Mechanisms of damage to myelin and oligodendrocytes and their relevance to disease

Oligodendrocytes synthesize and maintain myelin in the central nervous system (CNS). Damage may occur to these cells in a number of conditions, including infections, exposure to toxins, injury, degeneration, or autoimmune disease, arising both in the course of human disease and in experimental animal models of demyelination and dysmyelination; multiple sclerosis is the commonest human demyelinating disorder. Conventional classical accounts of the pathology of this and other myelin diseases have given great insights into their core features, but there remain considerable uncertainties concerning the timing, means and cause(s) of oligodendrocyte and myelin damage. At present, therapeutic efforts largely concentrate on immune manipulation and damage limitation, an approach that has produced only modest effects in multiple sclerosis. One reason for this must be the limited understanding of the mechanisms underlying cell damage - clearly, successful therapeutic strategies for preserving the oligodendrocyte-myelin unit must depend on knowledge of how oligodendrocyte damage and death occurs. In this review, mechanisms of oligodendrocyte and myelin damage are considered, and attempts made to relate them to disease processes, clinical and experimental. The hallmarks of different cell death processes are described, and oligodendrocyte-myelin injury by cellular and soluble mediators is discussed, both in vitro and invivo. Recent developments concerning the pathological involvement of oligodendrocytes in neurodegenerative disease are summarized. Finally, these neuropathological and applied neurobiological observations are drawn together in the context of multiple sclerosis.     

Willingness and competence of depressed and schizophrenic inpatients to consent to research

In this study, the willingness of psychiatric inpatients to volunteer for research and their capacity to consent to and distinguish between protocols offering different levels of risk and benefit were assessed. Twenty-two inpatients with major depressive disorder, 21 inpatients with schizophrenia, and 21 community control subjects were asked to consider participation in a lower-risk study offering the potential for direct medical benefit and a higher-risk study offering no direct medical benefit. Consent-related capacities were assessed with the MacArthur Competence Assessment Tool-Clinical Research. Depressed inpatients, while having a greater degree of impairment than control subjects, still demonstrated relatively high decision-making capacity and were able to distinguish levels of risk between studies. Their pattern of preferences did not differ from control subjects. However, they were more likely to decline to participate in the research, being six times more likely to decline the lower-risk study and 1.4 times more likely to decline the higher-risk study. Schizophrenic subjects demonstrated greater impairments in decision-making capacity and were even more likely than depressed subjects to decline to participate.     

Susceptibility of brainstem to kindling and transfer to the forebrain

Purpose: The kindling of seizures with stimulation of brainstem sites has been reported inconsistently in the literature. The characteristics of the kindling observed, involving high intensities of stimulation and immediate onset of generalized tonic–clonic convulsions, raise questions regarding the nature of kindling from these sites. Methods: We implanted chronic electrodes in either the nucleus reticularis pontis oralis (RPO), mesencephalic reticular formation (MRF), dorsal periaqueductal gray (dPAG), or ventrolateral periaqueductal gray (vlPAG) in male Long‐Evans rats, with a recording electrode in the amygdala. Rats received conventional high‐frequency kindling stimulation once daily for 30 days. To test for transfer, we kindled the amygdala beginning 7 weeks after the last brainstem kindling trial. Results: Tonic–clonic seizures were evoked by stimulation from all brainstem sites. Seizures were brief and were associated with characteristic low‐amplitude high‐frequency afterdischarge (AD). Kindling of the dPAG resulted in the development of classic AD and increased AD duration. Prior kindling of the dPAG facilitated subsequent kindling of the amygdala; however, no transfer was observed with prekindling of other brainstem sites. Discussion: The variability in the response to kindling stimulation suggests that certain brainstem sites are resistant to kindling, whereas other sites are more susceptible to kindling but are still relatively resistant in comparison to sites in the forebrain. The development of classic AD in later trials of dPAG stimulation suggests that epileptogenesis can occur even in the initial absence of classic AD when low‐amplitude high‐frequency AD is present.     

