Injury of mitochondria and the expressions of fas and bax mRNA in the hippocampus of epileptic rats of different latency

IN T R O D U C T IO N M itochondria provide cells energy through oxidative phosphorylation by m eans of ATP. Biochem icalevidence indicates that m ost ATP consum ptions in brain are used forthe electric activity ofneurons, so the sufficientenergy supply f…     

Changes in the Expression of Genes of the Glutamate Transporter and Subunits of the NMDA and AMPA Receptors in the Rat Amygdala in the Lithium–Pilocarpine Model of Epilepsy

The molecular changes in the glutamatergic system of the rat amygdala were studied during the latent phase of the lithium–pilocarpine model of temporal lobe epilepsy in order to identify the potential involvement of these changes in epileptogenesis. The real-time PCR method was used to evaluate the mRNA expression of the NMDA and AMPA receptor subunits, as well as the excitatory amino acid transporter-2 (EAAT2) in the basolateral nucleus of the amygdala 7 days after the seizures caused by administration of pilocarpine. The results of the experiments were as follows: (1) an increase in the expression ratio of the GluN2a/GluN2b NMDA receptor subunits with an unchanged expression level of the GluN1 subunit; (2) increased expression of the GluA2 subunit of AMPA receptors with the invariance of GluA1, and (3) enhanced expression of the EAAT2. According to literature data, the expression of the same genes decreased in the hippocampus in the same model of epilepsy. Neurodegeneration was reported in both brain regions. The opposite changes in the expression of the glutamatergic system genes in the hippocampus and amygdala during the latent period of the lithium–pilocarpine model suggest the occurrence of factors that can both contribute to and hinder epileptogenesis.     

Validity of auditory perceptual assessment of velopharyngeal function and dysfunction – the VPC-Sum and the VPC-Rate

ABSTRACT

Overall weighted or composite variables for perceptual auditory estimation of velopharyngeal closure or competence have been used in several studies for evaluation of velopharyngeal function during speech. The aim of the present study was to investigate the validity of a composite score (VPC-Sum) and of auditory perceptual ratings of velopharyngeal competence (VPC-Rate). Available VPC-Sum scores and judgments of associated variables (hypernasality, audible nasal air leakage, weak pressure consonants, and non-oral articulation) from 391 5-year olds with repaired cleft palate (the Scandcleft project) were used to investigate content validity, and 339 of these were compared with an overall judgment of velopharyngeal competence (VPC-Rate) on the same patients by the same listeners. Significant positive correlations were found between the VPC-Sum and each of the associated variables (Cronbachs alpha 0.55–0.87, P < 0.001), and a moderately significant positive correlation between VPC-Sum and VPC-Rate (Rho 0.698, P < 0.01). The latter classified cases well when VPC-Sum was dichotomized with 67% predicted velopharyngeal competence and 90% velopharyngeal incompetence. The validity of the VPC-Sum was good and the VPC-Rate a good predictor, suggesting possible use of both measures depending on the objective.     

Comparison of the behavioural and histological characteristics of the 6-OHDA and α-synuclein rat models of Parkinson's disease

Development of relevant models of Parkinson's disease (PD) is essential for a better understanding of the pathological processes underlying the human disease and for the evaluation of promising targets for therapeutic intervention. To date, most pre-clinical studies have been performed in the well-established rodent and non-human primate models using injection of 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). Overexpression of the disease-causing protein α-synuclein (α-syn), using adeno-associated viral (AAV) vectors, has provided a novel model that recapitulates many features of the human disease. In the present study we compared the AAV-α-syn rat model with models where the nigro-striatal pathway is lesioned by injection of 6-OHDA in the striatum (partial lesion) or the medial forebrain bundle (full lesion). Examination of the behavioural changes over time revealed a different progression and magnitude of the motor impairment. Interestingly, dopamine (DA) neuron loss is prominent in both the toxin and the AAV-α-syn models. However, α-syn overexpressing animals were seen to exhibit less cell and terminal loss for an equivalent level of motor abnormalities. Prominent and persistent axonal pathology is only observed in the α-syn rat model. We suggest that, while neuronal and terminal loss mainly accounts for the behavioural impairment in the toxin-based model, similar motor deficits result from the combination of cell death and dysfunction of the remaining nigro-striatal neurons in the AAV-α-syn model. While the two models have been developed to mimic DA neuron deficiency, they differ in their temporal and neuropathological characteristics, and replicate different aspects of the pathophysiology of the human disease. This study suggests that the AAV-α-syn model replicates the human pathology more closely than either of the other two 6-OHDA lesion models.     

