Stimulation by mitogens and neuronal membranes of lymphocytes from patients with motor neurone disease

Stimulation of lymphocytes from motor neurone disease patients by either concanavalin A or PHA was shown to be significantly depressed relative to that from normal controls, as assayed by incorporation of [3H]thymidine or [3H]leucine or by glucose uptake. Corresponding significant differences were not shown by assays based upon incorporation of [3H]uridine or of lactate release. Lymphocytes from 4 out of 14 motor neurone disease patients showed a blastogenic response to membranes from rat spinal cord cells, compared with those from 0 out of 9 normal controls. These results not only suggest the possibility of an impaired cellular immune control in MND patients but also indicate the presence of lymphocytes sensitised specifically to neuronal membrane components.     

Treatment developments and the unfolding of the quality of life discussion in childhood medulloblastoma: a review

Purpose

To describe how the quality of life (QOL) discussion in childhood medulloblastoma (MB) relates to treatment developments, survival and sequelae from 1920 to 2014.

Methods

Articles containing “childhood medulloblastoma” and “quality of life” were identified in PubMed. Those containing phrases pertaining to psychological, emotional, behavioral or social adjustment in the title, abstract or keywords were selected. Inclusion of relevant older publications was assured by cross-checking references.

Results

1920–1930s: suction, electro-surgery, kilovolt (KV) irradiation. Survival = months. Focus on operative mortality, symptoms and survival. 1940s: radiotherapy improved. 1950s: chemotherapy and intubation. Survival = years. Opinions oscillated between optimism/awareness of physical sequelae of radiotherapy. 1960s: magnified vision, ventriculo-peritoneal (VP) shunts, megavolt (MV) irradiation. Long-term survival shifted the attention towards neurological problems, disability and carcinogenesis of radiotherapy. 1970s: CT, microscope, bipolar coagulation, shunt filters, neuroanesthesia, chemotherapy trials and staging studies. Operative mortality decreased and many patients (re)entered school; emphasis on neuropsychological sequelae, IQ and academic performance. 1980s: magnetic resonance imaging (MRI), Cavitron ultrasonic aspiration (CUSA), laser surgery, hyper-fractionated radiotherapy (HFRT). Cerebellar mutism, psychological and social issues. 1990s: pediatric neurosurgery, proton beams, stem cell rescue. Reflections on QOL as such. 21st century: molecular genetics. Premature aging, patterns of decline, risk- and resilience factors.

Discussion

QOL is a critical outcome measure. Focus depends on survival and sequelae, determined after years of follow-up. Detailed measurements are limited by time, money and human resources, and self-reporting questionnaires represent a crude measure limited by subjectivity. Therapeutic improvements raise the question of QOL versus cure. QOL is a potential primary research endpoint; multicenter international studies are needed, as are web-based tools that work across cultures.     

Ethylmalonic Acid Induces Permeability Transition in Isolated Brain Mitochondria

Predominant accumulation of ethylmalonic acid (EMA) in tissues and biological fluids is a characteristic of patients affected by short chain acyl-CoA dehydrogenase deficiency and ethylmalonic encephalopathy. Neurological abnormalities are frequently found in these disorders, but the mechanisms underlying the brain injury are still obscure. Since hyperlacticacidemia is also found in many affected patients indicating a mitochondrial dysfunction; in the present work, we evaluated the in vitro and ex vivo effects of EMA plus Ca²⁺ on mitochondrial integrity and redox balance in succinate-supported brain organelles. We verified that the evaluated parameters were disturbed only when EMA was associated with exogenous micromolar Ca²⁺ concentrations. Thus, we found that this short chain organic acid plus Ca²⁺ dissipated the membrane potential and provoked mitochondrial swelling, as well as impaired the mitochondrial Ca²⁺ retention capacity, resulting in a rapid Ca²⁺ release and decreased NAD(P)H matrix content. In contrast, EMA was not able to stimulate mitochondrial hydrogen peroxide generation. We also observed that all these effects were prevented by the mitochondrial Ca²⁺ uptake inhibitor ruthenium red and the mitochondrial permeability transition (MPT) inhibitors cyclosporin A (CsA) and ADP. Furthermore, mitochondria isolated from rat brains after in vivo intrastriatal administration of EMA was more susceptible to Ca²⁺-induced swelling, which was fully prevented by CsA and ADP. Finally, EMA significantly decreased striatal slice viability, which was attenuated by CsA. The data strongly indicate that EMA reduced the mitochondrial threshold for Ca²⁺-induced MPT reinforcing the role of this cation in EMA-induced disruption of mitochondrial bioenergetics. It is, therefore, presumed that EMA acting synergistically with Ca²⁺ compromises mitochondrial energy homeostasis in the central nervous system that may explain at least in part the neurologic alterations presented by patients with abnormal levels of this organic acid.     

