• 【小鼠短暂性大脑中动脉闭塞后新皮层血管周围aquaporin-4的暂时性丧失。】 复制标题 收藏 收藏
    DOI:10.1073/pnas.0605796103 复制DOI
    作者列表:Frydenlund DS,Bhardwaj A,Otsuka T,Mylonakou MN,Yasumura T,Davidson KG,Zeynalov E,Skare O,Laake P,Haug FM,Rash JE,Agre P,Ottersen OP,Amiry-Moghaddam M
    BACKGROUND & AIMS: :The aquaporin-4 (AQP4) pool in the perivascular astrocyte membranes has been shown to be critically involved in the formation and dissolution of brain edema. Cerebral edema is a major cause of morbidity and mortality in stroke. It is therefore essential to know whether the perivascular pool of AQP4 is up- or down-regulated after an ischemic insult, because such changes would determine the time course of edema formation. Here we demonstrate by quantitative immunogold cytochemistry that the ischemic striatum and neocortex show distinct patterns of AQP4 expression in the reperfusion phase after 90 min of middle cerebral artery occlusion. The striatal core displays a loss of perivascular AQP4 at 24 hr of reperfusion with no sign of subsequent recovery. The most affected part of the cortex also exhibits loss of perivascular AQP4. This loss is of magnitude similar to that of the striatal core, but it shows a partial recovery toward 72 hr of reperfusion. By freeze fracture we show that the loss of perivascular AQP4 is associated with the disappearance of the square lattices of particles that normally are distinct features of the perivascular astrocyte membrane. The cortical border zone differs from the central part of the ischemic lesion by showing no loss of perivascular AQP4 at 24 hr of reperfusion but rather a slight increase. These data indicate that the size of the AQP4 pool that controls the exchange of fluid between brain and blood during edema formation and dissolution is subject to large and region-specific changes in the reperfusion phase.
    背景与目标: : 血管周围星形胶质细胞膜中的aquaporin-4 (AQP4) 池已被证明与脑水肿的形成和溶解密切相关。脑水肿是中风发病和死亡的主要原因。因此,必须了解缺血性损伤后AQP4的血管周围池是上调还是下调,因为这种变化将决定水肿形成的时间过程。在这里,我们通过定量免疫金细胞化学证明,在大脑中动脉闭塞90分钟后,缺血纹状体和新皮层在再灌注阶段显示出不同的AQP4表达模式。再灌注24小时时,纹状体核心显示血管周围AQP4丢失,没有随后恢复的迹象。皮质中受影响最大的部分也表现出血管周围aqp4的损失。这种损失的幅度与纹状体核心的损失相似,但在再灌注72小时后显示部分恢复。通过冷冻断裂,我们表明血管周围AQP4的丢失与颗粒的正方形晶格的消失有关,这些正方形晶格通常是血管周围星形胶质细胞膜的独特特征。皮质边界区与缺血性病变的中央部分不同,在再灌注24小时时未显示血管周围AQP4的丢失,但略有增加。这些数据表明,在水肿形成和溶解过程中控制大脑和血液之间流体交换的AQP4池的大小在再灌注阶段会发生较大且区域特定的变化。
  • 【具有局部视网膜功能障碍的CRB1杂合子: 对leber先天性黑蒙的基因检测的意义。】 复制标题 收藏 收藏
    DOI:10.1167/iovs.05-1637 复制DOI
    作者列表:Yzer S,Fishman GA,Racine J,Al-Zuhaibi S,Chakor H,Dorfman A,Szlyk J,Lachapelle P,van den Born LI,Allikmets R,Lopez I,Cremers FP,Koenekoop RK
    BACKGROUND & AIMS: PURPOSE:To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS:Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS:Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS:In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.
    背景与目标:
  • 3 Cerebral metastases--a therapeutic update. 复制标题 收藏 收藏

    【脑转移 -- 治疗更新。】 复制标题 收藏 收藏
    DOI:10.1038/ncpneuro0263 复制DOI
    作者列表:Cavaliere R,Schiff D
    BACKGROUND & AIMS: :Cerebral metastases remain a common complication among patients with cancer. Historically, whole-brain radiotherapy has remained the standard of care, with surgery being reserved for selected cases. Recent advances have changed our practice, however. In particular, stereotactic radiosurgery has emerged as a vital treatment modality for this disease. In addition, chemotherapy, including temozolomide, topoisomerase inhibitors and antimetabolites, and treatment sensitizers, such as efaproxiral and motexafin gadolinium, are actively being assessed in clinical trials, and are likely to play an increasing role in the management of cerebral metastases in the future. Nonetheless, many uncertainties remain, such as the optimal combination and timing of therapeutics. As the arsenal of therapeutics expands, it will be increasingly important to select appropriate patients for a particular treatment paradigm. Understanding the efficacy and toxicity of treatment is essential to this task.
