与对照组之间存在显著差异。AIS患者中TBX1基因(0.003803±0.00095 vs.0.00499±0.00113,p<0.001)和FAM46A基因(0.00146±0.00065 vs.0.00193±0.000638,p=0.003)的表达均显著低于对照组。两组NT5DC1基因的表达则无明显差异(0.00346±0.0009 vs 0.00381±0.00114,p=0.155)。在AIS患者中,FAM46A和NT5DC1基因表达量和患者BMI、月经初潮年龄、侧凸主弯Cobb角均无明显相关性(p均>0.05)。TBX1基因表达量和患者BMI及月经初潮年龄无显著相关性,但和患者主弯Cobb角度呈显著负相关(r=-0.514,p=0.001)。结论:Rs141903557、rs1978060、rs2467146、rs658839、rs482012在中国汉族人群中被证实与AIS发生相关。Rs1978060可能通过调控TBX1基因表达调控AIS畸形进展。第三章(第一节)序贯矫形技术治疗伴有C型冠状面失平衡的退变性脊柱侧凸的疗效评价:和传统双棒技术对比目的:比较序贯矫形技术和传统双棒技术治疗伴有C型冠状面失平衡的退变性脊柱侧凸患者的影像学和临床结果,分析序贯矫形技术的效果和优势。方法:回顾性分析2014年2月至2018年1月在我院接受矫形内固定手术治疗且随访满2年的伴有C型冠状面失平衡的退变性脊柱侧凸畸形患者。根据手术方式将患者分为序贯矫形技术组(sequential correction technique,SC)和传统矫形技术组(traditional 2-rod correction technique,TC)。分别测量术前、术后及末次随访时侧凸主弯Cobb角、最大后凸角(global kyphosis,GK)、冠状面平衡距离(coronal balance distance,CBD)、矢状面平衡(sagittal vertical axis,SVA)、腰椎前凸角(lumbar lordosis,LL)等参数,采用SF-36量表评估临床疗效。记录各组之间围手术期及随访时并发症及冠状面平衡恢复情况。采用Fisher精确检验比较两组各变量之间的分布差异,连续变量采用独立样本t检验进行比较分析。结果:本研究共纳入34名患者,其中SC组14例(平均年龄64.4±7.3岁),TC组20例(平均年龄60.0±7.2岁)。两组患者术前主弯Cobb角、GK、CBD、SVA等参数以及手术时间和出血量等参数无明显差异(P>0.05)。术后两组患者主弯Cobb角、CBD、GK、LL、SVA等参数均得到了不同程度的改善(P<0.05)。SC组患者,术前主弯Cobb角为57.1±7.0°,术后矫正到25.7±6.6°(p<0.001);术前CBD平均值为43.5±11.9mm,术后显著降低至15.0±6.3(P<0.001),末次随访时进一步改善至13.0±7.8(p=0.025)。SC组术后13例(92.3%)患者冠状面平衡改善为A型,1例(7.1%)患者术后冠状面平衡仍然为C型,所有患者在随访期间均未再次出现冠状面失衡。TC组术前主弯Cobb角为52.1±7.3°,术后矫正到25.0±6.1°(p<0.001);术前CBD平均值为45.6±7.9mm,术后显著降低至23.6±11.2mm(P<0.001),末次随访时为24.2±11.8mm。TC组术后冠状面平衡A型16例(80.0%),C型4例(20.0%),1例患者出现术后冠状面失衡加重现象。TC组在随访过程中,有2例患者的冠状不平衡从A型恶化为C型。TC组术后冠状面失衡的发生率比SC组高,但无明显统计学差异(20%vs.7.1%,P=0.243)。除总体健康维度外,两组患者末次随访时SF-36量表中各维度得分均得到统计学上的改善(P<0.05),并且SC组患者的总体健康水平也得到了改善(P<0.001)。SC组随访期间无断棒断钉、内固定拔出等植入物相关并发症发生,TC组3例(15.0%)患者出现断棒。结论:相比传统双棒矫形技术,序贯矫形技术治疗伴有C型冠状面失平衡的退变性脊柱侧凸患者能够更有效降低术后冠状面失平衡发生率,达到更好的矫形效果且可在随访中维持脊柱冠状面平衡及内固定稳定性。第三章(第二节)Ponte截骨联合卫星棒序贯矫形技术治疗重度特发性胸椎侧凸畸形目的:比较Ponte截骨联合卫星棒序贯矫行技术和传统双棒矫形技术治疗重度特发性胸椎侧凸畸形患者的影像学和临床疗效。方法:回顾性分析2013年10月至2017年10月在我院接受后路矫形内固定手术的重度特发性脊柱侧凸患者,纳入标准为:(1)主胸弯且Cobb角>80°;(2)行单一后路矫形内固定手术;(3)随访满2年以上且具有完整的临床及影像学资料。排除既往有脊柱手术史、术前进行牵引、行三柱截骨或分期手术的患者。根据手术方式的不同,将纳入患者分为传统双棒矫形组(traditional correction,TC)和序贯矫形组(sequential correction,SC)。分别测量术前、术后及末次随访时的主弯Cobb角、冠状面平衡距离(coronal balance distance,CBD)、顶椎偏移距离(apex vertebral translation,AVT)、胸椎局部后凸角(thoracic global kyphosis,TGK)、腰椎前凸角(lumbar lordosis,LL)、矢状面躯干偏移距离(sagittal vertebral axis,SVA)等参数。以SRS-22问卷量表评估生活质量。记录围手术期及随访中并发症情况。采用Fisher精确检验或者c2检验比较两组各变量之间的分布差异,采用独立样本t检验对连续变量进行比较分析。结果:SC组共33例(年龄22.8±7.6岁),TC组21例(年龄24.1±8.7岁)。SC组和TC组胸椎侧凸主弯Cobb角平均值分别为93.6±7.8°和89.8±6.6°(p=0.070),主弯柔韧性分别为28.8±8.7%和30.4±7.9%(p=0.498)。SC组和TC组在融合节段、Ponte截骨数量和术中失血量方面均无明显统计学差异(p>0.05)。SC组手术时间略低于TC组(251.5±42.8min vs.275.4±39.8min,p=0.020)。SC组冠状面主弯Cobb角平均矫正率高于TC组(55.8±9.2%vs.45.7±8.8%,p=0.000)。两组患者术后CBD、AVT、TGK、SVA、LL均无明显变化。SC组2年随访时冠状面和矢状面矫正丢失分别为1.1°和1.5°,均明显低于TC组(冠状面为2.9°,矢状面为2.1°,p均<0.05)。末次随访时,SC组患者SRS-22量表评分在外观和满意度评分高于TC组(p均<0.05)。