脑脊液Notch1、DLL1的检测在中枢神经系统感染性疾病中的临床价值
发布时间：2018-08-17 17:46
【摘要】：背景与目的 结核性脑膜炎(Tuberculous meningitis,TM)是临床上常见的中枢神经系统感染性疾病之一,近年来发病率有增加的趋势,正确的诊断、早期的治疗是决定预后的重要因素。由于临床抗生素的大范围使用和脑膜炎临床表现往往不典型而且复杂多变,细菌学检验因周期过长,加上敏感度低,病原菌检出困难等,往往不利于早期诊断,容易误诊和漏诊。 Notch信号属于进化上保守的转导通路,参与胚胎的发展和自我更新,以及调节细胞的命运,是生物发育中必不可少的途径。而且,这条途径涉及各信号之间复杂的相互作用,与许多疾病的病理生理过程相关。DLL1是Notch受体的配体之一,其功能缺失可能导致胚胎死亡,但DLL蛋白水平的变化,在疾病中的作用研究甚少。 我们前期的工作发现,TM患者血清和脑脊液(Cerebrospinal Fluid, CSF)中DLL1水平显著升高,具有较重要的诊断意义。在此基础上,本研究将继续采用酶联免疫吸附试验(Enzyme Linked Immunosorbent Assays, ELISA)和Western Blot的方法检测中枢神经系统感染性疾病患者CSF中可溶性Notch1和DLL1的水平,探索新的TM的诊断方法。 对象和方法 选取郑州大学第一附属医院神经内科2008年7月-2012年3月住院行腰椎穿刺术的患者289例,根据临床诊断进行分组。其中TM组127例。非TM的感染性脑(膜)炎对照90例,包括化脓性脑膜炎组(Purulent meningitis,PM)10例,病毒性脑膜炎组(Viral meningitis,VM)65例,新型隐球菌性脑膜炎组(Cryptococcus neoformans meningitis, CM)15例。非感染性神经系统疾病对照组72例,选择同期入住排除中枢神经系统感染的患者,包括吉兰-巴雷综合征(Guillain-Barre syndrome,GBS)20例,多发性硬化(Multiple sclerosis, MS)25例,阿尔茨海默病(Alzheimer disease, AD)8例,低颅压头痛10例,紧张性头痛9例。本研究经郑州大学第一附属医院医学伦理委员会批准,患者均签署知情同意书。采用ELISA和Western Blot的方法检测各组CSF中可溶性Notch1、DLL1的含量和表达。 结果 1.各组脑脊液中可溶性Notch1的含量,TM组也明显高于其余各组(P0.01)；以Notch1≥8.50pg/ml作为TM的判断值,其敏感度为86.8%,特异性为85.2%,但是此标准对于隐球菌脑炎区分较差,其余各组之间相比均无显著差异(P0.05)。 2.各组脑脊液中可溶性DLL1的含量,TM组显著高于其余各组(P0.01)；以DLL1≥0.77ng/ml作为TM的判断值,其敏感度为100%,特异性为96.9%,其余各组之间相比无明显差异(P0.05)。 3.伴发高甘油三酯与否脑脊液可溶性Notch1、DLL1的含量测定结果：TM组伴高甘油三酯、TM组伴正常甘油三酯的CSF中Nocth1含量分别为(6.85±2.32,7.30±1.35pg/m1),两者相比无显著性差异(P0.05)；其余各组伴高甘油三酯或正常甘油三酯CSF中Nocth1含量相比也无显著性差异(P0.05)。TM组伴高甘油三酯、TM组伴正常甘油三酯的CSF中DLL1含量分别为(3.18±2.92,3.62±1.79ng/ml),两者相比无显著性差异(P0.05)；其余各组伴高甘油三酯或正常甘油三酯CSF中Nocth1含量相比也无显著性差异(P0.05)。 4. Western Blot结果提示,TM组患者脑脊液中Notch1、DLL-1蛋白有较高的表达,其余各组患者极少表达。 5.39例TM组患者随访结果发现,37例有效化疗治疗4周后,CSF可溶性Notch1、DLL1水平显著下降(5.78±2.87pg/ml,1.89±0.58ng/ml),两者相比有显著性差异(P0.05),治疗12周可以降至正常水平(0.85±0.62pg/ml,2.05±1.21ng/ml),两者相比有显著性差异(P0.05)。2例治疗效果不佳,CSF可溶性Notch1、DLL1水平未见下降。 结论 本研究提示,TM患者CSF中可溶性Notch1、DLL1的含量显著升高,在VM、PM、隐球菌性脑膜炎和非感染性神经系统疾病患者的CSF中可溶性Notch1、DLL1的含量较低或检测不到。因此,CSF中Notch1及其配体DLL1含量的检测,有望成为诊断结核性脑膜炎的辅助指标。
[Abstract]:Background and purpose
Tuberculous meningitis (TM) is one of the common infectious diseases of the central nervous system in clinic. The incidence of TM is increasing in recent years. Correct diagnosis and early treatment are important factors for prognosis. Bacteriological examination is often not conducive to early diagnosis, easy to misdiagnose and miss diagnosis because of its long cycle, low sensitivity and difficult detection of pathogens.
