高中枢瘦素水平对脊柱侧凸影响的动物模型研究及Chiari畸形伴脊柱侧凸患者颈枕部影像学和临床治疗研究

发布时间：2018-05-03 18:27

本文选题：脊柱侧凸 + 瘦素　；参考：《南京大学》2012年博士论文

【摘要】：第一章双足直立小鼠模型高中枢瘦素水平对脊柱侧凸影响研究目的：研究中枢高瘦素水平对双足直立鼠模型脊柱侧凸发生率及严重程度的影响,从动物实验层次上验证脊柱侧凸中枢高瘦素水平假说。方法：选取3周龄雌性C3He/ej小鼠50只,于麻醉状态下切除小鼠前肢及尾部,建立双足直立鼠模型。建模成功后三天,将双足直立小鼠模型随机分成两组：一组通过颅内注射方式将瘦素过表达慢病毒载体注入小鼠下丘脑,建立中枢高瘦素水平双足直立鼠模型；另一种则通过颅内注射方式将空白慢病毒载体注入小鼠下丘脑,建立对照双足直立鼠模型。两组小鼠模型均于相同条件下饲养于鼠笼中并通过高位饮食诱导其直立体态。成功建模20周后,通过X-ray评估两组小鼠模型脊柱侧凸发生率及严重程度。然后处死小鼠取外周血液样本,通过ELISA试剂盒评估两组小鼠外周血中瘦素水平。结果：本研究结果显示中枢高瘦素水平组双足直立小鼠外周瘦素水平明显高于对照组(p0.05),但中枢高瘦素水平组体重较对照组虽有所减少,但未见显著差异(p0.05)。影像学结果显示25只中枢高瘦索水平组双足直立鼠中23只发生脊柱侧凸,平均Cobb角29.9°,而对照组25只小鼠中只有13只发生脊柱侧凸,平均Cobb角18.3°。上述结果显示中枢高瘦素水平组小鼠脊柱侧凸发生率明显高于对照组。而发生脊柱侧凸的小鼠中,中枢高瘦素水平组小鼠模型脊柱侧凸平均Cobb角显著高于对照组。结论：本研究结果显示中枢高瘦素水平不仅能够提高双足直立小鼠脊柱侧凸发生率,而且可能引起脊柱侧凸进一步进展,提示中枢高瘦素水平可能是导致脊柱侧凸发生的重要影响因素。第二章(第一节)青少年特发性脊柱侧凸患者小脑扁桃体位置与后颅窝容积间相关性研究目的：本研究通过磁共振(Magnetic Resonance Imaging, MRI)测量特发性脊柱侧凸(Idiopathic Scoliosis, IS)患者与年龄匹配正常对照后颅窝各骨性标志间线性距离,比较两组后颅窝容积差异,并分析IS患者后颅窝发育异常与小脑扁桃体生理性下疝间相关性。方法：从2009年1月至2011年6月我科收治500例IS患者中选取研究对象,入选标准为：(1)患者年龄16-20岁,Risser征均为5级。(2)患者术前行站立位全脊柱正侧位X线片及颈枕部MRI检查。选取年龄匹配正常对照组。测量两组研究对象头颈正中矢状位MRI中小脑扁桃体下缘超出BO线的距离(d值),枕骨大孔径(AB),斜坡长度(AD),枕上长度(BC)以及后颅窝矢状径(CD)等指标,比较两组小脑扁桃体位置及后颅窝容积差异。然后根据MRI影像学表现,再将IS患者按照是否伴发生理性小脑扁桃体下疝进行分组,分析后颅窝容积与小脑扁桃体生理性下疝间关系及主弯Cobb角与小脑扁桃体生理性下疝程度间相关性。结果：IS患者共70例,平均年龄17.2±1.5岁,男48例(68.6%),女22例(31.2%),平均Cobb角51.2土14.1。。对照组共58例,平均年龄17.3±1.4岁,男27例,女31例。研究结果显示IS患者的小脑扁桃体下缘超出BO线的距离(d值)明显大于正常对照组(p=0.009),其生理性小脑扁桃体下疝发生率为22.9%。IS患者枕骨大孔径明显大于正常对照组(p0.001),而斜坡长度(AD),枕上长度(BC)以及后颅窝矢状径(CD)均明显小于正常对照组(p0.001)。此外,IS患者d值与主弯Cobb角无显著相关性(p=0.585)。生理性下疝组IS患者枕上长度(BC)长度显著小于对照IS患者(p=0.008),而其他三项后颅窝线性指标两组间均未见显著性差异。结论：IS患者小脑扁桃体位置明显低于正常青少年,生理性小脑扁桃体下疝发生率为22.9%,这可能是由于IS患者后颅窝枕骨大孔增大而斜坡、枕骨发育受限有关,其病理机制尚需进一步研究探讨,提示IS患者颅骨发育过程中也存在成骨异常。第二章(第二节)Chiari畸形伴脊柱侧凸患者后颅窝线性容积研究目的：本研究通过MRI测量Chiari畸形Ⅰ型(Chiari Malformation Type Ⅰ, CMI)患者与年龄匹配正常青少年后颅窝各骨性标志间线性距离,比较两组后颅窝容积差异,分析CMI患者后颅窝容积与小脑扁桃体下疝程度及脊髓空洞间相关性。方法：患者选自2003年至2010年CMI患者,入选标准为：(1)年龄16-20岁,Risser征5级。(2)经头颈部MRI确诊为Chiari畸形Ⅰ型伴或不伴脊髓空洞。入选CMI患者均排除可致继发性CMI及颅骨破坏相关疾病。选取年龄匹配正常青少年作为对照组。测量两组研究对象头颈正中矢状位MRI中枕骨大孔径(AB),斜坡长度(AD),枕上长度(BC)以及后颅窝矢状径(CD)等指标,并将两组按性别分组后比较后颅窝容积差异。根据MRI影像学表现,将CMI患者按照小脑扁桃体下疝严重程度及是否伴发脊髓空洞进行分组,分析后颅窝容积与小脑扁桃体下疝程度及脊髓空洞间关系。结果：本研究中CMI患者共37例,平均年龄17.2岁,其中男23例(62.2%),女14例(37.8%)。对照组青少年共49例,平均年龄17.5岁,其中男24例(49.0%),女25例(51.0%)。结果显示CMI患者后颅窝各骨性标志间线性距离均明显小于同性别、年龄匹配对照组青少年。