甲泼尼龙冲击治疗放射性脊髓病14例临床观察

目的观察甲泼尼龙冲击疗法(MPPT)治疗放射性脊髓病(RMP)的疗效。方法将27例RMP患者随机分为治疗组(MPPT)与对照组(常规治疗),疗程3个月,观察治疗前后临床疗效、免疫功能指标变化。结果治疗组总有效率(78·51%)明显高于对照组(38·21%),免疫功能较对照组有明显改善。结论应用MPPT治疗RMP具有良好效果。     

甲泼尼龙在神经外科领域的应用

与其它糖皮质激素不同,甲泼尼龙是目前临床上治疗急性脊髓损伤的有效药物,主要通过抑制氧自由基诱导的脂质过氧化发挥神经保护作用。甲泼尼龙对中枢神经系统肿瘤、蛛网膜下腔出血也有一定的治疗效果,可作为手术、放、化疗的辅助用药。但甲泼尼龙对急性颅脑损伤是否同其治疗脊髓损伤一样有效,尚不十分清楚。     

间断甲泼尼龙琥珀酸钠治疗颈脊髓损伤伴不全瘫的临床疗效评价及安全性分析

目的探讨间断甲泼尼龙琥珀酸钠治疗颈脊髓损伤伴不全瘫患者临床疗效及安全性。方法选取我院2015-02—2016-02收治的48例颈脊髓损伤伴不全瘫患者,按计算机表法均分为观察组与对照组各24例。根据患者颈脊髓受压程度实施椎体减压以及植骨融合内固定手术,观察组在此基础上进行甲泼尼龙琥珀酸钠治疗。结果观察组治愈率、JOA评分、不良反应发生率均显著优于对照组,差异均有统计学意义(P0.05)。结论在颈脊髓损伤伴不全瘫患者治疗过程中应用间断甲泼尼龙琥珀酸钠治疗临床疗效显著,能够显著降低患者的不良反应发生率,提高治愈率,改善患者的JOA评分,值得临床推广。     

轻症吉兰-巴雷综合征患者免疫球蛋白与甲泼尼龙治疗效果比较

目的 比较甲泼尼龙与免疫球蛋白静脉注射(IVIG)治疗轻症吉兰-巴雷综合征(GBS)的临床效果.方法 回顾性分析我院1996年1月～2011年12月92例轻症GBS患者.根据治疗方法不同分为两组,52例采用IVIG治疗的患者为IVIG组,40例采用甲泼尼龙治疗的患者为甲泼尼龙组,观察两组疗效.结果 甲泼尼龙组与IVIG治疗轻症GBS效果显示,甲泼尼龙组治愈18例,显著进步10例,进步12例,总有效率100％；IVIG组治愈24例,显著进步16例,进步12例,总有效率100％；两组治疗效果比较差异无统计学意义(P＞0.05).结论 甲泼尼龙与丙种球蛋白静脉注射均是治疗轻症GBS的有效方法.     

替莫唑胺及甲泼尼龙对人胶质瘤细胞放射治疗敏感性的影响

目的探讨替莫唑胺(TMZ)和甲泼尼龙(MP)对人胶质瘤细胞系U251放射治疗敏感性的影响,以期为临床优化治疗方案提供依据。方法经体外传代培养的U251细胞根据治疗方案的不同,分为对照组、放射治疗(R)组、放射治疗+替莫唑胺(R+TMZ)组、放射治疗+甲泼尼龙(R+MP)组、放射治疗+替莫唑胺+甲泼尼龙(R+TMZ+MP)组,分别予以放射治疗(2 Gv/24 h)、替莫唑胺、甲泼尼龙及三者联合治疗。采用磺酰罗丹明B(SRB)比色法、流式细胞术和Western blotting法分析U251细胞增殖率和凋亡率,观察凋亡相关蛋白Bax和Bc1-2表达变化。结果放射线照射联合甲泼尼龙治疗后,U251细胞存活率明显升高(均P=0.000);但经体外培养24和48 h后,三者联合治疗组(R+TMZ+MP组)U251细胞增殖率显著高于放射治疗联合替莫唑胺组(P=0.000)。除对照组外,不同抗肿瘤治疗组U251细胞凋亡率均呈现升高趋势(P=0.000),但放射治疗联合甲泼尼龙组细胞凋亡率显著低于其他各组(均P=0.000)。经放射线照射联合替莫唑胺和三者联合治疗后,U251细胞Bax蛋白表达水平升高(P=0.000),而放射线照射联合甲泼尼龙和三者联合治疗,Bcl-2蛋白表达水平升高;其中以放射治疗联合替莫唑胺组Bax/Bcl-2比值最高(P=0.000),放射治疗联合甲泼尼龙组最低(P=0.000)。结论甲泼尼龙可以诱导人胶质瘤细胞产生放射抵抗,而替莫唑胺对甲泼尼龙诱导的放射抵抗具有增敏作用。提示:胶质母细胞瘤患者在应用甲泼尼龙减轻放射治疗不良反应过程中所诱导的放射治疗抵抗可通过同时应用替莫唑胺而抵消。     