术中矫形过程中TC组5例(23.8%)出现椎弓根螺钉切割或拔出,SC组为1例(3.0%)(p=0.026)。结论:Ponte截骨联合卫星棒序贯矫形技术能够提高重度特发性胸椎侧凸畸形的矫形效果,简化手术操作并减少术中并发症,远期随访矫正丢失少,能够维持较好的矫形效果,是一种安全而有效的手术方式。第三章(第三节)序贯矫形技术治疗先天性颈胸段侧凸畸形前期临床疗效分析目的:评估应用序贯矫形技术治疗的先天性颈胸段侧凸畸形患者影像学及临床疗效,并分析序贯矫形技术在治疗先天性颈胸段侧凸畸形患者中的优势。方法:回顾性分析2018年01月至2020年03月应用序贯矫形技术治疗的先天性颈胸段侧凸畸形患者共12例,其中男4例、女8例,平均年龄8.1±2.8岁。分别测量术前术后及末次随访时局部侧凸角、T1倾斜角、锁骨角、颈部偏斜角、头部偏移等参数,生活质量评估采用SRS-22量表。统计分析采用配对样本t检验。结果:12例患者手术时间平均为212.2±28.9 min,出血量平均为349.3±58.7ml,术后平均随访时间20.4±3.7个月。术前局部侧凸Cobb角为40.3±4.1°,术后减少至9.4±1.7°(p<0.001),末次随访时平均9.6±1.9°,未见明显矫正丢失(p=0.788)。术后T1倾斜角、锁骨角、颈部倾斜角及头部偏斜角均获得了显著改善(p值均<0.05)。本组患者术后SRS-22量表中外观维度评分、心理健康维度评分及患者总体评分均有显著提高(p<0.05)。所有患者随访中均未出现内固定断裂等并发症。结论:采用序贯矫形技术治疗颈胸段半椎体畸形可以降低手术操作难度、提高矫形效果,降低术后内固定并发症发生率。更多还原

【Abstract】 Chapter Ⅱ Replication of Association between the New Susceptibility Loci for Adolescent Idiopathic Scoliosis in Chinese Han PopulationObjective:To investigate the association of the novel identified susceptible loci with adolescent idiopathic scoliosis(AIS)in Chinese Han population,and to better define the functional role of the genes related to the validated single-nucleotide polymorphisms(SNPs)in the development and progression of AIS.Methods: Rs141903557 、 rs11205303 、 rs12029076 、 rs1978060 、 rs2467146 、rs11787412、rs188915802、rs658839、rs160335、rs482012、rs17011903、rs397948882、rs12149832、rs11341092 were genotyped in 1210 AIS female patients and 2500 controls.Paraspinal muscle samples were collected from 36 AIS patients and 36 agematched lumbar disc herniation(LDH)patients for the analysis of tissue expression.The differences of genotype and allele distributions between the patients and the controls were calculated using the Chi-square test.The Pearson correlation analysis was carried out to investigate the relation between the expression of the genes and the clinical characteristics of AIS.Results: Rs141903557(LOC101928978)、 rs1978060(TBX1)、 rs2467146(LINC02378/MIR3974)、rs658839(BCKDHB/FAM46A)and rs482012(NT5DC1)were significantly associated with the susceptibility of AIS in this study.Both expression of TBX1(0.003803±0.00095 vs.0.00499±0.00113,p < 0.001)and FAM46A(0.00146±0.00065 vs.0.00193±0.000638,p = 0.003)in the AIS patients was significantly lower compared with the controls.While there was no significant difference between the two groups regarding the expression of NT5DC1(0.00346±0.0009 vs 0.00381±0.00114,p = 0.155).There was a remarkable correlation between the curve magnitude and the TBX1 expression(r=-0.514,p=0.001).Conclusion: Rs141903557,rs1978060,rs2467146,rs658839 and rs482012 were associated with AIS in the Chinese Han population.Rs1978060 may be a functional variant regulating the expression of TBX1 which may play a functional role in the development or progression of AIS.Chapter Ⅲ(Section 1)Sequential correction technique in degenerative scoliosis with Type C