    背景与目标: : 脑转移仍然是癌症患者的常见并发症。从历史上看,全脑放疗一直是护理的标准,手术是为选定的病例保留的。然而,最近的进展改变了我们的做法。特别是,立体定向放射外科已成为该疾病的重要治疗方式。此外,化疗,包括替莫唑胺、拓扑异构酶抑制剂和抗代谢物,以及治疗敏化剂,如efaproxiral和motexafin钆,正在临床试验中积极评估,并可能在未来脑转移的管理中发挥越来越大的作用。尽管如此,仍然存在许多不确定性,例如治疗的最佳组合和时机。随着治疗学库的扩展,为特定的治疗范例选择合适的患者将变得越来越重要。了解治疗的疗效和毒性对于这项任务至关重要。
  • 【镉通过一系列三波活性氧影响烟草细胞,这有助于细胞毒性。】 复制标题 收藏 收藏
    DOI:10.1111/j.1365-3040.2006.01571.x 复制DOI
    作者列表:Garnier L,Simon-Plas F,Thuleau P,Agnel JP,Blein JP,Ranjeva R,Montillet JL
    BACKGROUND & AIMS: :Cadmium is suspected to exert its toxic action on cells through oxidative damage. However, the transition metal is unable to directly generate reactive oxygen species (ROS) via redox reactions with molecular oxygen in a biological environment. Here, we show that bright yellow-2 (BY-2) tobacco cells exposed to millimolar concentrations of CdCl(2) developed cell death within 2-3 h. The death process was preceded by two successive waves of ROS differing in their nature and subcellular localization. Firstly, these consisted in the transient NADPH oxidase-dependent accumulation of H(2)O(2) followed by the accumulation of O(2) (-*) in mitochondria. A third wave of ROS consisting in fatty acid hydroperoxide accumulation was concomitant with cell death. Accumulation of H(2)O(2) was preceded by an increase in cytosolic free calcium concentration originating from internal pools that was essential to activate the NADPH oxidase. The cell line gp3, impaired in NADPH oxidase activity, and that was unable to accumulate H(2)O(2) in response to Cd(2+), was nevertheless poisoned by the metal. Therefore, this first wave of ROS was not sufficient to trigger all the cadmium-dependent deleterious effects. However, we show that the accumulation of O(2) (-*) of mitochondrial origin and membrane peroxidation are key players in Cd(2+)-induced cell death.
    背景与目标: : 镉被怀疑通过氧化损伤对细胞产生毒性作用。然而,在生物环境中,过渡金属无法通过与分子氧的氧化还原反应直接产生活性氧 (ROS)。在这里,我们显示暴露于毫摩尔浓度的CdCl(2) 的亮黄色2 (BY-2) 烟草细胞在2-3小时内发生细胞死亡。死亡过程之前是连续两波ROS,其性质和亚细胞定位不同。首先,这些因素包括H(2)O(2) 的瞬时NADPH氧化酶依赖性积累,然后是线粒体中O(2) (-*) 的积累。由脂肪酸氢过氧化物积累组成的第三波ROS伴随细胞死亡。H(2)O(2) 的积累之前,来自内部池的胞质游离钙浓度增加,这对于激活NADPH氧化酶至关重要。细胞系gp3的NADPH氧化酶活性受损,并且无法响应Cd(2) 积累H(2)O(2),但仍被金属中毒。因此,第一波ROS不足以触发所有依赖镉的有害作用。然而,我们表明线粒体来源的O(2) (-*) 的积累和膜过氧化是Cd(2) 诱导的细胞死亡的关键因素。
  • 【[肉毒杆菌毒素治疗痉挛性婴儿脑瘫: 一年内27例结果]。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Sánchez-Carpintero R,Narbona J
    BACKGROUND & AIMS: INTRODUCTION AND OBJECTIVES:Positive outcome of patients with spastic cerebral palsy treated with botulinum toxin reported in the last three years has led us to perform this study with the aim to show our experience in the management of spastic cerebral palsy with the toxin, determine its indications, analyze the results and propose new possible indications in the future.

    MATERIAL AND METHODS:We include 10 hemiplegic and 17 diplegic patients with an average age of 6 years and 7 months, followed up between 5 and 17 months. Clinical improvement was monitored using the PRS and EVFEL scales and articular motion range was measured 6 months before and after the injection while continuing physiotherapy. The injected muscles were adductor, hamstrings, triceps and posterior tibialis, and the doses were 1-2 U/muscle/kg body weight.

