Structural abnormalities in neurons are sufficient to explain the clinical disease and fatal outcome of experimental rabies in yellow fluorescent protein-expressing transgenic mice

Under natural conditions and in some experimental models, rabies virus infection of the central nervous system causes relatively mild histopathological changes, without prominent evidence of neuronal death despite its lethality. In this study, the effects of rabies virus infection on the structure of neurons were investigated with experimentally infected transgenic mice expressing yellow fluorescent protein (YFP) in neuronal subpopulations. Six-week-old mice were inoculated in the hind-limb footpad with the CVS strain of fixed virus or were mock infected with vehicle (phosphate-buffered saline). Brain regions were subsequently examined by light, epifluorescent, and electron microscopy. In moribund CVS-infected mice, histopathological changes were minimal in paraffin-embedded tissue sections, although mild inflammatory changes were present. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and caspase-3 immunostaining showed only a few apoptotic cells in the cerebral cortex and hippocampus. Silver staining demonstrated the preservation of cytoskeletal integrity in the cerebral cortex. However, fluorescence microscopy revealed marked beading and fragmentation of the dendrites and axons of layer V pyramidal neurons in the cerebral cortex, cerebellar mossy fibers, and axons in brainstem tracts. At an earlier time point, when mice displayed hind-limb paralysis, beading was observed in a few axons in the cerebellar commissure. Toluidine blue-stained resin-embedded sections from moribund YFP-expressing animals revealed vacuoles within the perikarya and proximal dendrites of pyramidal neurons in the cerebral cortex and hippocampus. These vacuoles corresponded with swollen mitochondria under electron microscopy. Vacuolation was also observed ultrastructurally in axons and in presynaptic nerve endings. We conclude that the observed structural changes are sufficient to explain the severe clinical disease with a fatal outcome in this experimental model of rabies.     

APUD- and RAA- regulatory systems in acute radiation injury

An experimental morpho-functional assessment of rat APUD and RAA systems status in acute radiation injury (cerebral form) was performed. The named regulatory systems were found to display an actual momentary post-exposure reaction, followed by subsequent functional changes of a distinct phase character. The latter were shown to determine in many respects the clinical picture and in some cases the outcome of the disease.     

Cerebral Response to Peripheral Challenge with a Viral Mimetic

It has been well established that peripheral inflammation resulting from microbial infections profoundly alters brain function. This review focuses on experimental systems that model cerebral effects of peripheral viral challenge. The most common models employ the induction of the acute phase response via intraperitoneal injection of a viral mimetic, polyinosinic-polycytidylic acid (PIC). The ensuing transient surge of blood-borne inflammatory mediators induces a “mirror” inflammatory response in the brain characterized by the upregulated expression of a plethora of genes encoding cytokines, chemokines and other inflammatory/stress proteins. These inflammatory mediators modify the activity of neuronal networks leading to a constellation of behavioral traits collectively categorized as the sickness behavior. Sickness behavior is an important protective response of the host that has evolved to enhance survival and limit the spread of infections within a population. However, a growing body of clinical data indicates that the activation of inflammatory pathways in the brain may constitute a serious comorbidity factor for neuropathological conditions. Such comorbidity has been demonstrated using the PIC paradigm in experimental models of Alzheimer’s disease, prion disease and seizures. Also, prenatal or perinatal PIC challenge has been shown to disrupt normal cerebral development of the offspring resulting in phenotypes consistent with neuropsychiatric disorders, such as schizophrenia and autism. Remarkably, recent studies indicate that mild peripheral PIC challenge may be neuroprotective in stroke. Altogether, the PIC challenge paradigm represents a unique heuristic model to elucidate the immune-to-brain communication pathways and to explore preventive strategies for neuropathological disorders.     

亚低温抑制脑缺血再灌注大鼠细胞凋亡机制的研究进展

脑缺血再灌注损伤的主要机制是多种因素诱导的神经元凋亡。而神经元凋亡在一定程度上是可以调控和逆转的。亚低温以其对条件的要求不高实施方便等特点,奠定了其可以大范围推广的基础。作为能够辅助治疗脑缺血再灌注损伤的措施之一,亚低温的作用已经越来越多的得到了大家的重视,其脑缺血保护机制的相关研究也逐年增加。现阶段研究者对亚低温脑保护作用的研究重点放在了抑制细胞凋亡的机制上,也证实了亚低温的脑保护作用的机制和其抑制细胞凋亡密不可分。本文针对这一点,对近几年有关亚低温抑制大鼠脑缺血再灌注诱导的细胞凋亡机制的研究进展作一综述,为亚低温治疗脑缺血性疾病的临床应用提供理论支持。     

Can Babesia infections be used as a model for cerebral malaria?