coronal imbalance: a comparison with traditional 2-rod techniqueObjective.To compare the radiographic and clinical outcomes in degenerative scoliosis(DS)patients with Type C coronal imbalance undergoing sequential correction technique and traditional 2-rod technique during a minimum of 2 years follow-up.Methods.DS patients with Type C coronal imbalance undergoing posterior correction surgery from February 2014 to January 2018 were divided into SC group(sequential correction technique)and TC group(traditional 2-rod correction technique).Radiographic parameters including Cobb angle,coronal balance distance(CBD),global kyphosis(GK),thoracic kyphosis(TK),lumbar lordosis(LL),sagittal vertical axis(SVA),pelvic incidence(PI),pelvic tilt(PT)and sacral slope(SS)were assessed pre-and post-operatively.The Short Form 36 questionnaire was fulfilled to evaluate the quality of life.Results.A total of 34 patients were included including 14 in SC group and 20 in TC group.Significant post-operative improvement in Cobb angle of main curve,CBD,GK,TK,LL,SVA and PT were revealed in both groups(p<0.05).At post-operation,the coronal balance was Type A in 13 patients(92.9%)of SC group and 16 patients(80.0%)of TC group(P=0.298).In TC group,there was 1 patient with deteriorative coronal imbalance at immediate post-operation and coronal imbalance deteriorated from Type A to Type C in 2 patients during follow-up.The scores of physical functioning,rolephysical,bodily pain,vitality,social functioning,role-emotional and mental health were statistically improved at post-operation(P<0.05)in both groups,while patients with Type C coronal imbalance at the last follow-up were associated with relatively lower quality of life.There were no implant-related complications during follow-up in SC group while rod fracture was observed in 3 patients of TC group.Conclusions.Compared with traditional 2-rod technique,the sequential correction technique can simplify rod installation procedure,enhance internal instrumentation and reduce risk of implant failures.Sequential correction technique could be routinely recommended for DS patients with Type C coronal imbalance.Chapter Ⅲ(Section 2)Ponte Osteotomy Followed by Sequential Correction Technique with Satellite Rods for the Treatment of Severe Idiopathic Thoracic ScoliosisObjective.To compare the radiographic and clinical outcomes between sequential correction technique(SC)and traditional 2-rod correction technique(TC)in patients with severe thoracic idiopathic scoliosis(STIS)undergoing posterior-only correction surgery.Methods.This study reviewed a consecutive series of STIS patients undergoing posterior-only correction surgery between October 2013 and October 2017 with over 2-years follow-up.The radiographic parameters were assessed at preoperation,postoperation,and last follow-up.The radiographic