Neuropathology of acute liver failure

Cerebral edema has been identified in all forms of liver disease and is closely related to the development of hepatic encephalopathy. Cerebral edema is most readily recognized in acute liver failure (ALF), while the main cause of death in patients with ALF is multi-organ failure; brain herniation as a result of intracranial hypertension does remain a major cause of mortality. The mechanisms responsible for cerebral edema in ALF suggest both cytotoxic and vasogenic injury. This article reviews the gross and ultrastructural changes associated with cerebral edema in ALF. The primary cause of cerebral edema is associated with astrocyte swelling, mainly perivascular edema and ammonia still remains the primary neurotoxin involved in its pathogenesis. The astrocytic changes were confined to the gray matter. The other organelles involved in the pathogenesis of ALF include mitochondria, basement membrane, pericytes, microglial cells, blood-brain barrier (BBB) etc. Discrete neuronal changes have recently been reported. Recent studies in animal and humans have demonstrated the microglial changes which have the potential to cause neuronal dysfunction in ALF. The alterations in BBB still remain unclear though few studies have showed disruption of tight junction proteins indicating the involvement of BBB in cellular swelling.     

AQP-4在几种常见类型脑水肿中的表达及其作用

脑水肿是指各种原因导致的脑组织水含量增多,可导致脑容积增大、颅内压增高,脑水肿发病机制复杂,是多种颅脑疾病如脑静脉血栓形成、脑缺血、脑出血、脑组织创伤等的主要病理生理改变之一,其形成严重影响疾病预后,是颅脑疾病中致残、致死的主要原因。水通道蛋白(Aquaporin,缩写为AQP)是一个具有高度选择性通透水的膜通道蛋白家族,包括200多个家族成员,其蛋白质分子结构中有一狭窄的亲水性孔道,通过该孔道水分子从水位势能高的一侧迅速扩散到势能低的一侧,而其它的物质则不能通过;AQP-4是脑内含量最多的水通道蛋白,最近研究表明AQP-4参与多种颅脑疾病的脑水肿的形成及消退。本文就AQP-4在几种常见类型脑水肿中的表达及作用进行综述。     

水通道蛋白4与脑水肿研究进展

水通道蛋白4(AQP4)是膜水通道蛋白家族的一员,在脑组织中高表达,是控制水进出脑组织的通道。近年来发现,AQP4的功能和表达与脑水肿密切相关。同时脑水肿又是和脑疾病治疗密切相关的病理过程,对两者的研究或许可以为我们带来更多的临床治疗新思路。本文综述了AQP4的结构、表达、调控与功能以及AQP4与脑水肿关系的研究进展。     

Ischemia-induced brain iron delocalization: Effect of iron chelators

Tissue damage in cerebral ischemia may be produced by acidosis-induced delocalization of intracellular iron which acts as a catalyst in oxidative reactions. Acidosis was induced either by homogenization and incubation of rat cortical homogenates in acidified buffers or by submitting hyperglycemic rats to complete ischemia, a procedure that leads to intracellular lactic acidosis. The level of low molecular weight species (LMWS) iron was measured after filtration of tissue homogenates through a 10,000 Mr ultrafiltration membrane. When cortical tissue was homogenized in buffer pH 7, the level of LMWS iron was equal to 0.21 μg/g. It was significantly enhanced by acidification of the homogenization medium, reaching 0.34 μg/g at pH 6 and 0.75 μg/g at pH 5. When the tissue was homogenized in water, the LMWS iron level reached 0.17 μg/g in normoglycemic rats and 0.38 μg/g (p < 0.5) in hyperglycemic rats. Both aerobic incubation of homogenates for 1 h at 37°C and inclusion of EDTA in the homogenization medium led to further increases in the iron level. In order to demonstrate the deleterious role of iron in brain ischemia, the effect of treatment with bipyridyl, an iron-chelating agent, was assessed by measuring regional brain edema by the specific gravity method, 24 h following induction of thrombotic brain infarction. The treatment significantly attenuated the development of brain edema, reducing the water content of the infarcted area by about 2.5%. Taken together, these results support the hypothesis that a significant component of brain ischemic injury involves an iron-dependent mechanism.     