此外,本研究还发现Ⅰ度扁桃体下疝CMI患者斜坡长度(AD)明显大于Ⅱ、Ⅲ度扁桃体下疝CMI患者,余指标未见明显差异。CMI伴脊髓空洞患者与单纯CMI患者后颅窝各骨性标志间线性距离亦未见显著性差异。结论：本研究显示CMI患者存在明显的颅骨发育障碍,支持了CMI是由中胚层旁叶发育受限所致这一假说。此外,本研究还发现斜坡发育受限可能是促使CMI患者小脑扁桃体下疝加重的重要因素之一,而颅骨发育受限并非脊髓空洞的主要致病因素。第二章(第三节)儿童Chiari畸形伴脊柱侧凸的影像学特点与临床意义目的：通过对于Chiari畸形伴脊柱侧凸患儿的临床及影像学特征进行研究,探讨其临床意义。方法：研究对象选自2001年7月至2008年12月在我院就诊的儿童(年龄10岁)Chiari畸形伴脊柱侧凸患者。通过分析其临床及影像学资料,测量胸椎后凸、腰椎前凸、MRI上小脑扁桃体下疝程度、空洞形态和长度以及空洞与脊髓的最大比值(S/C最大比值),对以上测量指标进行比较分析。结果：共有患儿40例入选,其中男23例(57.5%),女17例(42.5%)。本组患儿中累及胸弯37例(92.5%),单胸腰弯2例(5%),单腰弯1例(2.5%),不典型侧凸的发生率47.5%(19/40例),其中左胸弯的发生率为22.5%(9/40例)。典型侧凸模式中不典型特征发生率为72.7%(16/21例)。胸椎后凸角平均25.40,胸椎正常后凸与过度后凸占总患者的60%,腰椎前凸角平均53.1°,MRI发现其中36例(90%)伴有脊髓空洞。结论：儿童Chiari畸形患者以胸弯累及多见,不典型弯型及典型弯型中不典型特征较多见,胸椎后凸角较大,对于具有上述特征的低龄脊柱侧凸患儿,建议行全脊柱MRI排除神经系统异常。第二章(第四节)Chairi畸形脊髓空洞枕大孔减压术后脊髓空洞的自然转归目的：研究儿童Chiari畸形伴脊柱侧凸患者接受枕骨大孔减压术(PFD)术后脊髓空洞的自然转归,探索脊髓空洞PFD术后转归的相关影响因素。方法：研究对象选自2000至2009年于本院接受PFD术的Chiari畸形伴脊髓空洞合并脊柱侧凸患者。入选标准为：(1)患者年龄均小于或等于18岁；(2)经MRI确诊为Chiari畸形伴脊髓空洞；(3)以脊柱侧凸为首诊主诉；(4)入选患者均接受术前及术后MRI随访进行评估Chiari畸形及脊髓空洞状态。此外,本研究入选对象均排除继发性Chiari畸形或接受脊髓空洞引流术的可能。本研究采用最大脊髓空洞/脊髓比(S/C ratio)及脊髓空洞长度作为评估术前及术后随访脊髓空洞状况的影像学指标。根据末次术后随访资料,脊髓空洞S/C ratio或长度较术前减少超过20%定义为脊髓空洞明显缓解,而脊髓空洞完全消失则定义为脊髓空洞完全缓解。结果：共有44例患者入选本研究。44例患者术前及术后6月均接受MRI检查。其中37例患者术后2年接受MRI随访,26例患者术后4年接受MRI随访,15例患者术后6年接受MRI随访。根据末次随访MRI影像学资料,97.7%(43/44)的患者PFD术后脊髓空洞明显缓解。本研究结果显示小脑扁桃体下疝距离(mm)与PFD术对脊髓空洞的疗效间存在显著相关性(r=0.116,p=0.013)。同时我们发现脊髓空洞PFD术后缓解主要发生在术后6月内,6月之后脊髓空洞缓解虽然仍持续进行,但是缓解速度明显减低。结论：绝大多数Chiari畸形伴脊髓空洞合并脊柱侧凸患者接受枕骨大孔减压术术后脊髓空洞显著改善。而这种脊髓空洞的显著改善主要发生在枕骨大孔减压术术后6月内,其后脊髓空洞缓缓改善。同时我们发现小脑扁桃体下疝严重程度可能是影响枕骨大孔减压术对脊髓空洞疗效的重要潜在因素。
[Abstract]:Chapter 1 the influence of high level PIP leptin level on scoliosis in bipedal erect mouse model
Objective: To investigate the effect of high leptin levels on the incidence and severity of scoliosis in the bipedal erect rat model, and to verify the hypothesis of the high leptin level in the scoliosis center from the animal experimental level.
Methods: 50 female C3He/ej mice of 3 weeks old were selected to excision the forelimb and tail of mice under anesthesia. The model of bipedal erect rat was established. After three days of successful modeling, the model of bipedal erect mice was randomly divided into two groups: a group of leptin overexpressed lentivirus vectors were injected into the hypothalamus of mice by intracerebral injection, and the central leptin was established. The other