• 【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。
  • 【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。
  • 【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。
  • 【全反式维甲酸 (维a酸) 治疗复发性脑胶质瘤。】 复制标题 收藏 收藏
    DOI:10.1023/a:1005743707803 复制DOI
    作者列表:Kaba SE,Kyritsis AP,Conrad C,Gleason MJ,Newman R,Levin VA,Yung WK
    BACKGROUND & AIMS: Malignant gliomas continue to be a significant source of mortality in young and middle aged adults. The introduction of new treatment strategies and multidisciplinary approaches has improved the outcome of patients with these tumors only slightly. Because retinoic acid has growth inhibitory activity against glioma and neuroblastoma cells in cultures, we assessed the efficacy of all-trans-retinoic acid in the treatment of recurrent cerebral gliomas. Thirty-six patients with recurrent cerebral gliomas were entered in the study and treated with 120 or 150 mg/ m2/day of all-trans-retinoic acid as a single agent. The drug was given for 3 weeks followed with one week of rest. Two blocks of 4 weeks constituted one course of treatment. One (3%) of 34 evaluable patients had a minor response and 14 (41%) had stable disease. In the rest of the patients (56%), tumors continued to progress despite treatment. The median time to progression of all evaluable patients was 8 weeks, and for the responders was 17 weeks. The higher dose level (150 mg/m2) was associated with high incidence of headache, which responded to dose reduction. The lower dose level was very well tolerated, with mild, mainly dermatological toxicity. All-trans-retinoic acid as a single agent has no significant activity against recurrent cerebral gliomas.

    背景与目标: 恶性神经胶质瘤仍然是中青年成年人死亡的重要来源。新的治疗策略和多学科方法的引入仅略微改善了这些肿瘤患者的预后。由于视黄酸对培养物中的神经胶质瘤和神经母细胞瘤细胞具有生长抑制活性,因此我们评估了全反式视黄酸在治疗复发性脑胶质瘤中的功效。36例复发性脑胶质瘤患者进入研究,并以120或150 mg/ m2/天的全反式维甲酸作为单一药物进行治疗。给药3周,然后休息一周。两个为期4周的块构成一个疗程。34名可评估患者中有1名 (3% 名) 反应轻微,14名 (41% 名) 疾病稳定。在其余患者 (56%) 中,尽管进行了治疗,但肿瘤仍在继续发展。所有可评估患者的中位进展时间为8周,应答者为17周。较高的剂量水平 (150 mg/m2) 与头痛的高发生率相关,头痛对剂量减少有反应。较低的剂量水平耐受性良好,具有轻度 (主要是皮肤病学毒性)。全反式维甲酸作为单一药物对复发性脑胶质瘤没有显着活性。
  • 【早产儿气管内吸痰过程中行为状态对脑氧合的影响。】 复制标题 收藏 收藏
    DOI:10.1055/s-2007-973682 复制DOI
    作者列表:Bernert G,von Siebenthal K,Seidl R,Vanhole C,Devlieger H,Casaer P
    BACKGROUND & AIMS: :Near infrared spectroscopy (NIRS) was used to investigate the effect of behavioural states on changes of oxygenated (O2Hb), deoxygenated haemoglobin (HHb) and total haemoglobin (tHb), during endotracheal suctioning. In an open prospective design, NIRS measurements have been done during 20 suctioning episodes in 13 preterm neonates. Heart rate, arterial oxygen saturation, and carbon dioxide tension were monitored continuously. Behavioural state (BS) observations were made and documented as well. The statistical analysis showed that in patients who were active, with crying periods during suctioning (behavioural states 4-5), changes of oxygenated (p < 0.005) and deoxygenated haemoglobin (p < 0.05), as well as of arterial oxygen saturation (p < 0.05) and heart rate (p < 0.05) were significantly greater than in patients who were quiet with predominant behavioural state 1, 2 and 3. These results underline the influence of behavioural states on the physiological answers to endotracheal suctioning. NIRS proved to be a valuable tool to evaluate possible harmful effects of different suctioning techniques.