甲泼尼龙琥珀酸钠对许旺细胞分泌功能的影响*☆

背景：许旺细胞分泌多种神经营养因子在神经再生中发挥关键作用，但其分泌能力受诸多因素影响，寻找可行方法促进许旺细胞分泌神经生长因子是神经缺损后再生的重要环节。 目的：观察不同浓度甲泼尼龙琥珀酸钠对许旺细胞分泌功能的影响。 方法：酶消化法分离培养SD乳鼠许旺细胞，倒置相差显微镜下观察细胞生长情况；传代后，一部分进行S-100蛋白免疫鉴定许旺细胞的纯度；另一部分用细胞计数板调整细胞浓度为1×109 L-1，移入到6孔平底培养板(接种15个孔)继续培养。培养板中培养4 d后4个孔分别加入不同浓度的甲泼尼龙琥珀酸钠(10-3，10-4，10-6，10-8 mol/L)，并设立1个孔为不加药物的空白对照组，分别作用于细胞24，48，72 h后行RT-PCR检测，观察许旺细胞24，48，72 h神经生长因子mRNA水平的变化。 结果与结论：原代细胞培养至第7天数量明显增加，细胞铺满培养瓶底部80%以上；传代细胞形态为梭形，有2个细长的突起，荧光染色阳性，成纤维细胞为圆形或扁圆形，荧光染色阴性。RT-PCR检测结果显示，10-8 mol/L的甲基强地松龙作用72 h分泌的神经生长因子与空白对照组及其他浓度、时间组相比均表达增加(P < 0.05)；10-3 mol/L甲基强地松龙在各时间段分泌的神经生长因子与空白对照组及其他浓度、时间组相比表达均减少(P < 0.05)。提示高浓度的甲泼尼龙琥珀酸钠抑制许旺细胞分泌神经生长因子，长时间、低浓度的甲泼尼龙琥珀酸钠则促进许旺细胞分泌神经生长因子。     

甲泼尼龙冲击治疗对视神经脊髓炎谱系病患者外周血滤泡辅助性T细胞百分率的影响

目的探究视神经脊髓炎谱系病(NMOSD)患者外周血滤泡辅助性T细胞(Tfh)百分率在甲泼尼龙冲击治疗前、后的变化。方法收集AQP-4抗体阳性的急性期NMOSD患者(NMOSD组)23例,采用流式细胞术检测甲泼尼龙冲击前、后外周血CXCR5~+ICOS~+的CD4~+T细胞(Tfh细胞),记录NMOSD组的EDSS评分,分析NMOSD组患者Tfh细胞百分率与患者AQP-4抗体滴度及EDSS评分的相关性。结果 NMOSD组患者甲泼尼龙冲击治疗前外周血Tfh细胞百分率[(1.77±0.74)%]显著高于甲泼尼龙冲击治疗后[(1.26±0.45)%](t=2.284,P=0.032)。首次发病NMOSD患者甲泼尼龙冲击治疗前Tfh细胞百分率与EDSS评分呈正相关(r=0.625,P=0.040),甲泼尼龙冲击治疗前、后Tfh细胞百分率与AQP-4抗体滴度无相关性(r=--0.02,P=0.928)。结论经甲泼尼龙冲击治疗后,NMOSD患者急性期外周血Tfh细胞百分率降低,首次发病NMOSD患者Tfh细胞百分率水平与EDSS评分有关。Tfh细胞百分率水平可能与NMOSD的复发有关。     