Modeling the Protonation States of the Catalytic Aspartates in β-Secretase and the Process of the Enzymatic Hydrolysis

背景：阿尔茨海默病(AD）主要表现为脑内β-淀粉样蛋白（Aβ）沉积，Aβ由β-淀粉酶（β- Secretase，BACE）催化水解淀粉样前体蛋白（amyloid precursor protein, APP）产生，但是BACE的催化机制至今仍不清楚。 目的：确定质子在BACE催化性氨基酸(Asp 32 和 Asp 228)中的精确定位，同时在计算机上模拟BACE催化底物APP蛋白的全部过程，揭示BACE催化水解底物的机制。 设计，时间和 SETTING: 全部的量子化学计算在中山大学中山医学院人体解剖教研室进行，2008年8月至2009年3月。 材料: 一台linux计算机工作站，商业性的大型药物设计软件包Schrodinger, 针对学术机构免费的量子化学软件 MOPAC 2007。 方法: 在计算机上构建了一个BACE催化模型，应用量子化学/分子力学(QM/MM)相结合的方法在密度泛函理论水平的基础上计算质子在BACE催化性氨基酸(Asp 32 和 Asp 228)中的精确定位； 在量子化学的半经验理论水平基础上模拟BACE催化水解底物肽EVNL/AAEF的全部过程。 主要结果指标: 计算BACE和底物在不同的单质子化状态下两个催化性氨基酸中的4个羧基氧原子的共面性；在模拟催化水解底物过程中检测BACE催化活性区域内空间和能量的变化。 结果： BACE的同分异构体228o,其4个催化氨基酸羧基氧原子形成的二面角为8.7°；而且利用这种同分异构体（228o）作为初始状态，催化水解底物的活化能最低（1.6959 kcal/mol），焓最高（-7.4055 kcal/mol）。 结论：在催化前，质子最有可能位于BACE的催化氨基酸Asp 228的外位羧基氧原子上,催化水解时，Asp 228作为催化酸，Asp 32 作为催化碱驱动催化水分子攻击底物，形成四面体中间物后，质子的换位到Asp 32的内位羧基氧原子上。     

Does age at the onset of narcolepsy influence the course and severity of the disease?

ObjectiveThe aim of the study is to compare the course and severity of narcolepsy in relation to different ages at the disease onset.MethodsClinical interviews with the completion of the Stanford questionnaire, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT) were evaluated in 105 patients (44 males, 61 females, mean age 45.4 ± 19.2, BMI 29.2 ± 5.8) suffering from narcolepsy.ResultsThe severity of the disease was judged by clinical complaints, ESS value and MSLT results. No relations with the age at onset and clinical tetrad were found, however, smoking may be associated with an increased risk of hypnagogic hallucinations. There was no correlation between the number of sleep and cataplectic attacks and the age at onset, nor did subjective ESS show any significant dependence. However, earlier onset of the disease correlated with shorter MSLT mean latency. A correlation was found between the BMI and narcolepsy sleepiness rating in the elderly and between degree of education attained and subjective complaints.ConclusionsThe clinical severity of narcolepsy does not depend on the age at onset.     

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a “limbic system,” a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain—that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.     

Effect of chronic administration of estradiol, progesterone, and tibolone on the expression and phosphorylation of glycogen synthase kinase-3β and the microtubule-associated protein tau in the hippocampus and cerebellum of female rat

Gonadal hormones regulate expression and activation of protein tau. Tibolone is a drug used as first- choice comprehensive treatment for the relief of menopausal symptoms, because it and its various metabolites have estrogenic properties and progestogenic/androgenic effects; however, the effect on the activation of tau protein and its signaling cascade in the brain is unknown. We studied the effect of chronic administration of estradiol (E2), progesterone (P4), and tibolone (TIB) on the expression and phosphorylation of microtubule-associated protein tau and glycogen synthase kinase-3β (GSK3β) in the hippocampus and cerebellum of ovariectomized rats. Ovariectomized adult female rats were implanted with pellets of vehicle, E2, or P4 or were treated with TIB by oral administration for 60 days. The animals were sacrificed, and tissue proteins were analyzed by Western blot. We observed that, in the hippocampus, administration of E2, P4, or TIB significantly decreased the protein content of hyperphosphorylated tau and increased the tau dephosphorylated form, whereas only treatment with TIB increased the content of the phosphorylated form of GSK3β. In the cerebellum, E2 and TIB treatments resulted in a significant decrease in the expression of hyperphosphorylated tau, whereas E2 and TIB increased phosphorylated GSK3β; P4 had no effect. These results indicate that chronic administration of gonadal hormones and tibolone modulates tau and GSK3β phosphorylation in hippocampus and cerebellum of the rat and may exert a neuroprotective effect in these tissues.     