    背景与目标: : 近红外光谱 (NIRS) 用于研究行为状态对气管内抽吸过程中含氧 (O2Hb),脱氧血红蛋白 (HHb) 和总血红蛋白 (tHb) 变化的影响。在开放的前瞻性设计中,已在13例早产新生儿的20次吸痰发作中进行了NIRS测量。连续监测心率,动脉血氧饱和度和二氧化碳张力。还进行了行为状态 (BS) 观察并记录在案。统计分析显示,在活动的患者中,在吸痰过程中有哭闹期 (行为状态4-5),氧合 (p < 0.005) 和脱氧血红蛋白 (p < 0.05) 的变化,动脉血氧饱和度 (p < 0.05) 和心率 (p < 0.05) 均显着高于以主要行为状态1、2和3安静的患者。这些结果强调了行为状态对气管内抽吸的生理答案的影响。事实证明,NIRS是评估不同抽吸技术可能产生的有害影响的宝贵工具。
  • 【在未成熟的绵羊胎儿中,与长期低氧血症相关的酸血症期间,脑氧输送减少。】 复制标题 收藏 收藏
    DOI:10.1159/000244440 复制DOI
    作者列表:McCrabb GJ,Harding R
    BACKGROUND & AIMS: Our aim was to determine the effects of 12 h of hypoxaemia on cerebral blood flow (CBF) and cerebral O2 delivery in ovine fetuses at 0.6 gestation. During fetal hypoxaemia, induced by reduced uterine blood flow, fetal SaO2 and PaO2 were reduced (p < 0.01) from control values of 77.0 +/- 1.6% and 27.3 +/- 1.0 mm Hg, respectively, to 28.4 +/- 3.4% and 15.6 +/- 0.6 mm Hg; fetal pHa decreased from control values of 7.37 +/- 0.01 to 7.20 +/- 0.02 at 3 h, but returned to control values before 12 h. CBF (ml/min/100 g) was 2.0- to 2.6-fold higher (p < 0.01) than control values during hypoxaemia, but only 1.7-fold higher (p < 0.01) at 3 h when pHa was lowest. Cerebral O2 delivery (ml/min/100 g) was lower (p < 0.01) than control values of 3.15 +/- 0.29 at 1.5h (2.09 +/- 0.36) and 3h (1.84 +/- 0.22) of hypoxaemia and higher 1 h after hypoxaemia had ceased (3.81 +/- 0.22, p < 0.01). We conclude that the ovine fetus at 0.6 gestation is unable to sustain increased CBF and hence maintain cerebral O2 delivery during the first 6 h of hypoxaemia, a time which coincides with acidaemia; in contrast, at 6 and 12 h of hypoxaemia, when pHa was normal, cerebral O2 delivery was similar to control values. Reduced cerebral O2 delivery during the early, acidaemic, stages of hypoxaemia may lead to impaired neural development.