替莫唑胺及甲泼尼龙对人胶质瘤细胞放射治疗敏感性的影响

目的探讨替莫唑胺（TMZ）和甲泼尼龙（MP）对人胶质瘤细胞系U251放射治疗敏感性的影响,以期为临床优化治疗方案提供依据。方法经体外传代培养的U251细胞根据治疗方案的不同,分为对照组、放射治疗（R）组、放射治疗＋替莫唑胺（R＋TMZ）组、放射治疗＋甲泼尼龙（R＋MP）组、放射治疗＋替莫唑胺＋甲泼尼龙（R＋TMZ＋MP）组,分别予以放射治疗（2Gy／24h）、替莫唑胺、甲泼尼龙及三者联合治疗。采用磺酰罗丹明B（SRB）比色法、流式细胞术和Western blotting法分析U251细胞增殖率和凋亡率,观察凋亡相关蛋白Bax和Bcl-2表达变化。结果放射线照射联合甲泼尼龙治疗后,U251细胞存活率明显升高（均P=0．000）;但经体外培养24和48h后,三者联合治疗组（R＋TMZ＋MP组）U251细胞增殖率显著高于放射治疗联合替莫唑胺组（P=0．000）。除对照组外,不同抗肿瘤治疗组U251细胞凋亡率均呈现升高趋势（P=0．000）,但放射治疗联合甲泼尼龙组细胞凋亡率显著低于其他各组（均P=0．000）。经放射线照射联合替莫唑胺和三者联合治疗后,U251细胞Bax蛋白表达水平升高（P=0．000）,而放射线照射联合甲泼尼龙和三者联合治疗,Bcl-2蛋白表达水平升高;其中以放射治疗联合替莫唑胺组Bax／Bcl-2比值最高（P=0．000）,放射治疗联合甲泼尼龙组最低（P=0．000）。结论甲泼尼龙可以诱导人胶质瘤细胞产生放射抵抗,而替莫唑胺对甲泼尼龙诱导的放射抵抗具有增敏作用。提示：胶质母细胞瘤患者在应用甲泼尼龙减轻放射治疗不良反应过程中所诱导的放射治疗抵抗可通过同时应用替莫唑胺而抵消。     

脊髓损伤后细胞的凋亡及其药物治疗

细胞凋亡是脊髓损伤后引起神经功能障碍及影响疗效的主要原因。本文对引起脊髓细胞凋亡的原因及其药物治疗的研究进展进行了概述。     

许旺细胞-海藻酸钠凝胶移植修复大鼠脊髓损伤*

目的：观察许旺细胞-海藻酸钠凝胶移植对大鼠脊髓损伤后细胞凋亡、Bcl-2表达及下肢运动功能恢复的影响。 方法：清洁级SD大鼠随机分为4组：正常对照组、单纯损伤组、许旺细胞组、许旺细胞-海藻酸钠凝胶组。后3组制作脊髓全横断损伤模型。正常对照组、单纯损伤组不进行移植处理,许旺细胞组植入吸附许旺细胞悬液的明胶海绵块、许旺细胞-海藻酸钠凝胶组植入许旺细胞-海藻酸钠凝胶。分别于 12 h,1,3,7,21 d对动物进行BBB评分后处死,取损伤区脊髓节段制成石蜡切片进行TUNEL、Bcl-2染色,观察脊髓内凋亡细胞、Bcl-2细胞的数量及分布变化。 结果：正常对照组仅有少量淡染Bcl-2阳性细胞;单纯损伤组神经元Bcl-2免疫反应阳性细胞表达的高峰在第3天,14 d时Bcl-2免疫反应阳性细胞表达接近正常水平。许旺细胞-海藻酸钠凝胶移植后损伤脊髓细胞Bcl-2免疫反应阳性细胞表达具有显著增高(P < 0.05),7 d高度表达并持续2周以上。单纯损伤组脊髓内细胞凋亡最多,并于损伤后1,7 d形成两个高峰,多分布于白质中。许旺细胞-海藻酸钠凝胶组BBB评分较单纯损伤组及许旺细胞组明显提高(P < 0.05)。 结论：许旺细胞-海藻酸钠凝胶移植能抑制大鼠脊髓损伤后脊髓细胞凋亡、促进Bcl-2的表达,提高了脊髓运动功能的恢复,但未达到正常水平。 关键词：脊髓损伤;细胞凋亡;许旺细胞;Bcl-2     