    RESULTS:The values on PRS improved an average of 24%, adductor angle 66% (p < 0.01), knee angle 40% (p = 0.05) and ankle angle 52% (p < 0.01); 96% of patients could get more physiological static or walking patterns because of the decrease of spasticity and those persisted after the effect of the toxin had worn off. It was maximum at 2 months, stabilized 4 to 6 months later and decreased during further 2 months.

    CONCLUSIONS:This experience leads us to propose higher starting dosage and to take into account the stability of postural pattern of each patient to choice the muscle to be injected. Other therapeutic possibilities are also proposed in children with fixed shortening e.g. combining the toxin with stretching casts.

    背景与目标: 简介和目标 : 最近三年报道的肉毒杆菌毒素治疗痉挛性脑瘫患者的积极结果导致我们进行这项研究,目的是展示我们在治疗痉挛性脑瘫方面的经验毒素,确定其适应症,分析结果并在将来提出新的可能适应症。
    材料和方法 : 我们包括10例偏瘫和17例双瘫患者,平均年龄为6岁7个月,随访5至17个月。使用PRS和EVFEL量表监测临床改善,并在注射前和注射后6个月测量关节运动范围,同时继续理疗。注射的肌肉是内收肌,绳肌,三头肌和胫后肌,剂量为1-2 U/肌肉/kg体重。
    结果 : PRS上的值平均提高了24%,内收角66% (p <0.01),膝角40% (p = 0.05) 和踝角52% (p < 0.01); 96% 患者由于痉挛程度的降低而获得更多的生理静态或行走模式,并且在毒素作用消失后持续存在。在2个月时达到最大值,在4到6个月后稳定下来,在接下来的2个月内下降。
    结论 : 这种经验使我们提出更高的起始剂量,并考虑到每位患者的姿势模式的稳定性,以选择要注射的肌肉。对于固定缩短的儿童,还提出了其他治疗可能性,例如将毒素与拉伸铸型结合使用。
  • 6 The cerebral palsied hip. 复制标题 收藏 收藏

    【大脑触诊的臀部。】 复制标题 收藏 收藏
    DOI:10.1097/00003086-199705000-00007 复制DOI
    作者列表:Black BE,Griffin PP
    BACKGROUND & AIMS: Controversy exists regarding the role of pelvic obliquity in hip dysplasia and cerebral palsy. Earlier authors noted such a relationship but did not confirm its existence by scientific study. The current study confirms the association of pelvic obliquity to hip dysplasia in spastic cerebral palsy. At presentation of subluxation or dislocation before surgery, 80 patients were indexed into 5 body alignment types. Reclassifications were performed with passage of time to study the natural history and effects of surgery. Hip dysplasia was found in all cases to be consistent with the forces related to pelvic obliquity.

    背景与目标: 关于骨盆倾斜在髋关节发育不良和脑瘫中的作用存在争议。较早的作者指出了这种关系,但并未通过科学研究证实其存在。目前的研究证实了痉挛性脑瘫中骨盆倾斜与髋关节发育不良的关系。在手术前出现半脱位或脱位时,将80例患者分为5种身体排列类型。随着时间的流逝进行了重新分类,以研究自然史和手术效果。在所有情况下都发现髋关节发育不良与骨盆倾斜相关的力一致。
  • 【脑弥散和T(2): 持续高原缺氧期间急性高山病的MRI预测因子。】 复制标题 收藏 收藏
    DOI:10.1038/jcbfm.2012.184 复制DOI
    作者列表:Hunt JS Jr,Theilmann RJ,Smith ZM,Scadeng M,Dubowitz DJ
    BACKGROUND & AIMS: :Diffusion magnetic resonance imaging (MRI) provides a sensitive indicator of cerebral hypoxia. We investigated if apparent diffusion coefficient (ADC) and transverse relaxation (T(2)) predict symptoms of acute mountain sickness (AMS), or merely indicate the AMS phenotype irrespective of symptoms. Fourteen normal subjects were studied in two groups; unambiguous AMS and no-AMS at 3,800 m altitude (intermediate AMS scores were excluded). T(2) relaxation was estimated from a T(2) index of T(2)-weighted signal normalized by cerebrospinal fluid signal. Measurements were made in normoxia and repeated after 2 days sustained hypoxia (AMS group symptomatic and no-AMS group asymptomatic) and after 7 days hypoxia (both groups asymptomatic). Decreased ADC directly predicted AMS symptoms (P<0.05). Apparent diffusion coefficient increased in asymptomatic subjects, or as symptoms abated with acclimatization. This pattern was similar in basal ganglia, white matter, and gray matter. Corpus callosum behaved differently; restricted diffusion was absent (or rapidly reversed) in the splenium, and was sustained in the genu. In symptomatic subjects, T(2,index) decreased after 2 days hypoxia and further decreased after 7 days. In asymptomatic subjects, T(2,index) initially increased after 2 days, but decreased after 7 days. T(2,index) changes were not predictive of AMS symptoms. These findings indicate that restricted diffusion, an indicator of diminished cerebral energy status, directly predicts symptoms of AMS in humans at altitude.