Infections with certain species of Plasmodium and Babesia induce, among other symptoms, cerebral pathology. The finding of heavily parasitized cerebral capillaries upon postmortem examination has led to the assumption that blockage of capillaries with infected red blood cells caused the cerebral symptoms and subsequent death. As this type of cerebrovascular pathology is found both in humans dying from malaria and in cattle dying from babesiosis, the latter could possibly be used as an animal model for the study of human cerebral malaria. However, before such a model system is adopted, the experimental data concerning cerebral pathology of babesiosis needs critical evaluation. Here, Theo Schetters and Wijnand Eling review the pathological mechanisms in cerebral babesiosis and relate these to cerebral malaria. Finally, they discuss the use of animal model systems for specific aspects of the pathological picture.     

1-H MRS changes in dorsolateral prefrontal cortex after donepezil treatment in patients with mild to moderate Alzheimer's disease

Magnetic resonance spectroscopy (MRS) noninvasively provides information on the concentration of some cerebral metabolites in vivo. Among those measurable by proton magnetic resonance spectroscopy (1H-MRS), N-acetyl-aspartate (NAA) is decreased, and myo-inositol (ml) and choline (Cho) levels are increased in patients with Alzheimer's disease (AD). Donepezil, an acetylcholinesteraze inhibitor, has proven effect on cognitive symptoms in patients with AD. In previous studies, treatment response was associated with an increase of NAA and NAA/Cr in the parietal lobe and hippocampi. Correlation of longitudinal changes of 1H-MRS detectable metabolites in dorsolateral prefrontal cortex (DLPFC) with clinically observable changes is a poorly researched topic. The objective of this non-interventional study is to assess whether changes in 1H-MRS measurable metabolites correlate with clinical outcome after donepezil treatment. Twelve patients with mild to moderate AD were evaluated during 26 weeks of donepezil treatment. 1H-MRS parameters in DLPFC were assessed before and after 26 weeks of donepezil treatment. Cognition was assessed with Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-Cog). A significant increase in NAA/Cr ratio and significantly lower decrease in mI/Cr ratio were found in AD patients with positive treatment response. The results of this study indicate possible modest donepezil effect on prevention of neuronal functional deterioration in DLPFC which correlates with clinical outcome and point the use of 1HMRS as technique of help in assessment of drug effect.     

A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.     

Deciphering the modifiers for phenotypic variability of X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (X-ALD), an inborn error of peroxisomal β-oxidation, is caused by defects in the ATP Binding Cassette Subfamily D Member 1 (ABCD1) gene. X-ALD patients may be asymptomatic or present with several clinical phenotypes varying from severe to mild, severe cerebral adrenoleuko-dystrophy to mild adrenomyeloneuropathy (AMN). Although most female heterozygotes present with AMN-like symptoms after 60 years of age, occasional cases of females with the cerebral form have been reported. Phenotypic variability has been described within the same kindreds and even among monozygotic twins. There is no association between the nature of ABCD1 mutation and the clinical phenotypes, and the molecular basis of phenotypic variability in X-ALD is yet to be resolved. Various genetic, epigenetic, and environmental influences are speculated to modify the disease onset and severity. In this review, we summarize the observations made in various studies investigating the potential modifying factors regulating the clinical manifestation of X-ALD, which could help understand the pathogenesis of the disease and develop suitable therapeutic strategies.     

Erythropoietin for the Treatment of Subarachnoid Hemorrhage: A Feasible Ingredient for a Successful Medical Recipe

Subarachnoid hemorrhage (SAH) following aneurysm bleeding accounts for 6% to 8% of all cerebrovascular accidents. Although an aneurysm can be effectively managed by surgery or endovascular therapy, delayed cerebral ischemia is diagnosed in a high percentage of patients resulting in significant morbidity and mortality. Cerebral vasospasm occurs in more than half of all patients after aneurysm rupture and is recognized as the leading cause of delayed cerebral ischemia after SAH. Hemodynamic strategies and endovascular procedures may be considered for the treatment of cerebral vasospasm. In recent years, the mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia following SAH, have been investigated intensively. A number of pathological processes have been identified in the pathogenesis of vasospasm, including endothelial injury, smooth muscle cell contraction from spasmogenic substances produced by the subarachnoid blood clots, changes in vascular responsiveness and inflammatory response of the vascular endothelium. To date, the current therapeutic interventions remain ineffective as they are limited to the manipulation of systemic blood pressure, variation of blood volume and viscosity and control of arterial carbon dioxide tension. In this scenario, the hormone erythropoietin (EPO) has been found to exert neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is administered systemically. However, recent translation of experimental data into clinical trials has suggested an unclear role of recombinant human EPO in the setting of SAH. In this context, the aim of the current review is to present current evidence on the potential role of EPO in cerebrovascular dysfunction following aneurysmal subarachnoid hemorrhage.     