Whose evidence? Lessons from the philosophy of science and the epistemology of medicine

OBJECTIVE: To demonstrate the inadequacies of empiricism as a scientific foundation for evidence-based approaches to psychiatry. METHOD: The principles of empiricism are reviewed in the light of developments in the philosophy of science and phenomenology. Case studies are selected from the history of physical sciences, biological science and clinical sciences (pathology, neuroscience, psychosocial science and psychopathology), paying particular attention to the role of observation in theory construction. RESULTS: The principles of empiricism, particularly its view of the nature of observation as the basis of evidence do not reflect the historical reality of scientific theorizing and practice. Science has constructed alternative models of its own activity that do justice to the complexities of its subject matter, including the world of human experience and mental illness. CONCLUSIONS: A failure to recognize both the limitations of empiricism in science and the conceptual richness of alternative formulations that accord more closely with the complexity of psychiatry's domain will result in a na?ve model of science and inadequate understanding of the limitations of 'evidence' that guide the training, clinical practice and research in our profession. The consequences will be the intellectual, clinical and ethical impoverishment of psychiatry.     

Glymphatic imaging and modulation of the optic nerve

Optic nerve health is essential for proper function of the visual system.However,the pathophysiology of certain neurodegenerative disease processes affecting the optic nerve,such as glaucoma,is not fully understood.Recently,it was hypothesized that a lack of proper clearance of neurotoxins contributes to neurodegenerative diseases.The ability to clear metabolic waste is essential for tissue homeostasis in mammals,including humans.While the brain lacks the traditional lymphatic drainage system identified in other anatomical regions,there is growing evidence of a glymphatic system in the central nervous system,which structurally includes the optic nerve.Named to acknowledge the supportive role of astroglial cells,this perivascular fluid drainage system is essential to remove toxic metabolites from the central nervous system.Herein,we review existing literature describing the physiology and dysfunction of the glymphatic system specifically as it relates to the optic nerve.We summarize key imaging studies demonstrating the existence of a glymphatic system in the optic nerves of wild-type rodents,aquaporin 4-null rodents,and humans;glymphatic imaging studies in diseases where the optic nerve is impaired;and current evidence regarding pharmacological and lifestyle interventions that may help promote glymphatic function to improve optic nerve health.We conclude by highlighting future research directions that could be applied to improve imaging detection and guide therapeutic interventions for diseases affecting the optic nerve.     

Emotion and Theory of Mind in Schizophrenia—Investigating the Role of the Cerebellum

Social cognitive dysfunction, including deficits in facial emotion recognition and theory of mind, is a core feature of schizophrenia and more strongly predicts functional outcome than neurocognition alone. Although traditionally considered to play an important role in motor coordination, the cerebellum has been suggested to play a role in emotion processing and theory of mind, and also shows structural and functional abnormalities in schizophrenia. The aim of this systematic review was to investigate the specific role of the cerebellum in emotion and theory of mind deficits in schizophrenia using previously published functional neuroimaging studies. PubMed and PsycINFO were used to search for all functional neuroimaging studies reporting altered cerebellum activity in schizophrenia patients during emotion processing or theory of mind tasks, published until December 2014. Overall, 14 functional neuroimaging studies were retrieved. Most emotion studies reported lower cerebellum activity in schizophrenia patients relative to healthy controls. In contrast, the theory of mind studies reported mixed findings. Altered activity was observed across several posterior cerebellar regions involved in emotion and cognition. Weaker cerebellum activity in schizophrenia patients relative to healthy controls during emotion processing may contribute to blunted affect and reduced ability to recognise emotion in others. This research could be expanded by examining the relationship between cerebellum function, symptomatology and behaviour, and examining cerebellum functional connectivity in patients during emotion and theory of mind tasks.     

Perception of patients’ unpredictability and beliefs on the causes and consequences of schizophrenia

Abstract.Background: The belief that mental disorders involve a high risk of unpredictable behaviours is a factor which influences negatively the social acceptance of the mentally ill. In this paper, we compare the beliefs about the causes and psychosocial consequences of schizophrenia expressed by 536 respondents who had the firm conviction that patients with schizophrenia are unpredictable and by 457 respondents who firmly believed that they are not.Methods: The survey was conducted in 30 Italian geographic areas, randomly selected taking into account their location and population density. The data were collected by the Questionnaire about Opinions on Mental Illness (QO).Results: Respondents who believed that patients with schizophrenia are unpredictable reported more frequently factors such as use of alcohol and drugs and frequenting bad company as being involved in the development of the disorder. In addition, this group showed more restrictive opinions about patients civil and affective rights. Low education was found to be significantly associated with perception of unpredictability in schizophrenia.Conclusions: These results suggest the need to: a) inform the general public on the main clinical characteristics of schizophrenia and on the risk of unpredictable behaviours in the acute phases of this mental disorder; b) carry out sensitisation campaigns against discrimination toward people with schizophrenia emphasising successful experiences of social integration.     