Effect of a single huge dose of methylprednisolone on blood flow,evoked potentials,and histology after acute spinal cord injury in the rat

Abstract

Effects ofa single, huge dose of methylprednisolone on post-traumatic spinal cord blood flow (SCBF), evoked potentials and histological changes were studied in a rat model ofspinal cord injury. The purpose of this study was to assess the optimal dose of methylprednisolone for the treatment of rat spinal cord injury. Twenty-five male Wistar rats were subjected to an acute clip compression injury at 51 g for 1 min at CB-T1, and then received an intravenous bolus injection of one of the following 30 min after injury: vehicle, 30, 60, 120 or 240 mg kg ^-1 methylprednisolone. SCBF was measured at the injury site and an adjacent area with the' hydrogen clearance technique. Sensory evoked potentials following sciatic stimulation were recorded from the somatosensory and cerebellar cortices. Descending volleys were recorded from T9-10 spinal cord following cerebellar stimulation. SCBF and evoked potential recordings were repeated until perfusion-fixation at 4 h after injury. After injury, SCBF at both levels significantly dropped, and all evoked potentials disappeared in all animals. None of the doses of methylprednisolone improved post-traumatic SCBF, or evoked potentials. Qua;ntitative histological assessment ,of the injured cords revealed no significant differences in hemorrhages or cavitation in the spinal cord among the treatment groups. This study showed that a single huge dose of methylprednisolone from 30 to 240 mg kg- ¹ had no beneficial effects on the traumatized rat spinal cord in the acute stage. [Neural Res 1997; 19: 289–299]     

Spinal taurine levels are increased 7 and 30 days following methylprednisolone treatment of spinal cord injury in rats

The amino acid taurine serves many functions in the nervous system serving as inhibitory neurotransmitter/neuromodulator, neurotrophin, antioxidant, and osmolyte. Taurine levels are increased following brain injury and glucocorticoid administration. Thus, the purpose of this study was to examine spinal taurine concentrations following spinal cord injury (SCI) and methylprednisolone (MP) treatment of SCI. A total of 44 adult male Sprague-Dawley rats were divided into control and lesion groups. Control rats received a T6 vertebral laminectomy while lesioned rats received a laminectomy followed by complete spinal transection. Half of the animals in each group received MP intravenously following sham-operation or SCI. Rats survived for 7 or 30 days and concentrations of taurine in spinal gray and white matter, in spinal segments both near and distant from the injury epicenter, were resolved by HPLC analysis. Taurine levels were increased 7 and 30 days following transection in spinal segments immediately adjacent to the lesion and were further elevated by MP treatment. No increases were seen in far rostral/caudal segments, and MP treatment alone had no effect on spinal taurine levels. These findings demonstrate that spinal injury results in increased taurine concentrations in spinal segments undergoing the greatest degree of cellular reactivity and tissue reorganization and that MP therapy potentiates these increases. These findings are significant in that they further characterize the effects of acute MP therapy in spinal tissue. Since taurine is thought to be involved in neuroprotection and/or regeneration following injury, the potentiation of taurine levels by MP treatment may relate to its therapeutic properties.     

甲基强的松龙对急性脊髓损伤神经元保护作用的实验研究

目的探讨甲基强的松龙对急性脊髓损伤(ASCI)后神经元是否具有保护作用。方法大鼠随机分为2组，即模型组和正常对照组(N组)，模型组建立脊髓半横断损伤模型后又分两组，即激素治疗组(M组)，腹腔注射甲基强的松龙(MP)；模型对照组(B组)术后不做处理。每组大鼠观察损伤后3d、7d、15d和30d。取脊髓损伤部位标本做光镜病理组织学检查，观察正常神经元和变性神经元的数量变化。结果(1)B组在ASCI早期脊髓损伤区的灰白质被明显的破坏，有出血及坏死，可见多量空泡状细胞和溃变的神经纤维，部分组织液化。在损伤灶内见正常神经元及神经纤维的数量稀少，多数神经元呈现不同程度的变性乃至坏死。随着时间的延长，神经元数量进一步减少，胶质细胞增生形成疤痕，或者液化形成囊腔。病变常常累及对侧组织，而M组的脊髓损伤区组织结构的变化与B组基本相同。(2)在ASCI后3d，M组的正常神经元数量少于B组，变性神经元数量与B组相近；在损伤7d以后，随着时间的延长，B组的变性神经元数量减少的同时，正常神经元的数量稍有减少，而M组的变性神经元数量减少的同时，正常神经元数量有所增加。结论(1)MP对ASCI后的继发性组织结构破坏无明显的改善作用；(2)MP在ASCI早期能促使神经元的死亡，但在后期能增加正常神经元的数量，其机理有待于进一步研究。     