Therapeutic hypothermia in the management of acute liver failure

A large body of experimental data and preliminary clinical studies point to the induction of mild hypothermia (32-35 °C) as a valuable approach to control the development of brain edema and intracranial hypertension in acute liver failure (ALF). The ability of hypothermia to affect multiple processes probably explains its efficacy to prevent these cerebral complications. Remarkably, mild hypothermia has been shown to prevent or attenuate most of the major alterations involved in the pathogenesis of the cerebral complications of ALF, including the accumulation of ammonia in the brain and the circulation, the alterations of brain glucose metabolism, the brain osmotic disturbances, the accumulation of glutamate and lactate in brain extracellular space, the development of inflammation and oxidative/nitrosative stress, and others. Limited information suggests that the systemic effects of hypothermia may also be beneficial for some peripheral complications of ALF. Translation of the beneficial effects of therapeutic hypothermia into standard clinical practice, however, needs to be confirmed in adequately designed clinical trials. Such trials will be important to determine the safety of therapeutic hypothermia, to identify which patients might benefit from it, and to provide the optimal guidelines for its use in patients with ALF.     

Modeling Brain Energy Metabolism and Function: A Multiparametric Monitoring Approach

Mathematical modeling of brain function is an important tool needed for a better understanding of experimental results and clinical situations. In the present study, we are constructing and testing a mathematical model capable of simulating changes in brain energy metabolism that develop in real time under various pathophysiological conditions. The model incorporates the following parameters: cerebral blood flow, partial oxygen pressure, mitochondrial NADH redox state, and extracellular potassium. Accordingly, all the model variables are only time dependent (`point-model' approach). Numerical runs demonstrate the ability of the model to mimic pathological conditions, such as complete and partial ischemia, cortical spreading depression under normoxic and partial ischemic conditions. They also show that, when properly tuned, a model of this type permits the monitoring of only one or two crucial variables and the computation of the remaining variables in real time during clinical or experimental procedures.     

A computer model for learning processes and the role of the cerebral commissures

A computer model of the two brain hemispheres is constructed of discrete populations of neurons, and it is shown to exhibit the characteristics of the great cerebral commissures, as has been pointed out by Sperry and others. For the range of parameters used we find that such systems respond in a specific manner to specific stimuli, and furthermore, whatever memory is transferred to one simulated hemisphere is also transferred to the other. However, this behavior changes when the two hemispheres are separated. We find that memory is not transferred from one hemisphere to the other when the interconnecting commissures are severed. The above findings verify Sperry's experimental observation that the split brain behaves as if it were indeed two separate brains, each performing concurrently and simultaneously diametrically opposite tasks.     

Reaction of neurons of the cerebral cingular area in rats to damage of the central monoaminergic systems]

Intracisternal injection of specific neurotoxins 6-oxydopamine and 5,7-dioxytryptamine, producing certain disorders in catecholaminergic and serotoninergic systems respectively, is accompanied with some ultrastructural rearrangements in the proper neurons of the rat cerebral cingular cortex. In the experimental material an essential increase in the amount of intranuclear inclusions--vacuole- and myelin-like--of fibrillar origin is observed. More often than in the control connection of the endoplasmic reticulum with the nuclear membrane is noted. Hypertrophy of cisterns in the Golgi complex, abundance of coated vesicles in its region, dilatation of cisterns of the endoplasmic reticulum are observed. The character of the ultrastructural rearrangements demonstrates certain changes in activity of metabolic processes of these cells, the changes being more pronounced in the case, when the cerebral serotoninergic system is damaged. The reaction of the cerebral cingular zone to injection of neurotoxins is characterized with a selective manifestation and is restricted with certain nervous cells of the II-V layers. According to their ultrastructural organization, these neurons can be considered as stellate and pyramidal.     

Functional characteristics of hemodynamics in adolescents under the conditions of different motor activities

The formation of functional systems in correspondence with the conditions of natural activity is the most important issue of developmental physiology. In this study, data on the assessment of the state of central and cerebral hemodynamics, as well as indices of spectral analysis of the heart rate’s variability (HRV) in adolescents depending on the level of motor activity has been collected and systematized. The possibility of integration of methods of rheoencephallography and cardiorythmography for the assessment of the characteristics of the ontogenetic formation of the cardiovascular system has been studied. Analysis of the formation of indices of hemodynamics during an academic year and the training cycle in swimmers and healthy adolescents who do not enroll in sports classes has been made. Changes in, and correlations between, the parameters of central hemodynamics and cerebral circulation, as well as parameters of HRV, have been detected. Analysis of the changes in the statistical indices of the cardiac rhythm in adolescents during an academic year on the basis of the qualitative and quantitative characteristics of the state of regulatory systems, as well as the determination of the direction of the response to the combination of academic loads and the factor of physical training, permitted a detailed study of changes that take place in some hemodynamic parameters in athletes and students, which is of particular importance for the diagnosis of their functional state.     