Notch signaling is an evolutionarily conserved transduction pathway involved in embryonic development and self-renewal, as well as the regulation of cell fate, which is essential in biological development. Loss of energy may lead to embryonic death, but there is little research on the role of DLL protein level in disease.
Our previous work found that the levels of DLL1 in serum and cerebrospinal fluid (CSF) of TM patients were significantly elevated, which is of great diagnostic significance. On this basis, this study will continue to use Enzyme Linked Immunosorbent Assays (ELISA) and Western Blot methods to detect central nervous system infections. The levels of soluble Notch1 and DLL1 in CSF of patients with sexual diseases were explored, and a new diagnostic method for TM was explored.
Objects and methods
A total of 289 patients with lumbar puncture in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University from July 2008 to March 2012 were selected and divided into two groups according to their clinical diagnosis, 127 patients in TM group and 90 patients in non-TM infectious meningitis control group, including 10 patients with purulent meningitis (PM) and 10 patients with viral meningitis (VM). 65 cases, 15 cases of Cryptococcus neoformans meningitis (CM), 72 cases of non-infectious nervous system disease control group, selected patients excluding central nervous system infection at the same time, including Guillain-Barre syndrome (GBS) 20 cases, multiple sclerosis (MS) 25 cases, Al This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University. The contents and expressions of soluble Notch1 and DLL1 in CSF were detected by ELISA and Western Blot.
Result
1. The content of soluble Notch1 in cerebrospinal fluid of each group was also significantly higher in TM group than in other groups (P 0.01); the sensitivity and specificity of TM were 86.8% and 85.2% respectively when Notch1 (>8.50pg/ml) was used as the judgment value of TM, but the standard was not well differentiated from cryptococcal encephalitis, and there was no significant difference among the other groups (P 0.05).
2. The content of soluble DLL1 in cerebrospinal fluid of each group was significantly higher in TM group than that in other groups (P 0.01); the sensitivity and specificity of TM were 100% and 96.9% respectively with DLL1 (>0.77 ng/ml), and there was no significant difference among the other groups (P 0.05).
3. Contents of soluble Notch1 and DLL 1 in cerebrospinal fluid with or without high triglycerides: The contents of Nocth1 in CSF with high triglycerides in TM group and normal triglycerides in TM group were (6.85 (+ 2.32), 7.30 (+ 1.35 pg/m1), respectively. There was no significant difference between the two groups (P 0.05). The content of DLL1 in CSF with high triglyceride in TM group and normal triglyceride in TM group was 3.18 (+ 2.92) and 3.62 (+ 1.79 ng/ml), respectively. There was no significant difference between the two groups (P 0.05). There was no significant difference in the content of Nocth1 in CSF with high triglyceride or normal triglyceride in other groups (P 0.05).
4. Western Blot results showed that the expression of Notch1 and DLL-1 protein in cerebrospinal fluid of TM group was higher than that of other groups.
The follow-up results of 5.39 TM patients showed that the levels of CSF soluble Notch 1 and DLL 1 decreased significantly (5.78 (+ 2.87 pg/ml) and 1.89 (+ 0.58 ng/ml) after 4 weeks of effective chemotherapy in 37 TM patients. There was significant difference between the two groups (P 0.05). After 12 weeks of treatment, the levels of CSF soluble Notch 1 and DLL 1 decreased to normal level (0.85 (+ 0.62 pg/ml) and 2.05 (+ 1.21 ng/ml). The CSF Notch1 and DLL1 levels did not decrease.
conclusion
This study suggests that the levels of soluble Notch1 and DLL1 in CSF of TM patients are significantly higher than those of VM, PM, cryptococcal meningitis and non-infectious nervous system diseases. The levels of soluble Notch1 and DLL1 in CSF of TM patients are lower or undetectable. Indicators.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R529.3
[Abstract]:Background and purpose
Tuberculous meningitis (TM) is one of the common infectious diseases of the central nervous system in clinic. The incidence of TM is increasing in recent years. Correct diagnosis and early treatment are important factors for prognosis. Bacteriological examination is often not conducive to early diagnosis, easy to misdiagnose and miss diagnosis because of its long cycle, low sensitivity and difficult detection of pathogens.