细胞移植治疗脊髓损伤的最新进展

一般认为脊髓损伤(spinal cord injury,SCI)造成患者局部甚至全身的瘫痪.大小便失禁和损伤平面以下的感觉消失等功能缺失是永久性的.     

不同来源成体神经干细胞促进大鼠脊髓损伤功能修复的比较研究

目的 评价大脑、骨髓和脂肪组织3种不同来源的神经干细胞对大鼠脊髓挫伤的治疗效果.方法 选取来源于同一大鼠成体中大脑、骨髓和脂肪的3个部位的组织,分离、诱导分化为不同来源的神经干细胞;应用自由落体损伤模型装置造成大鼠脊髓挫伤.将不同来源的神经干细胞分别移植入大鼠脊髓损伤部位,通过BBB评分比较修复脊髓损伤功能的效果,应用免疫荧光染色检测不同移植细胞在损伤脊髓中的存活、分布、迁移的情况.另设假手术对照组和生理盐水对照组.结果 与假手术对照组和生理盐水对照组比较,3个细胞处理组BBB评分在2～8周开始增加,9周以后更加明显,差异开始有统计学意义(P<0.05).在移植后1周和4周,细胞移植组中脑源性神经干细胞(SVZ-NSs)组Brdu/nestin+>神经元存活的数目明显高于其他2组.但差异没有统计学意义(P>0.05);到了第8周,3组均仅有少量Brdu/nestin+>细胞存活,相互之间比较差异无统计学意义(P>0.05).结论 植入来源于大脑、骨髓和脂肪组织的神经干细胞都可以在一定程度上提高脊髓损伤后运动功能恢复,但SVZ-NSs组的脊髓损伤大鼠运动功能恢复要比脂肪来源的神经干细胞(AD-NSs)组及骨髓来源的神经干细胞(BM-NSs)组更好.AD-NSs由于来源广泛和强有力的增殖能力,相比其他来源的神经干细胞,可能是更好的选择.     

促红细胞生成素联合甲强龙对脊髓损伤病人神经功能的影响

目的 探讨促红细胞生成素（EPO）联合甲强龙对脊髓损伤（SCI）病人神经功能的影响。方法 回顾性分析2018年1~12月收治的60例SCI的临床资料。采用EPO联合甲强龙治疗30例（观察组）,单用甲强龙治疗30例（对照组）。甲强龙首次用量30 mg/kg,在15 min内静脉注射,1 h后以5.4 mg/（kg·h）维持治疗24 h后;EPO治疗,3 000 IU/次,3次/周,持续8周。治疗前及治疗后1个月按照美国脊髓损伤协会（ASIA）评分评估神经功能,采用日常生活活动能力（ADL）评分评估生活能力。治疗前、治疗后2周检测红细胞和血红蛋白水平,准确记录两组病人治疗2周内并发症情况。结果 治疗前,两组ASIA评分、ADL评分、红细胞、血红蛋白水平均无统计学差异（P>0.05）。治疗后,两组ASIA评分、ADL评分、红细胞、血红蛋白水平均明显增高（P<0.05）,而且,观察组明显高于对照组（P<0.05）。观察组并发症发生率明显低于对照组（P<0.05）。结论 EPO联合甲强龙治疗有利于促进SCI病人神经功能的恢复,减少并发症,具有很好的临床疗效。     

Comparison of effects of methylprednisolone and anti-CD11d antibody treatments on autonomic dysreflexia after spinal cord injury