    背景与目标: 我们的目的是确定12小时低氧血症对0.6妊娠的绵羊胎儿脑血流量 (CBF) 和脑O2输送的影响。在胎儿低氧血症期间,由子宫血流量减少引起的胎儿SaO2和PaO2从77.0 +/- 1.6% 和27.3 +/-1.0毫米Hg的对照值分别降低到28.4 +/- 3.4% 和15.6 +/-0.6毫米Hg (p <0.01); 胎儿pHa在3小时从7.37 +/- 0.01的对照值降至7.20 +/- 0.02,但在12小时前恢复到对照值。在低氧血症期间,CBF (ml/min/100g) 比对照值高2.0至2.6倍 (p <0.01),但在3小时pHa最低时仅高1.7倍 (p <0.01)。低氧血症1.5小时 (2.09 +/- 0.36) 和3小时 (1.84 +/- 0.22) 时,脑O2递送 (ml/min/100g) 低于3.15 +/- 0.29的对照值 (p <0.01),低氧血症停止后1小时更高 (3.81 +/- 0.22,p <0.01)。我们得出的结论是,0.6妊娠的绵羊胎儿无法维持CBF的增加,因此在低氧血症的前6小时 (与酸血症相吻合) 中维持脑O2的输送; 相反,在低氧血症的6和12小时,当pHa正常时,脑O2输送与对照值相似。低氧血症的早期,酸血症阶段的脑O2输送减少可能导致神经发育受损。
  • 【哌替啶和阿芬太尼在清醒绵羊中的脑药代动力学。】 复制标题 收藏 收藏
    DOI:10.1097/00000542-199706000-00013 复制DOI
    作者列表:Upton RN,Ludbrook GL,Gray EC,Grant C
    BACKGROUND & AIMS: BACKGROUND:Different opioids have different delays (hysteresis) between their concentrations in blood and their cerebral effects. Possible mechanisms include differences in their rate of penetration into the brain and differences in their distribution volume in the brain. There have been few in vivo studies of the cerebral kinetics of opioids to differentiate these mechanisms.

    METHODS:The cerebral kinetics of meperidine and alfentanil were examined using conscious sheep that were fitted with long-term monitoring equipment to measure relative changes in cerebral blood flow and opioid concentration gradients across the brain through frequent sampling of arterial and sagittal sinus blood. The data were compared using hybrid physiologic modeling with membrane-limited (consistent with mechanism 1) and flow-limited (consistent with mechanism 2) models of cerebral kinetics.

    RESULTS:Alfentanil had a variable effect on relative cerebral blood flow, whereas meperidine induced a transient increase. The arteriovenous concentration gradients were small after alfentanil but large after meperidine. The flow-limited model gave acceptable descriptions of observed sagittal sinus concentrations for alfentanil and meperidine, whereas the membrane-limited model collapsed to a flow-limited model. The half-lives of equilibrium between blood and brain were 6.3 and 0.8 min for meperidine and alfentanil, respectively:

    CONCLUSIONS:The rate of penetration of both opioids into the brain was rapid and not rate-limiting. Large differences in the cerebral distribution volume of meperidine and alfentanil accounted for the respective delays in their peak brain concentration relative to blood.

    背景与目标: 背景 : 不同的阿片类药物在血液中的浓度与大脑作用之间具有不同的延迟 (滞后)。可能的机制包括它们渗透到大脑的速率的差异以及它们在大脑中的分布体积的差异。关于阿片类药物的脑动力学的体内研究很少,可以区分这些机制。
    方法 : 使用配备了长期监测设备的有意识的绵羊检查了哌替啶和阿芬太尼的脑动力学,以通过频繁采样动脉和矢状窦血来测量整个大脑中脑血流量和阿片类药物浓度梯度的相对变化。使用混合生理模型与脑动力学的膜受限模型 (与机制1一致) 和流量受限模型 (与机制2一致) 进行数据比较。
    结果 : 阿芬太尼对相对脑血流量有不同的影响,而哌替啶诱导了短暂的增加。阿芬太尼后动静脉浓度梯度较小,而哌替啶后动静脉浓度梯度较大。限流模型对观察到的阿芬太尼和哌替啶的矢状窦浓度给出了可接受的描述,而膜限流模型崩溃为限流模型。对于哌替啶和阿芬太尼,血液和大脑之间的平衡半衰期分别为6.3和0.8分钟:
    结论 : 两种阿片类药物进入大脑的速率是快速的,而不是限速。哌替啶和阿芬太尼的脑分布体积差异很大,导致其峰值脑浓度相对于血液的延迟。
  • 【多巴酚丁胺负荷心脏MRI峰值剂量时首过心肌灌注显像检测心肌缺血的附加价值。】 复制标题 收藏 收藏
    DOI:10.1007/s10554-006-9205-5 复制DOI
    作者列表:Lubbers DD,Janssen CH,Kuijpers D,van Dijkman PR,Overbosch J,Willems TP,Oudkerk M
