Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD)

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha- synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha- synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.      

Altered behavioral response to dopamine D3 receptor agonists 7-OH-DPAT and PD 128907 following repetitive amphetamine administration.

Behavioral sensitization, the progressive and enduring enhancement of certain behaviors following repetitive drug use, is mediated in part by dopaminergic pathways. Increased locomotor response to drug treatment, a sensitizable behavior, is modulated by an opposing balance of dopamine receptor subtypes, with D1/D2 dopamine receptor stimulation increasing and D3 dopamine receptor activation inhibiting amphetamine-induced locomotion. We hypothesize that tolerance of D3 receptor locomotor inhibition contributes to behavioral sensitization. In order to test the hypothesis that expression of behavioral sensitization results in part from release of D3 receptor-mediated inhibition, thereby resulting in decreased response to D3 receptor agonists, we examined the effect of repetitive amphetamine administration on the behavioral response to the D3 receptor preferring agonists 7-OH-DPAT and PD 128907. D3-selective effects have recently been described for both drugs at a low dose. At 1 week following completion of a repetitive treatment regimen, amphetamine-pretreated rats displayed a decreased response to D3-selective doses of both 7-OH-DPAT and PD 128907, when compared to animals receiving saline pretreatment. Moreover, in addition to the quantitative alteration in response, there was a change in the inter-relation between response to amphetamine and D3 agonist. A highly significant inverse relation between locomotor inhibitory response to PD 128907 and the locomotor-stimulant response to amphetamine was observed prior to amphetamine treatment. In contrast, 10 days following repetitive amphetamine treatment, the relation between response to PD 128907 and amphetamine was not detected. The observed behavioral alteration could not be accounted for by changes in D3 receptor binding in ventral striatum. These findings suggest a persistent release of D3 receptor-mediated inhibitory influence contributes to the expression of behavioral sensitization to amphetamine.     

The dopamine D3 receptor antagonist nafadotride inhibits development of locomotor sensitization to amphetamine

Behavioral sensitization is a well-studied model of behavioral plasticity mediated at least in part by dopaminergic systems believed to play an important role in several psychiatric conditions. In the rodent, locomotion is regulated by the opposing balance of D3 and D2 receptors, with D2 activation increasing and D3 stimulation inhibiting locomotion. However, receptor occupancy of D3 dopamine receptors is far greater than D2 or D1 occupancy at typical post-stimulant dopamine concentrations. We therefore hypothesized that tolerance of D3 receptor inhibition of locomotion contributes to the development of sensitization. To test this hypothesis, we examined the effect of the D3 receptor antagonist nafadotride on sensitization. As predicted, nafadotride inhibits augmentation of the locomotion response to repetitive amphetamine. This finding is consistent with the proposed model of adaptive down-regulation of D3 dopamine receptor function contributing to the development of behavioral sensitization.     

Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.     

自体骨髓单个核细胞经介入途径移植治疗股骨头坏死54例：12个月疗效随访

目的:观察经介入途径移植自体骨髓单个核细胞在股骨头坏死治疗中的应用,并评价其疗效。方法:选择2004-07/2005-11在解放军四六三院细胞治疗中心住院的,具有完整随访资料的股骨头坏死确诊患者共54例91髋。纳入确诊股骨头坏死,有关节疼痛、功能障碍等症状患者,性别、年龄不限;排除有严重心力衰竭、严重肾功能异常等不能耐受手术者。符合纳入标准54例,男45例,女9例,12～68岁。按ARCO分期Ⅱ期42髋,Ⅲ期47髋,Ⅳ期2髋。实验对象对治疗的相关内容知情同意并签知情同意。干预措施:抽取患者髂后上嵴骨髓进行单个核细胞悬液的制备。在DSA监视下将采集的单个核细胞混悬液经股动脉行Seldinger法穿刺,穿刺成功后,置入4F动脉鞘,经动脉鞘置入Cobra导管,将导管超选择至闭孔动脉及旋股内外侧动脉,平均注入单个核细胞悬液。术后定期随访症状变化情况,1年后复查X射线或CT,随访疼痛、关节活动度等情况。实验评估:①疼痛指数:无疼痛症状为3分,Harris髋关节评分疼痛分级A级;时有隐痛2分,Harris髋关节评分疼痛B级;轻度疼痛为1分,Harris髋关节评分疼痛C级;中度疼痛为0分,Harris髋关节评分疼痛D级。②功能指数:髋关节屈、伸、展、收、旋转度评分达Harris髋关节活动范围评分4～5分为3分;3～4分为2分;2～3分为1分;小于2分为0分。③X射线平片指数:股骨头形态无变化,应力骨小梁清晰,坏死区明显缩小为3分;坏死区略缩小为2分;治疗前后无明显变化为1分;坏死区扩大为0分。④血管指数:治疗后旋股内、外侧动脉及其分支增粗、增多,延长1cm以上者3分;1～0.5cm者2分;小于0.5cm者1分,无变化者0分。结果:54例患者均完成疼痛症状、关节功能及影像学随访1年。①术后12个月复查疼痛消失9髋,缓解61髋,无缓解21髋,缓解率为76.9%。②关节功能缓解33髋,无缓解58髋,缓解率为36.3%。③1年后X射线平片或CT、MRI示股骨头区可见不同程度的股骨头坏死区骨质密度改变,坏死区有吸收、缩小,股骨头形态变圆滑规整,改善28髋,无缓解或加重63髋,缓解率为30.1%。④12例24髋完成术后12个月复查股骨头供血动脉数字减影血管造影,好转18髋,好转率为72.2%。结论:经介入途径移植自体骨髓单个核细胞治疗股骨头坏死损伤小,可缓解临床相关症状。     

Dopaminergic regulation of dopamine D3 and D3nf receptor mRNA expression

Dopamine D3 receptors have the highest dopamine affinity of all dopamine receptors, and may thereby regulate dopamine signaling mediated by volume transmission. Changes in D3 receptor isoform expression may alter D3 receptor function, however, little is known regarding coordination of D3 isoform expression in response to perturbations in dopaminergic stimulation. To determine the effects of dopamine receptor stimulation and blockade on D3 receptor alternative splicing, we determined D3 and D3nf isoform mRNA expression following treatment with the D3 receptor antagonist NGB 2904, and the indirect dopamine agonist amphetamine. Expression of tyrosine hydroxylase (TH) mRNA, the rate‐limiting enzyme in dopamine synthesis, was also determined. The D3/D3nf mRNA expression ratio was increased in ventral striatum, prefrontal cortex, and hippocampus 6 h following D3 antagonist NGB 2904 treatment, and remained persistently elevated at 24 h in hippocampus and substantia nigra/ventral tegmentum. D3 mRNA decreased 65% and D3nf mRNA expression decreased 71% in prefrontal cortex 24 h following amphetamine treatment, however, these changes did not reach statistical significance. TH mRNA expression was unaffected by D3 antagonist NGB 2904, but was elevated by amphetamine in ventral striatum, hippocampus, and prefrontal cortex. These findings provide evidence for an adaptive response to altered D3 receptor stimulation involving changes in D3 receptor alternative splicing. Additionally, these data suggest D3 autoreceptor regulation of dopamine synthesis does not involve regulation of TH mRNA expression. Finally, the observation of regulated TH mRNA expression in dopamine terminal fields provides experimental support for the model of local control of mRNA expression in adaptation to synaptic activity. Synapse, 2010. © 2010 Wiley‐Liss, Inc.