Autonomic dysreflexia is a condition of episodic hypertension that develops after spinal cord injury (SCI). We previously showed that a two-day anti-inflammatory treatment with an anti-CD11d integrin monoclonal antibody (mAb), soon after SCI in rats, reduced the magnitude of dysreflexia for at least 6 weeks. Effects of methylprednisolone (MP), a commonly used neuroprotective treatment for SCI, on dysreflexia have never been examined. We compared the effects of a 2-day MP treatment and/or the anti-CD11d mAb on autonomic dysreflexia, elicited by colon distension, after clip-compression SCI at the 4th thoracic segment (T4) in rats. We assessed the effects of each treatment on the size of the calcitonin gene-related peptide (CGRP)-immunoreactive afferent arbour in the dorsal horn, as changes in this arbour can correlate with the development of dysreflexia. MP reduced autonomic dysreflexia by approximately 50% at 2 weeks after SCI, but this effect was lost by 6 weeks. At 2 weeks, the combined effects of MP and the mAb were not additive, reducing dysreflexia by approximately 50%. Neither MP nor the mAb treatment altered the area of CGRP-immunoreactive fibres in the lumbar cord, the crucial input region for dysreflexia initiated by colon distension. However, both treatments led to increased fibre areas in the T9 segment, correlated with greater tissue integrity and smaller lesions, delineated by inflammatory cells. In summary, MP only temporarily decreases autonomic dysreflexia after SCI. The early beneficial effects of both treatments on dysreflexia do not relate to changes in the CGRP-immunoreactive afferent arbour but may correlate with decreased lesion progression.     

Relatively low levels of calpain expression in juvenile rat correlate with less neuronal apoptosis after spinal cord injury

Approximately 5% of spinal cord injuries in the US occur in patients younger than 16 years. These young patients have an increased mortality within the 24 h after trauma but have a greater capacity for functional recovery than adults, suggesting age-related differences in injury tolerance. Unfortunately, the response of the developing cord to secondary injury has not been thoroughly investigated. Calpain, a Ca(2+)-dependent protease, has been implicated in the pathogenesis of spinal cord injury (SCI) in rats. Our current investigation revealed that following SCI, calpain upregulation was qualitatively less in the 21-day-old rats than in adult rats, as shown by immunofluorescent labeling. Decreased levels of TUNEL+ neurons were also noted in juvenile rat spinal cord, indicating that the developing cord may have an increased resistance to injury.     

胎鼠神经干细胞移植对大鼠脊髓损伤后神经细胞凋亡及凋亡抑制基因Bcl-2表达的影响

目的研究胎鼠神经干细胞(NSCs)移植对大鼠脊髓损伤(SCI)后神经细胞凋亡及凋亡抑制基因Bcl-2表达的影响。方法 40只SD大鼠随机分为正常对照组(Normal组),脊髓损伤组(SCI组),神经干细胞组(NSC组),神经干细胞标记组(BrdU+NSCs组)。采用电控脊髓损伤打击装置制作模型,5-溴脱氧尿嘧啶核苷(Br-dU)法标记处于对数生长期的NSCs,SCI后即刻进行NSCs移植。免疫组化法观察BrdU标记NSCs的存活、迁移及凋亡抑制基因Bcl-2的表达,TUNEL法标记凋亡细胞(免疫组化及免疫荧光显色),改良Rivlin法观察大鼠后肢运动功能的恢复情况。结果 BrdU+NSCs组在损伤脊髓区域可检测到BrdU标记的阳性NSCs。BrdU+NSC组与NSC组各时间点凋亡阳性细胞数均比SCI组减少(P<0.01),Bcl-2免疫阳性细胞光密度值比SCI组明显增加(P<0.01),且Bcl-2表达高峰延长至伤后7d;移植后7d、14d、28d后肢运动功能评分较SCI组明显升高(P<0.01)。Br-dU+NSC组与NSC组之间比较无明显差异(P>0.05)。结论体外培养的胚胎大鼠NSCs可在脊髓损伤区域存活、迁移,并能通过上调Bcl-2的表达来抑制大鼠脊髓损伤后神经细胞的凋亡,从而促进大鼠瘫痪肢体功能的恢复。     

脊髓损伤的细胞移植治疗及研究进展

目前针对脊髓损伤的治疗方式较多,但传统的药物疗法和手术减压等方式均有一定的局限性;因此,细胞移植治疗脊髓损伤作为一种新的治疗手段受到广泛关注.现从脊髓损伤的病理机制、细胞移植治疗原理及各种干细胞移植治疗脊髓损伤的研究进展等方面,详细阐述近年来细胞移植治疗脊髓损伤的发展状况.