    BACKGROUND & AIMS: :Purpose of this study was to assess the additional value of first pass myocardial perfusion imaging during peak dose of dobutamine stress Cardiac-MR (CMR). Dobutamine Stress CMR was performed in 115 patients with an inconclusive diagnosis of myocardial ischemia on a 1.5 T system (Magnetom Avanto, Siemens Medical Systems). Three short-axis cine and grid series were acquired during rest and at increasing doses of dobutamine (maximum 40 microg/kg/min). On peak dose dobutamine followed immediately by a first pass myocardial perfusion imaging sequence. Images were graded according to the sixteen-segment model, on a four point scale. Ninety-seven patients showed no New (Induced) Wall Motion Abnormalities (NWMA). Perfusion imaging showed absence of perfusion deficits in 67 of these patients (69%). Perfusion deficits attributable to known previous myocardial infarction were found in 30 patients (31%). Eighteen patients had NWMA, indicative for myocardial ischemia, of which 14 (78%) could be confirmed by a corresponding perfusion deficit. Four patients (22%) with NWMA did not have perfusion deficits. In these four patients NWMA were caused by a Left Bundle Branch Block (LBBB). They were free from cardiac events during the follow-up period (median 13.5 months; range 6-20). Addition of first-pass myocardial perfusion imaging during peak-dose dobutamine stress CMR can help to decide whether a NWMA is caused by myocardial ischemia or is due to an (inducible) LBBB, hereby preventing a false positive wall motion interpretation.
    背景与目标: : 这项研究的目的是评估多巴酚丁胺应激心脏MR (CMR) 峰值剂量期间首过心肌灌注成像的附加价值。多巴酚丁胺应激CMR在1.5 T系统 (Magnetom Avanto,Siemens Medical Systems) 上对115例未明确诊断为心肌缺血的患者进行。在休息期间和增加多巴酚丁胺的剂量 (最大40微克/千克/分钟) 获得了三个短轴电影和网格系列。在峰值剂量多巴酚丁胺之后立即进行首过心肌灌注成像序列。根据十六段模型对图像进行了四分制的分级。97名患者未显示新的 (诱发的) 壁运动异常 (NWMA)。灌注成像显示这些患者中有67例 (69%) 不存在灌注缺陷。在30例患者 (31%) 中发现了可归因于已知先前心肌梗塞的灌注缺陷。18例患者患有NWMA,指示心肌缺血,其中14例 (78% 例) 可以通过相应的灌注不足来确认。四名NWMA患者 (22%) 没有灌注缺陷。在这四名患者中,NWMA是由左束支传导阻滞 (LBBB) 引起的。在随访期间 (中位13.5个月; 范围6-20),他们没有心脏事件。在峰值剂量多巴酚丁胺应激CMR期间增加首过心肌灌注成像可以帮助确定NWMA是由心肌缺血引起还是由 (可诱导的) LBBB引起,从而防止假阳性壁运动解释。
  • 【MRI上睡眠呼吸障碍和大脑变化的关联。】 复制标题 收藏 收藏
    DOI: 复制DOI
    作者列表:Robbins J,Redline S,Ervin A,Walsleben JA,Ding J,Nieto FJ
    BACKGROUND & AIMS: STUDY OBJECTIVES:Population-based studies have demonstrated associations between sleep-disordered breathing (SDB), hypertension, and cardiovascular disease; few large-scale studies have examined associations of SDB with objective measures of cerebrovascular disease. This study tested the significance of associations of SDB with evidence of brain injury or ischemia determined by cerebral magnetic resonance imaging (MRI) studies. DESIGN:Cross-sectional and longitudinal analyses in a nested sample of Cardiovascular Health Study participants in the Sleep Heart Health Study. PARTICIPANTS:The 843 individuals (mean age 77, SD 4.3 years, 58% women) who had MRI studies as part of the Cardiovascular Health Study before and after polysomnography obtained as part of the Sleep Heart Health Study. MEASUREMENTS:A 12-channel polysomnogram was used to derive indexes of sleep-disordered breathing. Repeated MRI measurements provided indexes of infarct (presence and size) and white matter disease. Logistic regression analyses were used to model MRI changes of infarct-like lesions and white matter disease as a function of age, baseline white matter grade, and indexes of central and obstructive sleep-disordered breathing. RESULTS:Individuals who showed progression in white matter disease compared to those who did not were significantly more likely to show a Cheyne-Stokes respiration pattern and to have an increased number of central but not obstructive apneas. CONCLUSIONS:An association between change in white matter grade and measures of central sleep apnea was demonstrated that was consistent with a causal pathway in which central sleep apnea contributes to the progression of white matter disease; alternatively, central sleep apnea may be a marker of subclinical cerebrovascular or cardiovascular disease.