one was injected into the hypothalamus of mice by injecting the blank lentivirus vector into the hypothalamus by intracerebral injection. The two groups of mice were fed in the cage and induced their erect posture under the same condition. After 20 weeks of successful modeling, the model of two groups of mice was evaluated by X-ray. The incidence and severity of scoliosis were observed. Then the mice were sacrificed and peripheral blood samples were taken to evaluate the level of leptin in peripheral blood of two groups of mice by ELISA kit.
Results: the results of this study showed that the peripheral leptin level in the central high leptin level group was significantly higher than that of the control group (P0.05), but the weight of the central leptin group was less than the control group, but there was no significant difference (P0.05). The imaging results showed that 23 of the 25 central high leptin groups had spinal lateral scoliosis rats. The average Cobb angle was 29.9 degrees, while only 13 of the 25 mice in the control group had scoliosis, with an average Cobb angle of 18.3 degrees. The results showed that the incidence of scoliosis in the central high leptin level group was significantly higher than that in the control group. In the mice with scoliosis, the average Cobb angle in the central high leptin level mice model scoliosis was significantly higher than that of the central high leptin level mice. Control group.
Conclusion: the results of this study show that the high leptin level can not only improve the incidence of scoliosis in bipedal erect mice, but also may cause further progress in scoliosis, suggesting that the level of high leptin may be an important factor in the incidence of scoliosis.
The second chapter (Section 1) correlation between cerebellar tonsil location and posterior fossa volume in adolescent idiopathic scoliosis
Objective: to measure the linear distance between the patients with idiopathic scoliosis (Idiopathic Scoliosis (IS) and the age-matched normal control posterior fossa bone markers by Magnetic Resonance Imaging (MRI), to compare the volume difference between the two groups of posterior cranial fossa, and to analyze the abnormal development of posterior fossa in IS patients and the physiological hernia of the tonsil of the cerebellum. Inter correlation.