    背景与目标: 扩散磁共振成像 (MRI) 提供了脑缺氧的敏感指标。我们调查了表观扩散系数 (ADC) 和横向松弛 (T(2)) 是否可以预测急性高山病 (AMS) 的症状,或者仅指示AMS表型而与症状无关。研究了两组中的14名正常受试者; 3,800  m高度的明确AMS和no-AMS (排除中间AMS得分)。T(2) 松弛是根据脑脊液信号归一化的T(2) 加权信号的T(2) 指数估算的。在常氧下进行测量,并在持续缺氧2天 (有症状的AMS组和无症状的no-AMS组) 和缺氧7天 (两组均无症状) 后重复进行。ADC降低直接预测AMS症状 (P<0.05)。在无症状的受试者中,表观扩散系数增加,或者随着症状的适应而减轻。这种模式在基底神经节,白质和灰质中相似。Call体的行为不同; 脾脏中不存在 (或迅速逆转) 受限的扩散,并在基因组中持续存在。在有症状的受试者中,缺氧2 d后T(2,指数) 降低,7 d后进一步降低。在无症状的受试者中,T(2,指数) 在2天后最初增加,但在7天后降低。T(2,指数) 变化不能预测AMS症状。这些发现表明,受限的扩散是大脑能量状态降低的指标,直接预测了人类在海拔地区的AMS症状。
  • 【单胺受体激动剂和拮抗剂对人大脑皮层切片中环状AMP积累的影响。】 复制标题 收藏 收藏
    DOI:10.1139/y77-172 复制DOI
    作者列表:Tsang D,Lal S
    BACKGROUND & AIMS: :In human cerebral cortex slices noradrenaline, isoproterenol (a beta-adrenergic agonist), dopamine, apomorphine (a dopaminergic agonist), and serotonin stimulated cyclic AMP formation: noradrenaline greater than or equal to isoproterenol greater than dopamine = apomorphine = serotonin. Clonidine (and alpha-adrenergic agonist) was ineffective in stimulating cyclic AMP formation in temporal cortex slices. The stimulatory effect of noradrenaline and isoproterenol was blocked by propranolol (a beta-adrenergic blocker) but not by phentolamine (an alpha-adrenergic blocker). Pimozide (a selective dopaminergic antagonist) inhibited the increase of cyclic AMP formation induced by dopamine or apomorphine but not that induced by noradrenaline, isoproterenol, or serotonin. Neither propranolol or phentolamine had any effect on dopamine- or serotonin-stimulated cyclic AMP formation. Chlorpromazine blocked the increase of cyclic AMP formation induced by noradrenaline, dopamine or serotonin, while cyproheptadine, a putative central serotonergic antagonist, was ineffective. These observations suggest that there may be at least two monoamine-sensitive adenylate cyclases in human cerebral cortex which have the characteristics of a beta-adrenergic and a dopaminergic receptor, respectively, and also possibly a serotonergic receptor.