    背景与目标:
  • 【欧洲合作儿科脑静脉血栓形成数据库中复发性静脉血栓栓塞的危险因素: 一项多中心队列研究。】 复制标题 收藏 收藏
    DOI:10.1016/S1474-4422(07)70131-X 复制DOI
    作者列表:Kenet G,Kirkham F,Niederstadt T,Heinecke A,Saunders D,Stoll M,Brenner B,Bidlingmaier C,Heller C,Knöfler R,Schobess R,Zieger B,Sébire G,Nowak-Göttl U,European Thromboses Study Group.
    BACKGROUND & AIMS: BACKGROUND:The relative importance of previous diagnosis and hereditary prothrombotic risk factors for cerebral venous thrombosis (CVT) in children in determining risk of a second cerebral or systemic venous thrombosis (VT), compared with other clinical, neuroimaging, and treatment variables, is unknown. METHODS:We followed up the survivors of 396 consecutively enrolled patients with CVT, aged newborn to 18 years (median 5.2 years) for a median of 36 months (maximum 85 months). In accordance with international treatment guidelines, 250 children (65%) received acute anticoagulation with unfractionated heparin or low-molecular weight heparin, followed by secondary anticoagulation prophylaxis with low-molecular weight heparin or warfarin in 165 (43%). RESULTS:Of 396 children enrolled, 12 died immediately and 22 (6%) had recurrent VT (13 cerebral; 3%) at a median of 6 months (range 0.1-85). Repeat venous imaging was available in 266 children. Recurrent VT only occurred in children whose first CVT was diagnosed after age 2 years; the underlying medical condition had no effect. In Cox regression analyses, non-administration of anticoagulant before relapse (hazard ratio [HR] 11.2 95% CI 3.4-37.0; p<0.0001), persistent occlusion on repeat venous imaging (4.1, 1.1-14.8; p=0.032), and heterozygosity for the G20210A mutation in factor II (4.3, 1.1-16.2; p=0.034) were independently associated with recurrent VT. Among patients who had recurrent VT, 70% (15) occurred within the 6 months after onset. CONCLUSION:Age at CVT onset, non-administration of anticoagulation, persistent venous occlusion, and presence of G20210A mutation in factor II predict recurrent VT in children. Secondary prophylactic anticoagulation should be given on a patient-to-patient basis in children with newly identified CVT and at high risk of recurrent VT. Factors that affect recanalisation need further research.