Methods: from January 2009 to June 2011, 500 patients with IS were selected and selected. The criteria were: (1) the age of the patients was 16-20 years old, and the Risser sign was 5. (2) the patients were performed the normal lateral X-ray of the spine and the cervical occipital MRI before operation. The age matched normal control group was selected. The two groups of subjects were measured in the head and neck sagittal sagittal. The location of the two cerebellar tonsils and the volume difference between the posterior cranial fossa and the two groups of cerebellar tonsils were compared with the distance (D value), the large aperture (AB), the length of the occipital bone (AD), the length of the occipital (BC) and the sagittal diameter (CD) of the posterior fossa. Then, according to the imaging findings of the MRI, the patients with the cerebellar tonsil hernia were followed by the MRI imaging. The relationship between posterior cranial fossa volume and physiological lower hernia of cerebellar tonsil was analyzed, and the correlation between the Cobb angle of main bend and the degree of physiological herniation in cerebellar tonsil was analyzed.
Results: a total of 70 IS patients, the average age of 17.2 + 1.5 years, 48 men (68.6%), 22 women (31.2%), and the average Cobb angle 51.2 soil 14.1.. Control group were 58, the average age 17.3 + 1.4 years, male 27, and 31 cases. The results showed that the distance of the lower margin of the cerebellar tonsil of the IS patients (D value) was significantly greater than the normal control group (p=0.009), and its physiological characteristics were small. The large pore size of the occipital bone in 22.9%.IS patients was significantly greater than that of the normal control group (p0.001), while the slope length (AD), the length of the occipital (BC) and the posterior fossa sagittal diameter (CD) were significantly smaller than those of the normal control group (p0.001). Besides, there was no significant correlation between the D value of the IS patients and the main bend Cobb angle (p=0.585). The length of the occipital pillow in the physiological hernia group was on the occipital length. (BC) the length was significantly less than that of the control IS patients (p=0.008), while the other three posterior cranial fossa linear indices showed no significant difference between the two groups.
Conclusion: the position of cerebellar tonsil in IS patients is significantly lower than that of normal adolescents. The incidence of lower hernia is 22.9% in the physiological cerebellar tonsillar, which may be due to the enlargement of the occipital foramen in the posterior fossa of the IS patients and the restriction of the occipital bone development. The pathological mechanism of the occipital bone is still needed to be further studied. It is suggested that the osteogenesis in the development of the skull in the IS patients also exists in the process of osteogenesis. Often.
Second chapter (second). Posterior cranial fossa linear volume in patients with Chiari malformation associated with scoliosis
Objective: to measure the linear distance between the patients with Chiari malformation (Chiari Malformation Type I, CMI) and the posterior fossa bone markers of the age matched normal adolescents by MRI, the volume difference between the two groups of posterior cranial fossa was compared, and the correlation between the posterior cranial fossa volume and the degree of inferior hernia of the cerebellar tonsil and the cavities in the spinal cord of the cerebellar tonsil was analyzed.
Methods: the patients were selected from 2003 to 2010 CMI. The criteria were: (1) age 16-20, Risser sign 5. (2) Chiari malformation was diagnosed as type I with or without cavities in the head and neck. All CMI patients were excluded from secondary CMI and skull damage related diseases. Age matched normal adolescents were selected as control group. Two groups were measured. Two groups were measured. The large pore size (AB) of occipital bone (AD), the length of the occipital (BC) and the posterior fossa sagittal diameter (CD) in the median sagittal MRI of the head and neck were compared, and the difference of the volume of the posterior fossa was compared between the two groups according to sex. According to the MRI imaging findings, the severity of the hernia under the cerebellar tonsil and the concomitant cavities of the spinal cord were carried out in the CMI patients. The relationships between posterior cranial fossa volume and cerebellar tonsillar hernia and spinal cavity were analyzed.
Results: in this study, there were 37 cases of CMI patients, with an average age of 17.2 years old, including 23 men (62.2%) and 14 women (37.8%). The control group was 49 cases, with an average age of 17.5 years old, including 24 men (49%) and 25 (51%). The results showed that the linear distance between the bone markers in the posterior cranial fossa of CMI patients was significantly smaller than that of the same sex, age matched control group. In addition, the study also found that the slope length (AD) of CMI patients with I tonsillar hernia was significantly greater than that of II, and there was no significant difference in the residual index of CMI patients with lower hernia in the third degree tonsillar. There was no significant difference in the linear distance between the patients with.CMI with the cavities of the spinal cord and the posterior cranial fossa of the simple CMI patients.
