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。

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。

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。

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：

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：

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。

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。

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。

BACKGROUND & AIMS: The purpose of this study was to determine if quantitative measurements of regional asynergy add independent prognostic information to global ejection fraction in patients with chronic coronary artery disease. Four hundred eighty-six patients with a history of Q-wave myocardial infarction who underwent gated-equilibrium radionuclide angiography at least 3 months after infarction were monitored for a median duration of 4.7 years. During follow-up there were 95 deaths. Four of five regional asynergy indexes analyzed were associated with overall mortality. The strength of the association between overall mortality and the index that proved to be optimal (univariate chi2 = 26.4, p < 0.001) was stronger than for global ejection fraction (univariate chi2 = 21.5, p < 0.001). For patients with global ejection fraction <40%, 4-year survival was 87% for those with a low asynergy index versus 65% for those with a high asynergy index (p = 0.016). In conclusion, indexes of regional asynergy add independent prognostic information to global left ventricular ejection fraction.

背景与目标： 这项研究的目的是确定区域不同步的定量测量是否为慢性冠心病患者的整体射血分数增加了独立的预后信息。对486例有Q波心肌梗死病史的患者进行了监测，这些患者在梗死后至少3个月接受了门控平衡放射性核素血管造影，中位持续时间为4.7年。在随访期间，有95人死亡。分析的五个区域异步指数中有四个与总体死亡率相关。总死亡率与被证明是最佳的指数 (单变量chi2 = 26.4，p <0.001) 之间的关联强度强于整体射血分数 (单变量chi2 = 21.5，p <0.001)。对于整体射血分数 <40% 的患者，非同步指数低的患者87% 4年生存率，而非同步指数高的患者65% (p = 0.016)。总之，区域非同步指数为整体左心室射血分数增加了独立的预后信息。

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。

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。

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：

BACKGROUND & AIMS: :The evolution of oxygen transport hemoglobins occurred on at least two independent occasions. The earliest event led to myoglobin and red blood cell hemoglobin in animals. In plants, oxygen transport "leghemoglobins" evolved much more recently. In both events, pentacoordinate heme sites capable of inert oxygen transfer evolved from hexacoordinate hemoglobins that have unrelated functions. High sequence homology between hexacoordinate and pentacoordinate hemoglobins in plants has poised them for potential structural analysis leading to a molecular understanding of this important evolutionary event. However, the lack of a plant hexacoordinate hemoglobin structure in the exogenously ligand-bound form has prevented such comparison. Here we report the crystal structure of the cyanide-bound hexacoordinate hemoglobin from barley. This presents the first opportunity to examine conformational changes in plant hexacoordinate hemoglobins upon exogenous ligand binding, and reveals structural mechanisms for stabilizing the high-energy pentacoordinate heme conformation critical to the evolution of reversible oxygen binding hemoglobins.

背景与目标： : 氧转运血红蛋白的演变至少发生在两个独立的场合。最早的事件导致动物出现肌红蛋白和红细胞血红蛋白。在植物中，氧气运输 “leghe血红蛋白” 是最近进化的。在这两种情况下，能够惰性氧转移的五配位的血红素位点都是由具有无关功能的六配位的血红蛋白进化而来的。植物中六配位和五配位血红蛋白之间的高序列同源性使它们可以进行潜在的结构分析，从而对这一重要的进化事件有了分子理解。然而，由于缺乏外源配体结合形式的植物六配位血红蛋白结构，因此无法进行这种比较。在这里，我们报告了大麦中氰化物结合的六配位血红蛋白的晶体结构。这为研究外源配体结合后植物六配位血红蛋白的构象变化提供了第一个机会，并揭示了稳定对可逆氧结合血红蛋白的进化至关重要的高能五配位血红素构象的结构机制。

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：

BACKGROUND & AIMS: :Oxygen therapy can be life-saving for patients with chronic obstructive pulmonary disease (COPD) and is the backbone of any acute COPD treatment strategy. Although largely considered to be a benign drug, many publications have highlighted the need to accurately adjust oxygen delivery to avoid both hypoxemia and the problem of hyperoxia-induced hypercapnia. Recent clinical data have shown that the deleterious effects of excess oxygen treatment can not only alter carbon dioxide levels (which has been known for more than 60 years) but can also lead to an increase in mortality. Nevertheless, despite the extensive literature, the risks associated with hyperoxia are often overlooked and published clinical recommendations are largely ignored. This failure in knowledge translation has become increasingly important not only because of the desire to reduce medical error, but in a society with limited health care resources, the economic burden of COPD is such that it cannot afford to make preventable medical mistakes. Recently, novel devices have been developed to automatically adjust oxygen flow rates to maintain stable oxygen saturations. These closed-loop oxygen delivery systems have the potential to reduce medical error, improve morbidity and mortality, and reduce health care costs. Preliminary data in this field are promising and will require a significant amount of research in the coming years to determine the precise indications for these systems. The importance of appropriate oxygen dosing and the current literature regarding novel oxygen delivery systems are reviewed.

背景与目标： : 氧疗可以挽救慢性阻塞性肺疾病 (COPD) 患者的生命，并且是任何急性COPD治疗策略的支柱。尽管在很大程度上被认为是一种良性药物，但许多出版物都强调需要准确调整氧气输送以避免低氧血症和高氧诱导的高碳酸血症的问题。最近的临床数据表明，过量氧气治疗的有害影响不仅会改变二氧化碳水平 (已知已有60多年的历史)，还会导致死亡率增加。然而，尽管有大量文献，但与高氧相关的风险经常被忽视，发表的临床建议在很大程度上被忽视。这种知识翻译的失败变得越来越重要，这不仅是因为希望减少医疗错误，而且在医疗资源有限的社会中，COPD的经济负担使它无法承受可预防的医疗错误。最近，已经开发了新颖的设备来自动调节氧气流速以保持稳定的氧气饱和度。这些闭环氧气输送系统具有减少医疗错误，提高发病率和死亡率以及降低医疗保健成本的潜力。该领域的初步数据很有希望，并且在未来几年中将需要大量研究以确定这些系统的确切指示。回顾了适当的氧气剂量的重要性以及有关新型氧气输送系统的当前文献。