    背景与目标:
  • 【血™(聚乙二醇化羧基血红蛋白牛) 改善蛛网膜下腔出血后处于延迟脑缺血风险的脆弱大脑区域的脑血流量。】 复制标题 收藏 收藏
    DOI:10.1007/s12028-017-0418-3 复制DOI
    作者列表:Dhar R,Misra H,Diringer MN
    BACKGROUND & AIMS: BACKGROUND:Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) has been linked to focal reductions in cerebral blood flow (CBF) and microvascular impairments in oxygen delivery. Effective therapies that restore flow and oxygen transport to vulnerable brain regions are currently lacking. SANGUINATE is a dual-action carbon monoxide-releasing and hemoglobin-based oxygen transfer agent with efficacy in animal models of focal brain ischemia and tolerability in patients with sickle cell disease. METHODS:We performed a safety and proof-of-principle study in 12 SAH patients at risk of DCI across three escalating doses (160, 240, and 320 mg/kg). We used 15O-PET (performed at baseline, after SANGUINATE and at 24 h) to evaluate efficacy for improving CBF and restoring flow-metabolism balance (assessed by oxygen extraction fraction [OEF]) to vulnerable regions (defined as baseline OEF ≥ 0.50). RESULTS:SANGUINATE resulted in a transient rise in mean arterial pressure (116 ± 15-127 ± 13 mm Hg, p = 0.001) that normalized by 24 h and allowed three patients with DCI to be weaned off vasopressors. No adverse events were noted during infusion. Global CBF did not rise (43 ± 8-46 ± 9 ml/100 g/min) although a trend was seen at the highest dose (45 ± 7-51 ± 9, p = 0.044). However, a significant 16% rise in regional CBF associated with reduction in OEF was seen in vulnerable regions, but did not persist at 24 h. CONCLUSIONS:We demonstrated that this novel agent can improve regional CBF and may improve oxygen supply-demand balance. Clinical studies (likely with repeat dosing) are required to evaluate whether this effect can prevent DCI or cerebral infarction.
    背景与目标:
  • 【接受胸动脉瘤修复的患者的脑脊液中的热休克蛋白HSP70和HSP27与术后瘫痪的可能性相关。】 复制标题 收藏 收藏
    DOI:10.1007/s12192-008-0039-z 复制DOI
    作者列表:Hecker JG,Sundram H,Zou S,Praestgaard A,Bavaria JE,Ramchandren S,McGarvey M
    BACKGROUND & AIMS: :An understanding of the time course and correlation with injury of heat shock proteins (HSPs) released during brain and/or spinal cord cellular stress (ischemia) is critical in understanding the role of the HSPs in cellular survival, and may provide a clinically useful biomarker of severe cellular stress. We have analyzed the levels of HSPs in the cerebrospinal fluid (CSF) from patients who are undergoing thoracic aneurysm repair. Blood and CSF samples were collected at regular intervals, and CSF was analyzed by enzyme-linked immunosorbent assay for HSP70 and HSP27. These results were correlated with intraoperative somatosensory-evoked potentials measurements and postoperative paralysis. We find that the levels of these proteins in many patients are elevated and that the degree of elevation correlates with the risk of permanent paralysis. We hypothesize that sequential measurement intraoperatively of the levels of the heat shock proteins HSP70 and HSP27 in the CSF can predict those patients who are at greatest risk for paralysis during thoracic aneurysm surgery and will allow us to develop means of preventing or attenuating this severe and often fatal complication.