Psychodynamics and managed care: the art of the impossible?

Many mental health providers believe that psychodynamic psychotherapy under managed care is virtually impossible. Notwithstanding the many adversities posed by managed care, there are ways to productively apply psychodynamic principles within this health care financing system. This paper critically discusses the possibilities and costs of conducting psychodynamic psychotherapy under managed care using theory, practice applications, and a case vignette. Central to the discussion is elaboration of five central differences between traditional psychodynamic treatment versus that conducted under managed care.     

CPD — Education and self-assessment The epidemiology of epilepsy: the size of the problem

The prevalence of epilepsy is generally taken as between 5 and 10 cases per 1000 persons, and the overall incidence as about 50 cases per 100 000 persons. The rates are dependent on case ascertainment and on definitions used. The prognosis depends on many factors, including the number of seizures at presentation, the seizure type and the use of anti-epileptic drugs. Epilepsy carries an excess mortality; the cause of death can be unrelated to epilepsy, related to the underlying disease causing epilepsy, or related to epilepsy itself.     

Does the method of treatment of acutely ruptured intracranial aneurysms influence the incidence and duration of cerebral vasospasm and clinical outcome?

OBJECTIVES: Cerebral vasospasm remains the leading cause of death and permanent disability after subarachnoid haemorrhage. This study determined whether the method of aneurysm treatment plays an important role in determining the incidence of cerebral vasospasm and its clinical consequences. METHODS: Admission data, cranial computed tomography (CT), treatment details, transcranial Doppler (TCD) results, and clinical outcomes of patients who had surgical or endovascular management of their ruptured aneurysm were recorded and subject to multivariate analysis. RESULTS: Between January 1995 and December 1999, 292 eligible patients (206 female, 86 male) had definitive aneurysm treatment at our unit. 212 patients were clipped, 80 coiled. There was no significant difference in patient age, pre-treatment neurological grade, Fisher grade, or timing of treatment in the two groups. 48.3% patients developed TCD detected cerebral vasospasm and 16.1% patients developed permanent ischaemic neurological deficit. At clinical follow up, 84.2% of patients were well (mGOS 1 and 2) with a cumulative death rate of 6.5% from all causes. The only significant predictor of TCD-detected cerebral vasospasm was patient age (inversely, p = 0.004). Increased patient age, vasospasm, poor pre-treatment WFNS, and higher CT Fisher grades correlated with a poor discharge GOS. However, only poor pre-treatment WFNS grade and patient age correlated with poor GOS at follow up (p<0.001). CONCLUSION: The treatment method had no influence on the incidence or duration of TCD detected vasospasm and there was no significant difference in outcome at discharge or follow up between those patients who had surgery or endovascular management of their aneurysms.     

Changes in the Permeability and Expression of Markers of the Structural and Functional Integrity of the Blood–Brain Barrier under Early Postnatal Hypoxia in vivo

Pathologies associated with perinatal exposure of the CNS to damaging factors, including hypoxia, are a serious problem. However, the mechanisms by which they influence the development of brain damage have been insufficiently studied. The purpose of this study is to analyze the BBB permeability and expression of markers of its structural and functional integrity in animals with hypoxia (rats subjected to hypoxia at the age of P7) at the early (1 hour after the hypoxia) and delayed (P28) periods of their development. In sections of the rat brains, we immunohistochemically evaluated the expression of HIF-1 and Rac1; the Evans blue dye content was measured by the photometric method in the brain homogenates. In animals subjected to hypoxia, BBB permeability increased, CD31 expression was reduced, RAC1 expression increased, HIF-1-positive cells were retained in the hippocampus mainly at the early stage of development; CD31 and RAC1 expression was suppressed during the delayed period of development. The most-pronounced brain damage at the age of P7 corresponds to changes in the structural and functional integrity and permeability of the BBB; the recovery of a neurological deficit and the permeability of the BBB (at the age of P28) under damage to the brain corresponds to the period of reparative angiogenesis, as well as manifestations of HIF-1 effects in endothelial cells and astrocytes in the cortex and limbic system.