parameters,operation time,blood loss,and complications were compared between two groups.Results.A total of 33 patients were enrolled into SC group while 21 patients into TC group.There was no significant difference in age,gender and deformity magnitude(93.6±7.8° vs.89.8±6.6°,p=0.070)at pre-operation between groups.The operation time was shorter in SC group than TC group(251.5±42.8min verse 275.4±39.8min,p=0.020),while both blood loss(1284.6±483.3 verse 1398.0±558.4 ml,p=0.432)and fused levels(13.1±2.8 verse 13.6±2.4,p=0.503)were similar between two groups.Compared with TC group,patients in SC group had higher correction rate(55.8±9.2% vs.45.7±8.8%,p=0.000),less coronal(1.1±0.81° vs.2.9±0.93°,p=0.000)and sagittal(1.5±0.96° vs.2.1±0.64°,p=0.015)correction loss at 2-years follow-up,and lower incidence of intraoperative pedicle screw pull-out(3.0% vs.23.8%,p=0.026).Conclusion.The sequential correction technique could significantly and practically reduce the difficulty of rod installation with better deformity correction outcomes than traditional 2-rod technique.The sequential correction technique was an effective alternative for patients with severe thoracic idiopathic scoliosis.Chapter Ⅲ(Section 3)The preliminary results of sequential correction technique in congenital cervicothoracic scoliosisObjective: To evaluate the radiographic and clinical outcomes of sequential correction technique in congenital cervicothoracic scoliosis,and to illustrate the advantage of this technique.Methods: Twelve patients(4 males and 8 females)with congenital cervicothoracic scoliosis applying sequential correction technique from January 2018 to March 2020 were reviewed,of whom the mean age was 8.1±2.8 years.The radiographic parameters for analysis included local scoliosis,T1 tilt,clavicle angle,neck tilt,and head shift.The SRS-22 questionnaire was evaluated at preoperation and the last follow-up.The paired t test was used for the statistical analysis.Results: The mean operation time was 212.2±28.9 min,and the average blood loss was 349.3±58.7ml.The mean post-operative follow-up period was 20.4±3.7 months.Local scoliosis was significantly corrected from 40.3±4.1° preoperatively to 9.4±1.7° postoperatively(p<0.001)and 9.6±1.9° at last follow-up with no significant correction loss(p=0.788).Significant improvement in T1 tilt,clavicle angle,neck tilt,and head shift was obtained at postoperation(p<0.05 for all).The scores of SRS-22 were significantly improved in appearance,mental,and total satisfaction domains at last follow-up(p<0.05).There was no implant-related complications during follow-up.Conclusion: The sequential correction technique could be well used in congenital cervicothoracic scoliosis,which can simplify the surgical procedure,maximize deformity correction,and reduce the incidence of implant-related complications.更多还原