Conclusion: This study shows that CMI patients have obvious cranial dysplasia and support the hypothesis that CMI is due to the limitation of mesoderm development. Furthermore, this study also found that the limitation of development of the clivus may be one of the important factors contributing to the aggravation of the cerebellar tonsil hernia in CMI patients, and the limitation of the skull development is not the main cause of the cavities in the spinal cord. Disease factors.
The second chapter (third). The imaging features and clinical significance of Chiari malformation associated with scoliosis in children
Objective: To study the clinical and imaging features of children with Chiari malformation associated with scoliosis and to explore its clinical significance.
Methods: the subjects were selected from July 2001 to December 2008 in our hospital (10 years old) with Chiari malformation with scoliosis. Their clinical and imaging data were analyzed to measure the degree of hernia under the thoracic kyphosis, lumbar lordosis, MRI cerebellar tonsillar, cavity shape and length, and the maximum ratio of cavities to the spinal cord (S/C max). Comparison and analysis of the above measurement indexes.
Results: a total of 40 children were selected, including 23 males (57.5%) and 17 females (42.5%), including 37 thoracic bending (92.5%), 2 single thoracolumbar bending (5%), 1 cases (2.5%) of single lumbar bend (2.5%), and the incidence of atypical scoliosis (19/40 cases), among which the incidence of left chest bending was 22.5% (9/40). The incidence of atypical characteristics in typical scoliosis mode was 57.5% (16/21 The posterior convex angle of the thoracic vertebra was 25.40, the normal kyphosis and the overprotruding of the thoracic vertebrae accounted for 60% of the total, and the average lumbar anterior convex angle was 53.1 degrees. MRI found that 36 cases (90%) were accompanied by cavities in the spinal cord.
Conclusion: the patients with Chiari malformation are frequently involved in thoracic curvature. The atypical characteristics of the atypical bending and typical curved types are more common, and the posterior convex angle of the thoracic vertebrae is large. It is suggested that the whole spinal column MRI exclude the abnormal nervous system for the children with the above characteristics of the age of the scoliosis.
The second chapter (fourth). The natural outcome of syringomyelia after decompression of foramen magnum in Chairi malformation.
Objective: To study the natural outcome of the cavities of the spinal cord after the operation of the occipital foramen magnum decompression (PFD) for children with Chiari malformation and scoliosis, and to explore the related factors of the outcome after the operation of the spinal cord cavity PFD.
Methods: the subjects were selected from 2000 to 2009 with Chiari malformation with spinal cord cavities with scoliosis in our hospital. The criteria were: (1) the age of the patients was less than or equal to 18 years old; (2) MRI was diagnosed as Chiari malformation with spinal cavities; (3) scoliosis was the primary complaint; (4) all patients received preoperative and postoperative surgery. MRI was followed up to assess the status of Chiari malformation and spinal cavity. In addition, this study excluded the possibility of secondary Chiari malformation or spinal cavity drainage. The present study used the maximum spinal cord / spinal cord ratio (S/C ratio) and the length of the spinal cord as an imaging index to evaluate the status of the cavities in the spinal cord before and after the operation. According to the follow-up data after the last operation, the S/C ratio or length of the spinal cavity was defined as the obvious relief of the cavities in the spinal cord, while the complete disappearance of the spinal cavity was defined as complete remission of the cavities in the spinal cord.
Results: a total of 44 patients were enrolled in the study,.44 patients received MRI examination before and after operation in June. Of them, 37 patients received MRI follow-up 2 years after operation, 26 patients received MRI follow-up 4 years after operation, 15 patients received MRI follow-up after 6 years. According to the last follow-up of MRI imaging data, 97.7% (43/44) patients were obviously relieved of cavities in spinal cord after PFD operation. The results of this study showed a significant correlation between the cerebellar tonsillar hernia distance (mm) and the effect of PFD on the cavities of the spinal cord (r=0.116, p=0.013). Meanwhile, we found that the remission of the spinal cavity after PFD was mainly in June after the operation, and the remission of the spinal cord was still continued after June, but the remission rate was significantly reduced.
Conclusion: most of the patients with Chiari malformation with scoliosis with scoliosis were significantly improved after the occipital decompression of the occipital foramen. The significant improvement in the cavities of the spinal cord mainly occurred within June after the occipital decompression of the occipital orifice, followed by the gradual improvement of the cavities in the spinal cord, and we found the severity of the cerebellar tonsil hernia. It may be an important potential factor affecting the effect of foramen magnum decompression on the cavity of spinal cord.

【学位授予单位】：南京大学
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R682.3;R-332

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