    背景与目标: : 在人大脑皮层切片中去甲肾上腺素,异丙肾上腺素 (β-肾上腺素能激动剂),多巴胺,阿扑吗啡 (多巴胺能激动剂) 和5-羟色胺刺激的环状AMP形成: 去甲肾上腺素大于或等于异丙肾上腺素大于多巴胺 = 阿扑吗啡 = 5-羟色胺。可乐定 (和 α-肾上腺素能激动剂) 在刺激颞叶皮质切片中的环状AMP形成方面无效。去甲肾上腺素和异丙肾上腺素的刺激作用被普萘洛尔 (一种 β-肾上腺素能阻滞剂) 阻断,而酚妥拉明 (一种 α-肾上腺素能阻滞剂) 则不能。Pimozide (一种选择性多巴胺能拮抗剂) 抑制多巴胺或阿扑吗啡诱导的环AMP形成的增加,但不能抑制去甲肾上腺素,异丙肾上腺素或5-羟色胺诱导的环AMP形成。普萘洛尔或酚妥拉明均不会对多巴胺或5-羟色胺刺激的环状AMP形成产生任何影响。氯丙嗪阻止了由去甲肾上腺素,多巴胺或5-羟色胺引起的环状AMP形成的增加,而被认为是中枢5-羟色胺能拮抗剂的赛庚啶无效。这些观察结果表明,人大脑皮层中可能至少存在两种单胺敏感的腺苷酸环化酶,它们分别具有 β-肾上腺素能受体和多巴胺能受体的特征,也可能具有血清素能受体的特征。
  • 【小儿心脏手术后局部静脉血氧饱和度与混合静脉饱和度。】 复制标题 收藏 收藏
    DOI:10.1111/aas.12016 复制DOI
    作者列表:Moreno GE,Pilán ML,Manara C,Magliola R,Vassallo JC,Balestrini M,Lenz AM,Krynski M,Althabe M,Landry L
    BACKGROUND & AIMS: BACKGROUND:Central venous oxygen saturation (ScvO2) remains the gold standard surrogate for tissue oxygen extraction in paediatric cardiac surgery. Near-infrared spectroscopy (NIRS) has been developed as a non-invasive diagnostic tool for regional oxygen saturation. The aim was to compare regional oxygen saturation measured by NIRS with ScvO2 in postoperative paediatric cardiac patients. METHODS:In this prospective study, we included newborns and infants younger than 45 days undergoing heart surgery. We recorded continuous ScvO2 and NIRS regional saturation placed on the forehead (B) and right flank (S) for 48 h postoperatively. A Bland-Altman's analysis was used to assess the agreement between these measurements. RESULTS:A total of 23 patients were included with a median age of 12 days (2-46) and median weight of 3.1 kg (2.3-4.47). The mean difference (MD) ScvO2- B NIRS was 10.45% with limits of agreement (LOA) -17.23 to 38.13% and ScvO2- S NIRS MD 7.16% with LOA: -25.51 to 39.84%. The single ventricle ScvO2- S NIRS subgroup had MD within ± 5%; however, wide LOA was observed. The remaining subgroups showed MD nearly above ± 5%, with wide LOA. CONCLUSIONS:The regional oxygen saturation of brain and kidney did not match ScvO2 as estimation of global tissue perfusion. Nevertheless, NIRS may still provide information regarding regional circulation that may help in the management of neonatal cardiac surgery patients.
    背景与目标:
  • 【将非结构化的 α-突触核蛋白转化为其 α-螺旋构象会显着减弱活性氧的产生。】 复制标题 收藏 收藏
    DOI:10.1016/j.jinorgbio.2012.09.001 复制DOI
    作者列表:Zhou B,Hao Y,Wang C,Li D,Liu YN,Zhou F
    BACKGROUND & AIMS: :The intracellular α-synuclein (α-syn) protein, whose conformational change and aggregation have been closely linked to the pathology of Parkingson's disease (PD), is highly populated at the presynaptic termini and remains there in the α-helical conformation. In this study, circular dichroism confirmed that natively unstructured α-syn in aqueous solution was transformed to its α-helical conformation upon addition of trifluoroethanol (TFE). Electrochemical and UV-visible spectroscopic experiments reveal that both Cu (I) and Cu (II) are stabilized, with the former being stabilized by about two orders of magnitude. Compared to unstructured α-syn (Binolfi et al., J. Am. Chem. Soc. 133 (2011) 194-196), α-helical α-syn stabilizes Cu (I) by more than three orders of magnitude. Through the measurements of H(2)O(2) and hydroxyl radicals (OH) in solutions containing different forms of Cu (II) (free and complexed by unstructured or α-helical α-syn), we demonstrate that the significantly enhanced Cu (I) binding affinity helps inhibit the production of highly toxic reactive oxygen species, especially the hydroxyl radicals. Our study provides strong evidence that, as a possible means to prevent neuronal cell damage, conversion of the natively unstructured α-syn to its α-helical conformation in vivo could significantly attenuate the copper-modulated ROS production.