Notch signaling is an evolutionarily conserved transduction pathway involved in embryonic development and self-renewal, as well as the regulation of cell fate, which is essential in biological development. Loss of energy may lead to embryonic death, but there is little research on the role of DLL protein level in disease.
Our previous work found that the levels of DLL1 in serum and cerebrospinal fluid (CSF) of TM patients were significantly elevated, which is of great diagnostic significance. On this basis, this study will continue to use Enzyme Linked Immunosorbent Assays (ELISA) and Western Blot methods to detect central nervous system infections. The levels of soluble Notch1 and DLL1 in CSF of patients with sexual diseases were explored, and a new diagnostic method for TM was explored.
Objects and methods
A total of 289 patients with lumbar puncture in the Department of Neurology of the First Affiliated Hospital of Zhengzhou University from July 2008 to March 2012 were selected and divided into two groups according to their clinical diagnosis, 127 patients in TM group and 90 patients in non-TM infectious meningitis control group, including 10 patients with purulent meningitis (PM) and 10 patients with viral meningitis (VM). 65 cases, 15 cases of Cryptococcus neoformans meningitis (CM), 72 cases of non-infectious nervous system disease control group, selected patients excluding central nervous system infection at the same time, including Guillain-Barre syndrome (GBS) 20 cases, multiple sclerosis (MS) 25 cases, Al This study was approved by the Medical Ethics Committee of the First Affiliated Hospital of Zhengzhou University. The contents and expressions of soluble Notch1 and DLL1 in CSF were detected by ELISA and Western Blot.
Result
1. The content of soluble Notch1 in cerebrospinal fluid of each group was also significantly higher in TM group than in other groups (P 0.01); the sensitivity and specificity of TM were 86.8% and 85.2% respectively when Notch1 (>8.50pg/ml) was used as the judgment value of TM, but the standard was not well differentiated from cryptococcal encephalitis, and there was no significant difference among the other groups (P 0.05).
2. The content of soluble DLL1 in cerebrospinal fluid of each group was significantly higher in TM group than that in other groups (P 0.01); the sensitivity and specificity of TM were 100% and 96.9% respectively with DLL1 (>0.77 ng/ml), and there was no significant difference among the other groups (P 0.05).
3. Contents of soluble Notch1 and DLL 1 in cerebrospinal fluid with or without high triglycerides: The contents of Nocth1 in CSF with high triglycerides in TM group and normal triglycerides in TM group were (6.85 (+ 2.32), 7.30 (+ 1.35 pg/m1), respectively. There was no significant difference between the two groups (P 0.05). The content of DLL1 in CSF with high triglyceride in TM group and normal triglyceride in TM group was 3.18 (+ 2.92) and 3.62 (+ 1.79 ng/ml), respectively. There was no significant difference between the two groups (P 0.05). There was no significant difference in the content of Nocth1 in CSF with high triglyceride or normal triglyceride in other groups (P 0.05).
4. Western Blot results showed that the expression of Notch1 and DLL-1 protein in cerebrospinal fluid of TM group was higher than that of other groups.
The follow-up results of 5.39 TM patients showed that the levels of CSF soluble Notch 1 and DLL 1 decreased significantly (5.78 (+ 2.87 pg/ml) and 1.89 (+ 0.58 ng/ml) after 4 weeks of effective chemotherapy in 37 TM patients. There was significant difference between the two groups (P 0.05). After 12 weeks of treatment, the levels of CSF soluble Notch 1 and DLL 1 decreased to normal level (0.85 (+ 0.62 pg/ml) and 2.05 (+ 1.21 ng/ml). The CSF Notch1 and DLL1 levels did not decrease.
conclusion
This study suggests that the levels of soluble Notch1 and DLL1 in CSF of TM patients are significantly higher than those of VM, PM, cryptococcal meningitis and non-infectious nervous system diseases. The levels of soluble Notch1 and DLL1 in CSF of TM patients are lower or undetectable. Indicators.
【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R529.3
【参考文献】
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1 李尽义;贾延R，
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