Pathophysiology of idiopathic dystonia: findings from genetic animal models

Dystonia is a common movement disorder which is thought to represent a disease of the basal ganglia. However, the pathogenesis of the idiopathic dystonias, i.e. the neuroanatomic and neurochemical basis, is still a mystery. Research in dystonia is complicated by the existence of various phenotypic and genotypic subtypes of idiopathic dystonia, probably related to heterogeneous dysfunctions.In neurological diseases in which no obvious neuronal degeneration can be found, such as in idiopathic dystonia, the identification of a primary defect is difficult, because of the large number of chemically distinct, but functionally interrelated, neurotransmitter systems in the brain.The variable response to pharmacological agents in patients with idiopathic dystonia supports the notion that the underlying biochemical dysfunctions vary in the subtypes of idiopathic dystonia. Hence, in basic research it is important to clearly define the involved type of dystonia.Animal models of dystonias were described as limited. However, over the last years, there has been considerable progress in the evaluation of animal models for different types of dystonia.Apart from animal models of symptomatic dystonia, genetic animal models with inherited dystonia which occurs in the absence of pathomorphological alterations in brain and spinal cord are described.This review will focus mainly on genetic animal models of different idiopathic dystonias and pathophysiological findings. In particular, in the case of the mutant dystonic (dt) rat, a model of generalized dystonia, and in the case of the genetically dystonic hamster (dt^sz), a model of paroxysmal dystonic choreoathetosis has been used, as these show great promise in contributing to the identification of underlying mechanisms in idiopathic dystonias, although even a proper animal model will probably never be equivalent to a human disease.Several pathophysiological findings from animal models are in line with clinical observations in dystonic patients, indicating abnormalities not only in the basal ganglia and thalamic nuclei, but also in the cerebellum and brainstem. Through clinical studies and neurochemical data several similarities were found in the genetic animal models, although the current data indicates different defects in dystonic animals which is consistent with the notion that dystonia is a heterogenous disorder.Different supraspinal dysfunctions appear to lead to manifestation of dystonic movements and postures. In addition to increasing our understanding of the pathophysiology of idiopathic dystonia, animal models may help to improve therapeutic strategies for this movement disorder.     

利塞膦酸钠在防治绝经后骨质疏松症中的作用

目的　观察利塞膦酸钠防治绝经后骨质疏松症的疗效。方法　绝经后骨质疏松症共4 8例 ,随机分为 2组 ,对照组 2 4例 ,服安慰剂 ;试验组 2 4例 ,服利塞膦酸钠 5mg/d。另外 ,两组患者每日均服钙维生素D3 合剂 (凯思立 ) 1片 ,两组共服药 12个月 ,试验后 0、1、3、6、9、12个月进行随访。结果　利塞膦酸钠组腰椎、股骨颈及大粗隆的骨密度均明显升高 (P <0 0 5 ) ,其中腰椎骨密度治疗前为 0 80± 0 0 9,治疗后 6个月及 12个月均达到 0 82± 0 0 9,增加率为 2 93%及 2 85 % ,均明显高于对照组 (P <0 0 5 )。 6个月及 12个月治疗总有效率试验组为 80 95 %及 71 4 3% ,显著高于对照组的4 5 4 5 %及 31 82 % (P <0 0 5 )。两组患者均无严重副作用。结论　利塞膦酸钠能明显提高绝经后骨质疏松症患者的骨密度 ,副作用轻。     

少弱精子症与精浆附性腺标志物的相关性分析

目的分析少弱精子症患者精液参数与精浆附性腺标志物的相关性,探讨附性腺功能对男性生育力的影响。方法采用精液常规、精子形态、精浆附性腺标志物分析方法,检测正常供精者和门诊就诊的少弱精子症患者的精液相关指标。结果少弱精子症组正常形态精子百分数、精子穿透功能、精浆中性α-糖苷酶显著低于正常对照组。相关分析结果显示,少弱精子症患者组,精液量与精子活动率呈负相关(r=-0.415,P<0.05),精子数与形态呈正相关(r=0.393,P<0.05)。结论少弱精子症患者同时存在不同程度的附睾功能障碍,精子功能下降,精子畸形率显著升高,睾丸生精功能越低下,精子畸形发生率越高。     

次氯酸对人血清白蛋白的氧化修饰影响及与高级氧化蛋白产物的关系

目的 研究次氯酸对人血清白蛋白(HSA)的氧化修饰影响及与高级氧化蛋白产物(AOPPs)之间的关系。 方法 有氧条件下在恒定浓度的HSA(60 mg/ml)内加入不同浓度次氯酸(0、1、5、10、20、30、40、50、60 mmol/L，最终浓度)，观察氧化剂对HSA的修饰作用。凝胶排阻色谱法检验HSA氧化修饰结果，在线光谱扫描(190 nm~400 nm)分析修饰产物的光谱特性。结果 次氯酸可氧化修饰人血清白蛋白，其修饰产物主要为二聚体HSA和六聚体HSA。发现次氯酸对HSA单体和HSA二聚体的氧化修饰为一级反应；对诱导生成的AOPPs为准一级反应；而对诱导生成的HSA六聚体则为二级修饰反应。同时发现白蛋白对AOPPs的主要贡献者是六聚体形式的HSA，光谱分析表明HSA聚集体的最大吸收峰发生红移，提示HSA聚集体是由于蛋白中的酪氨酸残基通过氧化交联方式而聚集形成的。 结论 HSA经次氯酸处理后主要发生了蛋白聚集。而对AOPPs的主要贡献者是六聚体形式的HSA。     