The Utility of Cerebral Blood Flow as a Biomarker of Preclinical Alzheimer’s Disease

There is accumulating evidence suggesting that changes in brain perfusion are present long before the clinical symptoms of Alzheimer’s disease (AD), perhaps even before amyloid-β accumulation or brain atrophy. This evidence, consistent with the vascular hypothesis of AD, implicates cerebral blood flow (CBF) in the pathogenesis of AD and suggests its utility as a biomarker of preclinical AD. The extended preclinical phase of AD holds particular significance for disease modification, as treatment would likely be most effective in this early asymptomatic stage of disease. This highlights the importance of identifying reliable and accurate biomarkers of AD that can differentiate normal aging from preclinical AD prior to clinical symptom manifestation. Cerebral perfusion, as measured by arterial spin labeling magnetic resonance imaging (ASL-MRI), has been shown to distinguish between normal controls and adults with AD. In addition to demonstrating diagnostic utility, CBF has shown usefulness as a tool for identifying those who are at risk for AD and for predicting subtle cognitive decline and conversion to mild cognitive impairment and AD. Taken together, this evidence not only implicates CBF as a useful biomarker for tracking disease severity and progression, but also suggests that ASL-measured CBF may be useful for identifying candidates for future AD treatment trials, especially in the preclinical, asymptomatic phases of the disease.     

THE TREATMENT OF CRANIOCEREBRAL INJURIES AND PREVENTION OF ANOXIA

Even mild head injuries may cause cerebral swelling and vascular alterations, including vasoparalysis and increased vascular permeability. The severer the injury, the more pronounced these changes. They may cause death.Maintenance of adequate oxygen supply to the brain is the most effectual means of preventing or reducing the severity of this secondary effect of cerebral trauma, and the preservation of a good respiratory exchange is therefore essential in a patient who is comatose as a result of a head injury.The commonly employed measures such as an oral airway, suction and oxygen therapy may be tried first, but if the patient continues to have respiratory distress or cyanosis, an intratracheal tube should be employed for 24 hours; and then if there is no improvement, tracheotomy should be carried out. If the injury is severe, tracheotomy from the beginning may be a life-saving measure.     

Influence of Plasma and Cerebrospinal Fluid Levels of Endothelin-1 and No in Reducing Cerebral Vasospasm after Subarachnoid Hemorrhage During Treatment with Mild Hypothermia,in a Dog Model

Using vascular heat-exchange controller implemented mild hypothermia treatment, the authors established the cerebral vasospasm model in which blood was injected twice into dog’s foramen magnum; and it was discussed the influence of the concentration of endothelin-1 and NO in blood plasma and cerebrospinal fluid through continuing treatment of mild hypothermia at different times in secondary brain vasospasm model after subarachnoid hemorrhage. Thirty healthy mongrel dogs were randomly divided into five groups; artificial cerebrospinal fluid group (group A), normal temperature control group (group C), mild hypothermia 8 h group (group H1), mild hypothermia 16 h group (group H2), and mild hypothermia 32 h group (group H3). The authors injected the artificial CSF into dog’s foramen magnum in group A while the other four groups were injected with autologous arterial blood. The normal group’s temperature maintained 38.5°C. The authors set the temperature at 33.5°C in mild hypothermia groups and this was maintained for 8, 16, and 32 h, respectively. ET-1 and NO levels in the cerebrospinal fluid and plasma were assayed in each group on days 0, 7, 14, and 21. Then the changes of the diameter of blood vessels of cerebral basilar artery and overall performance categories score in each group through application of CT angiography were recorded. In the cerebral vasospasm model which was constructed by injecting the blood to dog twice, mild hypothermia treatment, through the application of vascular heat-exchange controller, could reduce cerebral vasospasm. It was observed that the duration of the mild hypothermia is directly proportional to the longer duration of the relieving of cerebral vasospasm. The reciprocal changes observed in the levels of ET-1 and NO in cerebrospinal fluid and plasma revealed that it might be possible to reduce the cerebral vasospasm by regulating the rising amplitude of ET-1 and the decrease in NO in CSF and plasma.