    背景与目标: : 细胞内 α-突触核蛋白 (α-syn) 蛋白的构象变化和聚集与Parkingson病 (PD) 的病理密切相关,在突触前末端高度聚集,并保留在 α-螺旋构象中。在这项研究中,圆二色性证实,加入三氟乙醇 (TFE) 后,水溶液中的原生非结构化 α-syn转化为其 α-螺旋构象。电化学和紫外可见光谱实验表明,Cu (I) 和Cu (II) 都是稳定的,前者稳定了大约两个数量级。与非结构化 α-syn (Binolfi等人,J. Am. Chem. Soc. 133 (2011) 194-196) 相比,α-螺旋 α-syn使Cu (I) 稳定超过三个数量级。通过测量含有不同形式的Cu (II) (游离并通过非结构化或 α-螺旋 α-syn络合) 的溶液中的H(2)O(2) 和羟基自由基 (OH),我们证明了显着增强的Cu (I) 结合亲和力有助于抑制高毒性活性氧的产生,尤其是羟基自由基。我们的研究提供了有力的证据,表明作为防止神经元细胞损伤的一种可能手段,在体内将非结构化的 α-syn转化为其 α-螺旋构象可以显着减弱铜调节的ROS的产生。
  • 【3-羟基-3-甲基戊二酰辅酶a还原酶 (HMGCR) 途径通过异戊烯化依赖的信号通路调节发育性脑血管稳定性。】 复制标题 收藏 收藏
    DOI:10.1016/j.ydbio.2012.11.024 复制DOI
    作者列表:Eisa-Beygi S,Hatch G,Noble S,Ekker M,Moon TW
    BACKGROUND & AIMS: :Spontaneous intracranial hemorrhage is a debilitating form of stroke, often leading to death or permanent cognitive impairment. Many of the causative genes and the underlying mechanisms implicated in developmental cerebral-vascular malformations are unknown. Recent in vitro and in vivo studies in mice have shown inhibition of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway to be effective in stabilizing cranial vessels. Using a combination of pharmacological and genetic approaches to specifically inhibit the HMGCR pathway in zebrafish (Danio rerio), we demonstrate a requirement for this metabolic pathway in developmental vascular stability. Here we report that inhibition of HMGCR function perturbs cerebral-vascular stability, resulting in progressive dilation of blood vessels, followed by vessel rupture, mimicking cerebral cavernous malformation (CCM)-like lesions in humans and murine models. The hemorrhages in the brain are rescued by prior exogenous supplementation with geranylgeranyl pyrophosphate (GGPP), a 20-carbon metabolite of the HMGCR pathway, required for the membrane localization and activation of Rho GTPases. Consistent with this observation, morpholino-induced depletion of the β-subunit of geranylgeranyltransferase I (GGTase I), an enzyme that facilitates the post-translational transfer of the GGPP moiety to the C-terminus of Rho family of GTPases, mimics the cerebral hemorrhaging induced by the pharmacological and genetic ablation of HMGCR. In embryos with cerebral hemorrhage, the endothelial-specific expression of cdc42, a Rho GTPase involved in the regulation of vascular permeability, was significantly reduced. Taken together, our data reveal a metabolic contribution to the stabilization of nascent cranial vessels, requiring protein geranylgeranylation acting downstream of the HMGCR pathway.
    背景与目标: 自发性颅内出血是中风的一种衰弱形式,通常导致死亡或永久性认知障碍。与发育性脑血管畸形有关的许多致病基因和潜在机制尚不清楚。最近在小鼠中进行的体外和体内研究表明,抑制3-羟基-3-甲基戊二酰-coa还原酶 (HMGCR) 途径可有效稳定颅骨血管。使用药理学和遗传学方法相结合的方法来特异性抑制斑马鱼 (Danio rerio) 中的HMGCR途径,我们证明了这种代谢途径在发育血管稳定性中的需求。在这里,我们报告了HMGCR功能的抑制会干扰脑血管的稳定性,导致血管进行性扩张,然后血管破裂,模仿人和鼠模型中的脑海绵状畸形 (CCM) 样病变。通过事先补充香叶基焦磷酸 (GGPP) (HMGCR途径的20碳代谢产物) 来挽救脑部出血,这是Rho GTPases膜定位和激活所必需的。与该观察结果一致,吗啉代诱导的香叶基转移酶I (GGTase I) 的 β 亚基耗竭,该酶促进了GGPP部分翻译后转移到Rho gtp酶家族的C末端,模拟了HMGCR的药理和遗传消融引起的脑出血。在脑出血的胚胎中,参与调节血管通透性的Rho GTPase cdc42的内皮特异性表达显着降低。总之,我们的数据揭示了对新生颅骨血管稳定的代谢贡献,需要在HMGCR途径下游起作用的蛋白质香叶基。
  • 【在感冒患者中使用血管扩张剂非洛地平作为长期氧气治疗的佐剂。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Bratel T,Hedenstierna G,Nyquist O,Ripe E
    BACKGROUND & AIMS: :Eight patients with chronic obstructive lung disease (COLD) and pulmonary hypertension were given an infusion of a calcium antagonist, felodipine, during ongoing, long-term oxygen treatment (LTOT). The effects on central haemodynamics and ventilation-perfusion matching were studied. At rest pulmonary and systemic vascular resistances (PVR and SVR) were reduced by 18% (NS) and 26% (p less than 0.05), respectively. Cardiac output increased by 23%. There was a tendency to increased perfusion of low alveolar ventilation-perfusion ratio (VA/Q) areas (VA/Q less than 0.1) and to increased shunt compared to pretreatment values. Arterial oxygen tension (PaO2) fell by 0.7 kPa (p less than 0.001) but total oxygen transport increased by 23% (p less than 0.001). After treatment with oral felodipine (7.5-15 mg.day-1) for a mean time of 14 wks, PVR and SVR were reduced by 16% (p less than 0.05) and 7% (NS), respectively, as compared to pretreatment values at rest. Cardiac output rose by 13%. The VA/Q ratios and the PaO2 returned towards pretreatment values. The total oxygen transport increased by 11% (p less than 0.05) at rest and increased by 19% (p less than 0.05) during exercise as compared to the pretreatment value. The positive effect on central haemodynamics indicates that felodipine may be a valuable adjunct to ongoing LTOT.