The effect of supplementation with fish oil during pregnancy on breast milk immunoglobulin A, soluble CD14, cytokine levels and fatty acid composition

BACKGROUND: Breast milk contains many immunomodulatory factors (soluble CD14 (sCD14), IgA and cytokines) with the potential to influence infant immune development. OBJECTIVE: To determine if changes in breast milk omega-3 polyunsaturated fatty acid (n-3 PUFA) composition as a result of maternal dietary fish oil supplementation during pregnancy can modify levels of these immunological parameters in breast milk. METHOD: In a randomized controlled trial, 83 atopic women received either 4 g fish oil capsules (containing 3.7 g n-3 PUFA) (n = 40) or 4 g olive oil capsules (n = 43) from 20 weeks gestation until delivery. Breast milk was collected 3 days post-partum and fatty acids were analysed by gas liquid chromatography and IgA, sCD14 and cytokines (IL-5, IL-6, IL-10, TNF-alpha and IFN-gamma) were quantitated by ELISA or time resolved fluorescence (TRF). RESULTS: Omega-3 docosahexaenoic acid (DHA; 22:6n-3) and eicosapentaenoic acid (EPA; 20:5n-3) levels were significantly higher (P < 0.001) in breast milk from women supplemented with fish oil (n = 33, DHA mean 1.15%, SD 0.47% and EPA mean 0.16%, SD 0.07%) than in samples from the control group (n = 40, DHA mean 0.50%, SD 0.17% and EPA mean 0.05%, SD 0.02%). Breast milk arachidonic acid (AA; 20:4n-6) levels were significantly lower (P = 0.045) in the fish oil group (mean 0.55%, SD 0.12%) compared with the control group (mean 0.61%, SD 0.14%). Breast milk IgA was positively correlated with DHA (P = 0.046) and 22:5n-3 (P = 0.003), but inversely correlated with linoleic acid (LA; 18:2n-6) (P=0.034). Levels of sCD14 were also positively correlated with 22:5n-3 (P=0.009). Cytokines involved in IgA synthesis (IL-10 and IL-6) were also significantly correlated with both IgA and n-3 PUFA levels, although there were no differences in the levels of breast milk IgA, sCD14 or cytokines between study groups. CONCLUSION: Supplementation with fish oil during pregnancy significantly alters early post-partum breast milk fatty acid composition. omega-3 PUFA levels were positively associated with IgA and sCD14 levels, suggesting a relationship between fatty acid status and mucosal immune function.     

藻酸钙凝胶-成骨细胞-骨粉构建工程化骨修复兔颅骨缺损的实验研究

目的探讨藻酸钙凝胶、成骨细胞、骨粉复合构建的可塑形组织工程骨修补兔颅骨缺损后的形态学变化和成骨效果.方法28只日本大耳白兔,随机分为A(n=20)、B(n=8)两组,手术在兔颅顶骨矢状缝两侧分别各建立一个直径1cm的圆形全层缺损,用两种方法藻酸钙凝胶、成骨细胞、骨粉和藻酸钙凝胶、骨粉分别构建组成可塑形的组织工程骨复合材料,分别填补修复A组兔颅骨左右两侧的缺损,B组为空白对照组,通过大体、组织学、X线观察材料的形态变化、成骨情况,并对X线片和组织学切片进行评分.结果材料植入后,局部未见红肿、积液、渗出等异常反应.①藻酸钙凝胶-成骨细胞-骨粉组修补后12周颅骨缺损基本被硬性组织所修复,镜下见修复材料大多被骨组织替代,骨粉基本被吸收,有块状凝胶残留其中,组织学评分为(5.50±1.00).X线片见兔颅骨缺损处有高密度骨痂影存在,布满整个缺损区,X线片评分为(3.25±0.95).②藻酸钙凝胶-骨粉组修补后12周部分颅骨缺损被硬性组织所修复,镜下见修复材料部分转变成骨组织,骨粉基本被吸收,有凝胶残留其中,组织学评分为(3.25±1.50).X线片见兔颅骨缺损处有高密度骨痂影存在,主要分布在缺损区的边缘部位,X线片评分(2.25±0.25).③空白对照组骨缺损主要被膜样纤维组织修复,在紧邻骨缺损边缘处有硬性组织形成,镜下见修复组织边缘有骨组织存在,中央大部为膜状致密纤维组织,组织学评分为(1.50±0.50),X线片仅见靠近骨缺损边缘的部位存在致密骨痂影,X线片评分为(1.00±0.57).结论藻酸钙凝胶、成骨细胞、骨粉构建的可塑形组织工程骨可根据颅骨缺损的形态进行塑形填补,在体内有良好的成骨能力,可达到对兔颅骨缺损的骨性修复,但部分藻酸盐凝胶吸收缓慢,手术后12周仍不能满意吸收.     