Development of Prolonged Focal Cerebral Edema and Regional Cation Changes Following Experimental Brain Injury in the Rat

The present study examined the formation of regional cerebral edema in adult rats subjected to lateral (parasagittal) experimental fluid-percussion brain injury. Animals receiving fluid-percussion brain injury of moderate severity over the left parietal cortex were assayed for brain water content at 6 h, 24 h, and 2, 3, 5, and 7 days post injury. Regional sodium and potassium concentrations were measured in a separate group of animals at 10 min, 1 h, 6 h, and 24 h following fluid-percussion injury. Injured parietal cortex demonstrated significant edema, beginning at 6 h post injury (p less than 0.05) and persisting up to 5 days post injury. In the hippocampus ipsilateral to the site of cortical injury, significant edema occurred as early as 1 h post injury (p less than 0.05), with resolution of water accumulation beginning at 3 days. Sodium concentrations significantly increased in both injured cortex (1 h post injury, p less than 0.05) and injured hippocampus (10 min post injury, p less than 0.05). Potassium concentrations fell significantly 1 h post injury within the injured cortex (p less than 0.05), whereas significant decreases were not observed until 24 h post injury within the injured hippocampus. Cation alterations persisted throughout the 24-h post injury period. These results demonstrate that regional brain edema and cation deregulation occur in rats subjected to lateral fluid-percussion brain injury and that these changes may persist for a prolonged period after brain injury.     

Amino Acids as Osmolytes in the Retina

Amino acids play a role as osmolytes during the regulatory volume decrease subsequent to hyposmotic swelling, but less is known about its role when swelling occurs in isosmotic conditions. In this work we examined the efflux of labelled GABA, taurine and glutamate (traced as D-aspartate) from the chick retina, after isosmotic swelling evoked by KCl-containing solutions, and compared its features to those in hyposmotic swelling. In both conditions, GABA and taurine efflux were more sensitive to swelling than glutamate, as assessed by the activation threshold and the amount released. The amino acid efflux in hyposmotic media was decreased by DIDS, tamoxifen and NPPB, agents acting as Cl channels blockers, which also inhibit the osmosensitive Cl efflux. The component associated with swelling in the KCl-stimulated efflux was assessed by the reduction observed when Cl is replaced by an impermeant anion, or by the influence of hyperosmotic media. GABA and taurine efflux exhibited a large swelling-dependent component, which was lower for D-aspartate. This component was markedly decreased by NPPB, but this was due to an effect of the blocker preventing swelling. These results suggest that the influx of Cl, acting as K counterion, which is responsible for cell swelling, occurs through a pathway sensitive to NPPB, similarly to that activated by hyposmolarity. This finding may be of interest in studies aiming at preventing the cell edema which occurs in a number of pathologies.     

Ghrelin治疗脑出血大鼠脑水肿及MMP-9表达的影响

目的:研究Ghrelin对大鼠脑出血后脑水肿及脑组织中基质金属蛋白酶-9(MMP-9)表达的影响。方法:选取雄性SD大鼠80只,随机分为对照组(NC组)20只、假手术组(SHAM组)20只、脑出血组(ICH组)20只、Ghrelin治疗组(Ghrelin组)20只。利用自体动脉血注入法建立大鼠脑出血模型;Ghrelin组于建立脑出血模型后经股静脉注射Ghrelin 10 nmol/Kg·d。分别于12 h、24 h、3d、5 d、7 d时间点根据Berderson评分法评估各组大鼠神经系统功能;利用干湿重法测定各组大鼠脑组织含水量;利用蛋白质免疫印迹法(WB)检测脑组织中MMP-9表达情况。结果:在12 h、24 h、3 d、5 d、7 d,ICH组、Ghrelin组大鼠Berderson评分及脑组织含水量高于NC组、SHAM组(P0.05);在5 d、7 d,ICH组大鼠Berderson评分及脑组织含水量高于Ghrelin组(P0.05)。WB结果表明在12 h、24 h、3 d、5 d、7 d,ICH组大鼠脑组织中MMP-9的表达均高于NC组、SHAM组(P0.05);Ghrelin组MMP-9的表达在12 h、24 h、3 d高于NC组、SHAM组(P0.05),在5 d、7 d,与NC组、SHAM组无明显差异(P0.05);在5 d、7 d,ICH组MMP-9表达高于Ghrelin组(P0.05)。结论:在本研究中,Ghrelin可以在5 d后降低脑出血大鼠脑组织中MMP-9的表达程度,从而减轻脑水肿,改善脑出血大鼠神经功能。     

A note on the labial swelling of a pregnant orang-utan,Pongo pygmaeus abelii

Labial swellings following copulation were recorded during each of seven pregnancies for an adult female Sumatran orang-utan (Pongo pygmaeus abelii). These swellings persisted throughout pregnancy and disappeared within a short time after the termination of pregnancy. Labial swellings may be a useful tool in diagnosing pregnancy in orang-utans.     