Neocortical pyramidal cells: a model with dendritic calcium conductance reproduces repetitive firing and epileptic behavior

A computer model of a neocortical pyramidal cell has been constructed using ideas similar to those used for hippocampal pyramidal cells. This model has been applied to the study of (a) repetitive firing, and (b) the paroxysmal depolarizing shift (PDS), an important intracellular event during seizures. Although calcium spikes have not been demonstrated directly in neocortical cells, we have postulated (by analogy with hippocampal pyramidal cells) a dendritic calcium conductance and a 'slow potassium' conductance modulated by intracellular calcium ion. With these dendritic ionic conductances, the model is able to reproduce the following experimental features of neocortical pyramidal cells: the afterdepolarization and succeeding afterhyperpolarization after an antidromic spike, and the f-I (firing rate-injected current) curve. Some of the differences between 'fast' and 'slow' pyramidal tract neurons (PTNs) -- narrower spikes and a steeper f-I curve in the fast PTNs -- may be explained by differences in Hodgkin-Huxley potassium kinetics between the two kinds of cell. The same model which faithfully reproduces repetitive firing behavior also reproduces (given appropriate synaptic inputs) the following intracellular events recording during epileptic seizures: (a) a burst of action potentials superimposed on and followed by a PDS, and (b) rapid repetitive firing succeeded by an IPSP. Thus, a single set of parameters can reporduce both normal physiological behavior and 'epileptic' behavior: the particular behavior seen depending on how the cell is stimulated. This overall result is the same as for our model of the CA1 hippocampal cell. It suggests that certain acutely acting epileptogenic agents, e.g. penicillin, may act by increasing synaptic input (perhaps both excitatory and inhibitory) to pyramidal cells, rather than by altering their membrane properties. As in our CA1 hippocampal cell model, bursting seems to be a phenomenon generated by the apical dendrite.     

The timing of the involvement of the frontal eye fields and posterior parietal cortex in visual search

The frontal eye fields (FEFs) and posterior parietal cortex (PPC) are important for target detection in conjunction visual search but the relative timings of their contribution have not been compared directly. We addressed this using temporally specific double pulse transcranial magnetic stimulation delivered at different times over FEFs and PPC during performance of a visual search task. Disruption of performance was earlier (0/40 ms) with FEF stimulation than with PPC stimulation (120/160 ms), revealing a clear and substantial temporal dissociation of the involvement of these two areas in conjunction visual search. We discuss these timings with reference to the respective roles of FEF and PPC in the modulation of extrastriate visual areas and selection of responses.     

A randomized placebo-controlled trial of risperidone for the treatment of aggression,agitation, and psychosis of dementia

BACKGROUND: This randomized, double-blind, placebo-controlled trial examined the efficacy and safety of risperidone in the treatment of aggression, agitation, and psychosis in elderly nursing-home patients with dementia. METHOD: Elderly patients with a DSM-IV diagnosis of dementia of the Alzheimer's type, vascular dementia, or a combination of the 2 (i.e., mixed dementia) and significant aggressive behaviors were randomized to receive, for a period of 12 weeks, a flexible dose of either placebo or risperidone solution up to a maximum of 2 mg/day. Outcome measures were the Cohen-Mansfield Agitation Inventory (CMAI), the Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD) rating scale, and the Clinical Global Impression of Severity (CGI-S) and of Change (CGI-C) scales. RESULTS: A total of 345 patients were randomized to treatment with risperidone or placebo, and 337 patients received at least one dose of study drug. The trial was completed by 67% of patients in the placebo group and 73% of patients in the risperidone group. The mean +/- SE dose of risperidone was 0.95 +/- 0.03 mg/day. The primary endpoint of the study, the difference from baseline to endpoint in CMAI total aggression score, showed a significant reduction in aggressive behavior for risperidone versus placebo (p <.001). A similar improvement was also seen for the CMAI total non-aggression subscale (p <.002) and for the BEHAVE-AD total (p <.001) and psychotic symptoms subscale (p =.004). At endpoint, the CGI-S and the CGI-C scores indicated a significantly greater improvement with risperidone compared with placebo (p <.001). Overall, 94% and 92% of the risperidone and placebo groups, respectively, reported at least 1 adverse event. Somnolence and urinary tract infection were more common with risperidone treatment, whereas agitation was more common with placebo. There was no significant difference in the number of patients who reported extrapyramidal symptoms between the risperidone (23%) and placebo (16%) groups. CONCLUSION: Treatment with low-dose (mean = 0.95 mg/day) risperidone resulted in significant improvement in aggression, agitation, and psychosis associated with dementia.     

Rivastigmine in vascular dementia

Vascular dementia (VaD), like Alzheimer's disease (AD), is associated with cholinergic deficits. Rivastigmine provides sustained, brain-selective inhibition of acetylcholinesterase and butyrylcholinesterase. Preliminary data suggest that rivastigmine may provide significant benefits in patients with AD and cerebrovascular disease (mixed dementia), and in patients with VaD. Open-label rivastigmine treatment has been associated with improved cognitive and functional abilities, behavioral symptoms, and reduced caregiver stress in a small pilot study in these patients. Larger, prospective, double-blind studies of rivastigmine in patients with VaD are under way. These studies will confirm whether rivastigmine is an efficacious treatment option for a range of patients for whom, until now, there have been few symptomatic therapies.