    背景与目标: : 在正在进行的长期氧气治疗 (LTOT) 期间,对8名患有慢性阻塞性肺疾病 (COLD) 和肺动脉高压的患者进行了钙拮抗剂非洛地平的输注。研究了对中心血流动力学和通气-灌注匹配的影响。静止时,肺和全身血管阻力 (PVR和SVR) 分别降低了18% (NS) 和26% (p小于0.05)。心输出量增加23%。与预处理值相比,低肺泡通气-灌注比 (VA/Q) 区域的灌注增加 (VA/Q小于0.1) 和分流增加的趋势。动脉血氧张力 (PaO2) 下降了0.7 kPa (p小于0.001),但总输氧增加了23% (p小于0.001)。在用口服非洛地平 (7.5-15 mg.day-1) 治疗14 wks的平均时间后,与休息时的预处理值相比,PVR和SVR分别降低了16% (p小于0.05) 和7% (NS)。心输出量上升了13%。VA/Q比和PaO2返回预处理值。与预处理值相比,总氧传输在静止时增加11% (p小于0.05),在运动期间增加19% (p小于0.05)。对中枢血流动力学的积极影响表明,非洛地平可能是正在进行的LTOT的有价值的辅助手段。
  • 【一种超声细胞学方案,用于诊断皮肤默克尔细胞癌患者的局部淋巴结。】 复制标题 收藏 收藏
    DOI:10.1111/bjd.12107 复制DOI
    作者列表:Righi A,Asioli S,Caliendo V,Macripò G,Picciotto F,Risio M,Eusebi V,Bussolati G
    BACKGROUND & AIMS: BACKGROUND:The status of regional lymph nodes (LNs) is one of the most consistent predictors of survival in Merkel cell carcinoma (MCC). In cases of clinically localized disease, current practice involves sentinel lymph node (SLN) assessment. OBJECTIVES:To propose ultrasonography (US) followed by fine needle aspiration cytology (FNAC) and immunohistochemistry as a useful diagnostic tool in the pre-surgical management of patients with MCC. METHODS:US of LNs was performed in 75 patients with MCC (22 with stage III tumours; 53 with stage I-II). In patients with US suspected disease, US coupled with FNAC of the LN was performed. Smears were examined by routine cytological staining supplemented with immunohistochemical staining for cytokeratin 20. All patients underwent surgical removal of regional LNs. RESULTS:In all 22 patients with stage III tumours, US was indicative of tumour deposits and FNAC confirmed metastases to LNs. In 11 of 53 patients with localized MCC without clinical evidence of nodal disease, US revealed enlarged, equivocal nodes where FNAC was performed. Ten LNs were cytologically positive for metastases, and one was negative. Upon histological examination, the FNAC-negative case showed a metastasis 5 mm in diameter. In all the other 42 cases with no clinical or US evidence of LN involvement, only SLN biopsy was performed and in six cases small metastatic foci were detected. Ultimately, of the 53 stage I-II MCC, 17 had positive LN involvement. In 10 cases (59%) metastases were detected by FNAC, and in seven cases, were detected by SLN biopsy. CONCLUSIONS:In a selected subset (∼20%) of patients with MCC with clinically localized disease, US followed by FNAC in the suspect LN is a valid alternative to the classical protocol of SLN histological examination.