    背景与目标: : 了解大脑和/或脊髓细胞应激 (缺血) 期间释放的热休克蛋白 (hsp) 的时间过程以及与损伤的相关性对于理解hsp在细胞存活中的作用至关重要,并且可能提供临床上有用的生物标志物严重的细胞应激。我们已经分析了正在接受胸动脉瘤修复的患者的脑脊液 (CSF) 中HSPs的水平。定期收集血液和CSF样本,并通过酶联免疫吸附法分析CSF中的HSP70和hsp27。这些结果与术中体感诱发电位测量和术后瘫痪相关。我们发现许多患者中这些蛋白质的水平升高,并且升高的程度与永久性瘫痪的风险相关。我们假设,术中连续测量CSF中热休克蛋白HSP70和HSP27的水平可以预测那些在胸动脉瘤手术中瘫痪风险最大的患者,并将使我们能够开发预防或减轻这种严重且通常致命的并发症的方法。
  • 【二甲双胍单次肠道灌注对大鼠肠道通透性的影响。】 复制标题 收藏 收藏
    DOI:10.3748/wjg.v12.i25.4064 复制DOI
    作者列表:Song NN,Li QS,Liu CX
    BACKGROUND & AIMS: AIM:To characterize the intestinal transport and mechanism of metformin in rats and to investigate whether or not metformin is a substrate for P-glycoprotein (P-gp). METHODS:The effective intestinal permeability of metformin was investigated using single-pass intestinal perfusion (SPIP) technique in male Waster rats. SPIP was performed in three isolated intestinal segments (duodenum, jejunum and ileum) at the same concentration of metformin (50 microg/mL) to test if the intestinal transport of metformin exhibited site-dependent changes, and in a same isolated intestinal segment (duodenal segment) at three different concentrations of metformin (10, 50, 200 microg/mL) to test if the intestinal transport of metformin exhibited concentration-dependent changes. Besides, P-gp inhibitor verapamil (400 microg/mL) was co-perfused with metformin (50 microg/mL) in the duodenum segment to find out if the intestinal absorption of metformin was affected by P-gp exiting along the gastrointestinal track. Stability studies were conducted to ensure that the loss of metformin could be attributed to intestinal absorption. RESULTS:The effective permeability values (P(eff)) of metformin in the jejunum and ileum at 50 microg/mL were significantly lower than those in the duodenum at the same concentration. Besides, P(eff) values in the duodenum at high concentration (200 microg/mL) were found to be significantly lower than those at low and medium concentrations (10 and 50 microg/mL). Moreover the co-perfusion with verapamil did not increase the P(eff) value of metformin at 50 microg/mL in the duodenum. CONCLUSION:Metformin could be absorbed from the whole intestine, with the main absorption site at duodenum. This concentration-dependent permeability behavior in the duodenum indicates that metformin is transported by both passive and active carrier-mediated saturable mechanism. The P(eff) value can not be increased by co-perfusion with verapamil, indicating that absorption of metformin is not efficiently transported by P-gp in the gut wall. Furthermore metformin is neither a substrate nor an inducer of P-gp. Based on the P(eff) values obtained in the present study and using established relationships, the human fraction dose absorbed for metformin is estimated to be 74%-90% along human intestine.
    背景与目标:
  • 【阿魏酸通过抑制大鼠脑缺血/再灌注损伤后氧化应激相关凋亡的ICAM-1提供神经保护。】 复制标题 收藏 收藏
    DOI:10.1016/j.brainres.2008.02.090 复制DOI
    作者列表:Cheng CY,Su SY,Tang NY,Ho TY,Chiang SY,Hsieh CL
    BACKGROUND & AIMS: :Our previous studies have shown that ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) inhibits intercellular adhesion molecule-1 (ICAM-1) expression in the ischemic striatum after 2 h of reperfusion in a transient middle cerebral artery occlusion model in rats. The purpose of this study is to further investigate the neuroprotective effects of FA during reperfusion after cerebral ischemia. Rats were subjected to 90 min of ischemia; they were then sacrificed after 2, 10, 24 and 36 h of reperfusion. ICAM-1 and macrophage-1 antigen (Mac-1) mRNA were detected using semi-quantitative RT-PCR at 2 h of reperfusion. Mac-1, 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), active caspase 3, neuronal nuclei (NeuN) and TUNEL positive cells were measured at 2, 10, 24 and 36 h of reperfusion. FA (100 mg/kg, i.v.) administered immediately after MCAo inhibited ICAM-1 and Mac-1 mRNA expression in the striatum at 2 h of reperfusion, and reduced the number of Mac-1, 4-HNE and 8-OHdG positive cells in the ischemic rim and core at 10, 24 and 36 h of reperfusion. FA decreased TUNEL positive cells in the penumbra at 10 h, and in the ischemic boundary and core at 24 and 36 h of reperfusion. FA curtailed active caspase 3 expression in the penumbra at 10 h and restored NeuN-labeled neurons in the penumbra and ischemic core at 36 h of reperfusion. FA decreased the level of ICAM-1 mRNA and the number of microglia/macrophages, and subsequently down-regulated inflammation-induced oxidative stress and oxidative stress-related apoptosis, suggesting that FA provides neuroprotection against oxidative stress-related apoptosis by inhibiting ICAM-1 mRNA expression after cerebral ischemia/reperfusion injury in rats.