如何评估和管理脑卒中的危险

1脑卒中的危险因素流行病学研究已经明确了许多脑卒中的危险因素,其中一些可以通过药物或非药物进行干预,因此,正确识别卒中危险因素对卒中的一级和二级预防至关重要。已经证实的可改变的卒中危险因素包括:高血压、某些心脏疾病(特别是心房纤颤)、糖尿     

Sensitization to caffeine and cross-sensitization to amphetamine: influence of individual response to caffeine

The present study evaluated the ability of a subchronic intermittent administration of caffeine to induce a sensitized motor response and correlated the individual susceptibility of rats to acute caffeine to the development of sensitization. Moreover, individual susceptibility to caffeine and development of motor behaviour sensitization were correlated to the behavioural response obtained after a challenge with amphetamine. To this end, rats were subdivided in "low" and "high" responders according to their individual susceptibility to acute caffeine established on the basis of the motor activity observed after the first caffeine administration. "Low" and "high" responder rats were then repeatedly and intermittently treated with caffeine (15 mg/kg, i.p.), or vehicle, every other day for fourteen days. Three days after treatment discontinuation, behavioural activation induced by acute amphetamine (0.5 mg/kg, s.c.) was measured in vehicle- and caffeine-pretreated rats. Subchronic caffeine resulted in motor sensitization of a variable degree among rats and no difference were observed between "low" and "high" responders. Moreover, caffeine pretreatment potentiated the behavioural effects of amphetamine according to the degree of caffeine sensitization but not to individual susceptibility to acute caffeine. These results demonstrate that individual susceptibility to acute caffeine does not influence the modifications in caffeine motor effects produced by its subchronic administration and does not affect the enhancement of acute behavioural effects of amphetamine in caffeine-pretreated rats, rather sensitization to subchronic caffeine administration critically influences the behavioural effects of amphetamine.     

How to measure and to manage the risk of stroke

Neurological Sciences - Several risk factors for stroke have been identified. Some of them can be modified through pharmacological or non-pharmacological interventions. The presence of multiple...     

The effect of corticosterone in rats submitted to the elevated plus-maze and to to pentylenetetrazol-induced convulsions

1. 1. In order to examine the effects of corticosterone in the anxiety response, the effect of acute, subchronic and chronic corticosterone (CORT) administration were studied using two animal models to study anxiolytic effects of drugs: the elevated plus-maze and the blockade of pentylenetetrazol (PTZ)-induced clonic convulsion.

2. 2. The results obtained with the plus-maze showed an increase in the percentage of open arm entries and time spent in the open arms after acute treatment with the CORT. These results may be interpreted as an anxiolytic effect of corticosterone. Three days of vehicle treatment followed by an acute CORT administration, produced results that should also indicate anxiolytic effect of the corticosteroid. No effect was seen after 14 days of vehicle treatment followed by an acute CORT injection. Subchronic or chronic CORT treatment did not produce results different from controls. CORT treatment did not affect the PTZ-induced clonic convulsion.

3. 3. In conclusion these results suggest that the acute anxiolytic effect observed in the elevated plus-maze did not occur after repeated CORT administration or mild Stressors. Moreover they also suggest that the anxiolytic effect did not involve GABA mechanisms.

Response of nonhuman animals to speech and to species-specific sounds.

Three questions relate to how nonhuman species respond to speech and species-specific sounds: (1) Do nonhuman species perceive human speech in a human-like fashion? (2) How do nonhuman species perceive their own vocalizatios? and (3) How does human perception of animal sounds differ from the animals' perception of those sounds? Four methodologies are available for studying an animal's perception of sounds: (1) discriminative conditioning; (2) habituation-dishabituation; (3) playbacks in captivity; and (4) playbacks in situ. Each of these techniques has a different degree of ecological validity and has different intrinsic biases toward the conclusions one might draw. Experiments using these methodologies for each of the three questions are reviewed and the methodological problems of each are discussed. A two-stage model of perceiving species-specific sounds is presented which accounts for both categorical perception of sounds and within category discrimination of sounds.     

A comparison of cognitive impairment due to benzodiazepines and to narcotics

In an attempt to determine the source of cognitive impairment in 106 consecutively admitted patients at the Johns Hopkins Chronic Pain Treatment Center, EEG, the Wechsler Adult Intelligence Scale, Memory Quotient, and Bender Gestalt tests were administered. Patients receiving benzodiazepines alone demonstrated alterations in cognitive functioning and EEG evidence of a sedative effect. Patients receiving narcotics alone and a group of patients not receiving medication did not show signs of cognitive impairment. The effects of benzodiazepines on sleep and perception of chronic pain, in combination with the cortical changes that they produce, imply that these drugs should not be used in most patients with chronic pain.     