Recovery from Edema and of Protein Synthesis Differs Between the Cortex and Caudate Following Transient Focal Cerebral Ischemia in Rats

Postischemic recovery from brain edema and of protein synthesis was examined following 1 h of middle cerebral artery (MCA) occlusion in rats. Recovery from brain edema and of protein synthesis showed a good correlation until 7 days after reperfusion in each area (cerebral cortex or lateral caudate) in the occluded MCA side. However, regional differences in the above types of recovery in the cortex and in the lateral caudate were found for the first time in this experiment. A profound inhibition of protein synthesis and formation of brain edema began sooner in the lateral caudate than in the cortex and continued long after reperfusion. Grades of cerebral blood flow during ischemia and the early period of reperfusion were almost the same in the two regions. Therefore, the regional differences in the above recoveries may not be due to the difference in the blood flow during ischemia and reperfusion, but may be partly attributable to the imbalance of excitatory and inhibitory innervation in the above two areas of the brain, may be due to a distinctive response to ischemic stress, and may be caused also by the potentiative effect of free arachidonate on the excitotoxic mechanism.     

Investing in early human development: Timing and economic efficiency

Policy discussions to ameliorate socioeconomic (SES) inequalities are increasingly focused on investments in early childhood. Yet such interventions are costly to implement, and clear evidence on the optimal time to intervene to yield a high economic and social return in the future is meagre. The majority of successful early childhood interventions start in the preschool years. However socioeconomic gradients in cognitive skills, socio-emotional functioning and health can be observed by age three, suggesting that preventative programmes starting earlier in childhood may be even more effective. We discuss the optimal timing of early childhood intervention with reference to recent research in developmental neuroscience. We motivate the need for early intervention by providing an overview of the impact of adverse risk factors during the antenatal and early childhood periods on outcomes later in life. We provide a brief review of the economic rationale for investing early in life and propose the “antenatal investment hypothesis”. We conclude by discussing a suite of new European interventions that will inform this optimal timing debate.     

Role of early edema in the development of regional seizure-related brain damage

Kainic acid-induced seizures produced early (2 hr) generalized edema and later (24 and 48 hr) necrotic edema in temporal cortex and hippocampus as measured by specific gravity changes. Mannitol given during the seizure partially protected against the early edema and prevented the necrotic edema indicating early edema may play a role in later brain damage. However, H₂O intoxication, causing much greater generalized edema than the kainic acidinduced seizures, caused no necrotic edema in temporal cortex or hippocampus at 48 hr. Thus it appears that mannitol protection against kainic acid-induced brain damage may be by a mechanism in addition to dehydration.Special Issue dedicated to Dr. O. H. Lowry.     

吡拉西坦联合甘露醇对老年脑出血后脑水肿的疗效比较

目的:观察吡拉西坦联合甘露醇对老年脑出血后脑水肿患者颅内压、脑水肿体积、脑血肿体积及认知功能的影响。方法:104例脑出血后脑水肿老年患者随机分为观察组(54例)和对照组(50例)。对照组在常规治疗的基础上给予20%甘露醇注射液,观察组在对照组的基础上给予吡拉西坦注射液。治疗7天,观察两组颅内压、脑水肿体积、脑血肿体积及认知功能(分别采用MMSE、Mo CA评估)的变化。结果:治疗后,两组颅内压、脑水肿体积、脑血肿体积均明显下降而MMSE、Mo CA明显上升,且观察组各指标变化幅度均大于对照组,治疗后同期比较差异均有统计学意义(P0.05)。结论:吡拉西坦联合甘露醇治疗老年脑出血后脑水肿,控制颅内压、改善脑水肿与脑血肿,作用优于单用甘露醇,能更大程度保护认知功能。     

Polyamine Metabolism in Experimental Brain Tumors of Rat

Abstract: Biosynthesis and accumulation of the polyamines putrescine, spermidine, and spermine are closely associated with cellular growth processes. We examined polyamine levels and the activity of their first rate-limiting enzyme, ornithine decarboxylase (ODC), in stereotactically induced experimental gliomas of the rat brain 1 and 2 weeks after implantation. Regional ODC activity and polyamine levels were determined in the tumor and in the ipsi- and contralateral striatum, white matter, and cerebral cortex. In the tumor, both ODC activity and polyamine levels markedly increased with progressive tumor growth, as compared to those in the white matter of the opposite hemisphere. In the peritumoral brain tissue, ODC activity did not change, but there was a marked increase of putrescine and, to a lesser degree, of spermidine and spermine almost throughout the whole ipsilateral hemisphere. ODC activity, therefore, seems to be a reliable marker of neoplastic growth in the brain, which may be of use for new clinical concepts of the diagnosis and therapy of brain tumors. The more diffuse distribution of polyamines, however, may be associated with the formation and spreading of edema, which would explain some of the biological effects of tumors on distant brain tissue.     