Growth factor pre-treatment differentially regulates phosphoinositide turnover downstream of lysophospholipid receptor and metabotropic glutamate receptors in cultured rat cerebrocortical astrocytes

Reactive gliosis is an aspect of neural plasticity and growth factor (GF) stimulation of astrocytes in vitro is widely regarded as a model system to study astrocyte plasticity. Astrocytes express receptors for several ligands including lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P), agonists for the G-protein-coupled lysophospholipid receptors (lpRs). Activation of lpRs by LPA or S1P leads to multiple pharmacological effects including the influx of calcium, phosphoinositide (PI) hydrolysis, phosphorylation of extracellular receptor regulated kinase (ERK), release of arachidonic acid, and induces mitogenesis. Treatment of astrocytes in vitro with a growth factor cocktail (containing epidermal growth factor [EGF], basic fibroblast growth factor [bFGF] and insulin) led to a marked attenuation of lpR-induced PI hydrolysis. In contrast, under identical conditions, GF treatment led to marked potentiation of PI hydrolysis downstream of activation of another abundantly expressed G-protein coupled receptor, mGluR5. Quantitative gene expression analysis of GF-treated or control astrocytes by TaqMan RT-PCR indicated that GF treatment did not change gene expression of lpa1 and s1p1, but increased gene expression of s1p5 which is expressed at very low levels in basal conditions. These results suggest that GF differentially affected PLC activation downstream of mGluR5 versus lpR activation and that the changes in mRNA levels of lpRs do not account for marked attenuation of agonist-induced phosphoinositide turnover.     

1,6-二磷酸果糖改善兔脑血肿周围组织能量代谢的研究

目的:观察1,6二磷酸果糖(FDP)对血肿周围组织能量代谢的影响。方法:健康大耳白兔随机分成正常组,假手术组,脑出血组和治疗组,其中后3组又按各时间点分成1、6、12、24、48和72h组。两次注血法制作脑出血模型,测定各时点血肿周围组织乳酸含量、三磷酸腺苷(ATP)含量和磷酸果糖激酶(PFK)活性。结果:脑出血组24h后ATP含量有明显下降,治疗组ATP含量明显增高。1、6、12h治疗组乳酸含量降低,且治疗组乳酸峰值延迟至24h。治疗组PFK活性均高于脑出血组。结论:FDP可改善血肿周围组织的能量代谢。     

田径运动员最大摄氧量和无氧功测试中血乳酸的应用

目的:研究田径运动员最大摄氧量和Wingate测试后血乳酸的变化,分析血乳酸对测试结果的意义。方法:测试田径短跑运动员36例和中长跑运动员29例的最大摄氧量和Wingate无氧功,以及测试后的血乳酸值。结果:最大摄氧量测试后血乳酸数值为9～11mmol/L左右,摄氧量与乳酸值没有直接相关关系,但不同项目之间有一定的差异;Wingate测试后血乳酸数值一般大于12mmol/L,测试的主要评价指标与乳酸值都有较高的相关关系。结论:血乳酸值对于最大摄氧量测试意义不大,但对于Wingate测试可以作为一项辅助评价指标。     

Patency of the infarct-related coronary artery — a pertinent factor in late recovery of myocardial fatty acid metabolism among patients receiving thrombolytic therapy?

The decrease in mortality among patients receiving thrombolytic therapy for myocardial infarction is greater than would be expected from the improvement in left ventricular contractile function alone; thus some additional advantage of recanalization of the infarctrelated coronary artery probably exists. Changes in the post-infarction myocardial metabolic state with respect to artery patency have not been studied with a gamma camera previously. A single-photon emission tomography scan using the fatty acid analogue para-¹²³I-iodophenylpentadecanoic acid was performed at rest before hospital discharge on nine patients with first anterior myocardial infarction. All patients had received intravenous thrombolytic therapy at the beginning of the insult. The semiquantitative analysis of the left ventricle included a total of 44 segments in each patient. The test was repeated 3 months later, with the patients divided into two groups: six patients had an angiographically patent left anterior descending coronary artery (group A), and three an occluded artery (group B). In group A the number of myocardial segments with abnormal (<70% of maximum) fatty acid uptake was initially 20.2±4.7 (mean±SD) and was reduced to 11.3±6.1 during the follow-up (95% confidence interval of the decrease 16.0–1.7 segments). In group B the number of these aberrant segments was fairly constant (21.7±13.1, initial test, and 21.3±13.3, retest). Our preliminary results suggest that even when thrombolytic therapy fails to prevent myocardial infarction, myocardial fatty acid metabolism has a better change of recovering if the relevant coronary artery has regained its patency. This finding emphasizes the need for further study to establish whether a direct link exists between myocardial metabolic state and patient survival after infarction.