Duty to Avoid Injury to Oneself and Thereby Psychiatric Injury to Others

Tortious liability for causing foreseeable mental harm to others is a complex category of tort law. It continues to evolve as plaintiffs devise novel arguments to test the parameters of what used to be known as pure psychiatric injury law. In Homsi v Homsi [2016] VSC 354, J Forrest J was called upon to rule on whether a mother could sue her deceased son for driving negligently and causing his own death and thereby causing her mental harm. Forrest J declined to permit recovery but in the course of his judgement helpfully analysed the current state of mental harm law in Australia, reviewed the circumstances in which relatives are able to sue one another for mental harm caused by self-injury, and articulated a range of policy considerations in relation to indeterminate liability for defendants. His judgement provides an important opportunity to reflect on the directions in which mental harm law should evolve to arrive at a rapprochement between plaintiffs’ reasonable aspirations for recovery and ensuring that the liability of defendants is not unreasonably wide.     

Differential Response of Growth Hormone, Cortisol, and Prolactin to Seizures and to Stress

Plasma concentrations of growth hormone (GH), cortisol, and prolactin (PRL), following a spontaneous generalized seizure in epileptic men were compared with similar measurements made in nonepileptic, stressed men to determine the role of stress in the hormonal response to seizures. Nonepileptic, nonstressed men served as control subjects. GH concentrations increased significantly within 60 min postictally, and as expected, so did cortisol and PRL. A subgroup of alcoholic patients exhibited a smaller GH response to seizures. Stressed patients had significantly less elevated cortisol and PRL plasma values, but no rise of GH. The data suggest that neurogenic stimuli responsible for the postictal release of GH, cortisol, and PRL are, at least in part, independent of stress mechanisms and that GH response is blunted in alcoholic patients.     

Preferential adhesion of brain astrocytes to laminin and central neurites to astrocytes

Astrocytes from either fetal or newborn rat brain adhered preferentially to surfaces coated with active laminin. Neurites from septal neurons did not show a preference for active over inactive laminin. However, when given a choice between laminin and an astrocytic surface, septal cells preferred to extend neurities over astroglial processes. Hence, laminin paths can guide astrocyte migration, which, in turn, can guide neurite elongation.     

Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics

Individualized medicine through molecular pharmacogenetics is one of the major future goals in clinical medicine. In psychopharmacology, pharmacogenetics became an expanding research component. Major research results were already attained: first, it is now feasible to predict a major proportion of the interindividual variation of plasma levels of most antidepressants and antipsychotics by using the DNA-sequence variation in genes for crucial CYP P450-enzymes as CYP2D6. Second, it is now possible to relate serious side effects (tardive dyskinesia, weight gain) of antipsychotics to specific genetic variants of genes for target proteins. Third, a long list of mainly functional variants in target protein genes was explored for their predictive power for the beneficial and adverse treatment outcome. Although specific results transferable into clinical practice were not yet obtained in this respect, the proof of principle could be demonstrated.     

Contribution of allelic variations to the phenotype of response to antidepressants and antipsychotics

Individualized medicine through molecular pharmacogenetics is one of the major future goals in clinical medicine. In psychopharmacology, pharmacogenetics became an expanding research component. Major research results were already attained: first, it is now feasible to predict a major proportion of the interindividual variation of plasma levels of most antidepressants and antipsychotics by using the DNA-sequence variation in genes for crucial CYP P450-enzymes as CYP2D6. Second, it is now possible to relate serious side effects (tardive dyskinesia, weight gain) of antipsychotics to specific genetic variants of genes for target proteins. Third, a long list of mainly functional variants in target protein genes was explored for their predictive power for the beneficial and adverse treatment outcome. Although specific results transferable into clinical practice were not yet obtained in this respect, the proof of principle could be demonstrated.

     

Semiology: witness to a seizure--what to note and how to report

This article reviews the Cleveland Epilepsy Classification (CEC) of seizure semiology. It defines the concept of semiology, and reviews its importance in epilepsy in defining the Symptomatogenic Zone, one of the five zones that make up the Epileptogenic Zone. It details the four broader spheres that contain all of the possible patient signs and symptoms (cognitive, autonomic, consciousness, and motor spheres), and reviews the specific seizure types that are classified within those spheres. Evidence-based information on usefulness of semiology for localization and lateralization is reviewed. A "user-friendly" reference table is provided.