    背景与目标:
  • 【转移至区域烧伤中心的患者的结果分析: 转移状态不影响生存率。】 复制标题 收藏 收藏
    DOI:10.1016/j.burns.2006.04.001 复制DOI
    作者列表:Klein MB,Nathens AB,Heimbach DM,Gibran NS
    BACKGROUND & AIMS: BACKGROUND:Optimal burn care is provided at specialized burn centers. Given the geographic location of these centers, many burn patients receive initial treatment at local emergency departments prior to transfer. The purpose of this study was to determine whether patients transferred from other facilities have worse outcomes than those admitted directly from the field. STUDY DESIGN:A retrospective cohort study was performed comparing the outcomes of patients admitted to our burn center directly from the field with patients requiring transfer from a preliminary care facility. The outcomes of interest were mortality, length of stay, length of stay/TBSA burned, number of operations and hospital charges. Poisson regression or Cox proportional hazards model was used to evaluate differences in outcomes after adjusting for potential confounders. RESULTS:From 2000 to 2003 a total of 1877 patients were admitted to our burn center and 953 (51%) were transferred from a preliminary care facility. No difference (p<0.05) was found in length of stay, number of operations, hospital charges and mortality between the two cohorts. CONCLUSIONS:This study demonstrates that patients transferred to a regional burn center from local hospitals have equivalent mortality, length of stay and hospital charges as those admitted directly from the field.
    背景与目标:
  • 【TNFSF4基因多态性rs3861950而非rs3850641与中国人群脑梗死风险相关。】 复制标题 收藏 收藏
    DOI:10.1007/s11239-012-0849-9 复制DOI
    作者列表:Feng J,Liu YH,Yang QD,Zhu ZH,Xia K,Tan XL,Xia J,Gu WP,Zhou L,Xiao B,Tang BS,Huang Q
    BACKGROUND & AIMS: :Tumor necrosis factor superfamily member 4 (TNFSF4) plays a key role in the process of atherosclerosis, a common risk factor for both myocardial and cerebral infarctions. Recent studies indicate that the single nucleotide polymorphism (SNP) rs3850641 in TNFSF4 is associated with higher risk of myocardial infarction, but little is known about the association between TNFSF4 variation and cerebral infarction (CI). A case-control study involving 385 CI patients and 385 age-matched, sex-matched non-CI controls was conducted in a Chinese population, only the most common subtype, atherosclerosis CI, was recruited. Two SNPs of TNFSF4, rs3850641 and rs3861950, were genotyped by the TaqMan SNP genotyping method, and verified partly by genomic DNA sequencing. The results revealed a significant allelic association between rs3861950 and CI (Odds ration = 1.733, 95 % confidence interval = 1.333-2.254, P = 0.000). Genotypic association analysis demonstrated that the CC genotype of rs3861950 confers susceptibility to CI (Odds ration = 2.896, 95 % confidence interval = 1.368-6.132), and it was associated with a significantly higher risk of ischemic stroke (Odds ration = 3.520, 95 % confidence interval = 1.546-8.015, P = 0.003) after adjusting for the other confirmed risk factors such as the history of hypertension, diabetes, CAD, smoking and alcohol drinking. While the odds ratio of the T allele to the C allele was 1.733 (95 % confidence interval: 1.333-2.254). However, there was no significant association between rs3850641 and CI (Odds ration = 1.288, 95 % confidence interval = 0.993-1.670, P = 0.056). TNFSF4 gene polymorphism rs3861950, but not rs3850641, is associated with the risk of atherosclerosis CI in a Chinese population.
    背景与目标: : 肿瘤坏死因子超家族成员4 (TNFSF4) 在动脉粥样硬化过程中起关键作用,动脉粥样硬化是心肌和脑梗塞的常见危险因素。最近的研究表明,TNFSF4中的单核苷酸多态性 (SNP) rs3850641与心肌梗死的高风险相关,但对TNFSF4变异与脑梗死 (CI) 之间的关系知之甚少。在中国人群中进行了385例CI患者和385年龄匹配,性别匹配的非CI对照的病例对照研究,仅招募了最常见的亚型动脉粥样硬化CI。TNFSF4的两个SNP,rs3850641和rs3861950,通过TaqMan SNP基因分型方法进行了基因分型,并通过基因组DNA测序进行了部分验证。结果显示rs3861950和CI之间存在显着的等位基因关联 (赔率 = 1.733,95% 置信区间 = 1.333-2.254,P = 0.000)。基因型关联分析表明,rs3861950的CC基因型赋予CI易感性 (赔率 = 2.896,95% 置信区间 = 1.368-6.132),并且与缺血性中风的风险显着增加相关 (赔率 = 3.520,95% 置信区间 = 1.546-8.015,P = 0.003) 在调整其他已确认的危险因素 (例如高血压,糖尿病,CAD,吸烟和饮酒史) 后。而T等位基因与C等位基因的比值比为1.733 (95% 置信区间: 1.333-2.254)。然而,rs3850641与CI之间没有显着关联 (赔率 = 1.288,95% 置信区间 = 0.993-1.670,P = 0.056)。TNFSF4基因多态性rs3861950 (而非rs3850641) 与中国人群动脉粥样硬化CI的风险相关。

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