    背景与目标: : 我们先前的研究表明,在大鼠短暂性大脑中动脉闭塞模型中,再灌注2小时后,阿魏酸 (4-羟基-3-甲氧基肉桂酸,FA) 抑制缺血纹状体中细胞间粘附分子-1 (ICAM-1) 的表达。目的进一步探讨FA在脑缺血再灌注过程中的神经保护作用。大鼠缺血90分钟; 然后在再灌注2、10、24和36小时后处死它们。在再灌注2 h时,使用半定量rt-pcr检测ICAM-1和巨噬细胞-1抗原 (Mac-1) mRNA。在2时测量Mac-1,4-羟基-2-壬醛 (4-HNE),8-羟基-2 '-脱氧鸟苷 (8-OHdG),活性半胱天冬酶3,神经元核 (NeuN) 和TUNEL阳性细胞,再灌注10、24和36小时。FA (100 mg/kg,i.v.) 后立即给予MCAo抑制了再灌注2 h时纹状体中ICAM-1和Mac-1 mRNA的表达,并减少了Mac-1,4-hne和8-OHdG阳性细胞的数量。缺血边缘和核心在10,再灌注24和36 h。FA在再灌注10 h时减少半影中的TUNEL阳性细胞,在再灌注24和36 h时减少缺血边界和核心中的TUNEL阳性细胞。FA在10小时减少了半影中的caspase 3活性表达,并在再灌注36小时恢复了半影和缺血核心中的NeuN标记神经元。FA降低了ICAM-1 mRNA的水平和小胶质细胞/巨噬细胞的数量,随后下调了炎症诱导的氧化应激和氧化应激相关的凋亡,提示FA通过抑制大鼠脑缺血/再灌注损伤后ICAM-1 mRNA的表达来提供针对氧化应激相关凋亡的神经保护。
  • 【通过互信息和自适应预测对肾脏灌注图像序列进行自动2D配准。】 复制标题 收藏 收藏
    DOI:10.1007/s10334-012-0337-4 复制DOI
    作者列表:Positano V,Bernardeschi I,Zampa V,Marinelli M,Landini L,Santarelli MF
    BACKGROUND & AIMS: UNLABELLED:The objective of this study was to develop an automatic image registration technique capable of compensating for kidney motion in renal perfusion MRI, to assess the effect of renal artery stenosis on the kidney parenchyma. MATERIALS AND METHODS:Images from 20 patients scheduled for a renal perfusion study were acquired using a 1.5 T scanner. A free-breathing 3D-FSPGR sequence was used to acquire coronal views encompassing both kidneys following the infusion of Gd-BOPTA. A two-step registration algorithm was developed, including a preliminary registration minimising the quadratic difference and a fine registration maximising the mutual information (MI) between consecutive image frames. The starting point for the MI-based registration procedure was provided by an adaptive predictor that was able to predict kidney motion using a respiratory movement model. The algorithm was validated against manual registration performed by an expert user. RESULTS:The mean distance between the automatically and manually defined contours was 2.95 ± 0.81 mm, which was not significantly different from the interobserver variability of the manual registration procedure (2.86 ± 0.80 mm, P = 0.80). The perfusion indices evaluated on the manually and automatically extracted perfusion curves were not significantly different. CONCLUSIONS:The developed method is able to automatically compensate for kidney motion in perfusion studies, which prevents the need for time-consuming manual image registration.
    背景与目标:

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