糖尿病性视网膜病变早期mfERG的研究

目的:探讨糖尿病患者糖尿病性视网膜病变早期多焦视网膜电图(multifocal electroretinogram,mfERG)的特点。方法:应用德国ROLAND公司RETIscan系统对24例40眼糖尿病患者,同时对27例40眼正常对照眼记录mfERG。按机器的默认值一阶反应进行记录。整个记录过程中可以分为12个时段,每个时段记录为时间47秒。结果:mERG测得的糖尿病患者组1～5环所在位置的P1波的振幅密度随离心度的增加而降低,P1波和N1波幅值降低和潜伏时延迟。各象限的P1、N1波振幅密度、波幅值降低,潜伏时延迟。结论:糖尿病性视网膜病变受累的区域多发生在黄斑部,功能上的改变早于形态学的变化;病变的早期功能改变最先出现于视网膜的后极偏颞上方;糖尿病患者在未出现眼底改变时各个象限视网膜的外层已经严重受累。     

肛周坏死性筋膜炎抗感染治疗12例报告

目的探讨坏死性筋膜炎诊断及有效治疗方法。方法回顾性分析总结12例坏死性筋膜炎的临床表现及治疗过程（包括彻底扩创引流,全身抗感染治疗及营养支持治疗）。结果12例患者痊愈。结论早期明确诊断,尽早切开引流,抗感染及营养支持的方法,是治疗坏死性筋膜炎的有效方法。     

低剂量灌注CT成像诊断胰腺癌的研究进展

随着MSCT的不断发展以及检查技术的不断完善,胰腺疾病的诊断率也不断进步。CT可以对胰腺进行普通平扫、多期增强扫描及CT灌注扫描(CTPI)。其中,普通平扫及增强扫描对小的胰腺癌病灶诊断率较低;普通灌注扫描可以通过监测胰腺组织血流动力学评价胰腺功能,对于早期胰腺癌的诊断率较高,但辐射剂量也较高,因此对患者的远期影响较大。因此,在满足对胰腺癌疾病诊断条件的前提下,减少CT扫描对患者的辐射剂量是目前临床研究的热点。灌注扫描通过监测患者血流量(BF)、血容量(BV)对正常胰腺及胰腺癌病灶进行观察,能够在减少辐射剂量的同时获得灌注数据,从而提供更多的诊断信息,进而满足临床诊断的要求。     

Melatonin renders neuroprotection by protein kinase C mediated aquaporin-4 inhibition in animal model of focal cerebral ischemia

Aim

Aquaporin-4(AQP4) expression in the brain with relation to edema formation following focal cerebral ischemia was investigated. Studies have shown that brain edema is one of the significant factors in worsening stroke outcomes. While many mechanisms may aggravate brain injury, one such potential system may involve AQP4 up regulation in stroke patients that could result in increased edema formation. Post administration of melatonin following ischemic stroke reduces AQP4 mediated brain edema and confers neuroprotection.

Materials and methods

An in-silico approach was undertaken to confirm effective melatonin-AQP4 binding. Rats were treated with 5 mg/kg, i.p. melatonin or placebo at 30 min prior, 60 min post and 120 min post 60 min of middle cerebral artery occlusion (MCAO) followed by 24 h reperfusion. Rats were evaluated for battery of neurological and motor function tests just before sacrifice. Brains were harvested for infarct size estimation, water content measurement, biochemical analysis, apoptosis study and western blot experiments.

Key findings

Melatonin at 60 min post ischemia rendered neuroprotection as evident by reduction in cerebral infarct volume, improvement in motor and neurological deficit and reduction in brain edema. Furthermore, ischemia induced surge in levels of nitrite and malondialdehyde (MDA) were also found to be significantly reduced in ischemic brain regions in treated animals. Melatonin potentiated intrinsic antioxidant status, inhibited acid mediated rise in intracellular calcium levels, decreased apoptotic cell death and also markedly inhibited protein kinase C (PKC) influenced AQP4 expression in the cerebral cortex and dorsal striatum.

Significance

Melatonin confers neuroprotection by protein kinase C mediated AQP4 inhibition in ischemic stroke.     

Role of aquaporins in cell migration and edema formation in human brain tumors

The aquaporins (AQPs) are a family of transmembrane water channel proteins widely distributed and play a major role in transcellular and transepithelial water movement. Moreover, recent evidence indicates that AQPs may be involved in cell migration, angiogenesis, and tumor growth. This review article summarizes literature data concerning the involvement of AQP-1 and -4 in human brain tumor growth and edema formation and suggests a potential therapeutic approach by antagonizing their biological activity.