Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration

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Reduced ACTH, while normal beta-endorphin CSF levels in early epileptic encephalopathies

Since ACTH and the opioids display opposite effects on experimentally-induced seizures, cerebrospinal fluid (CSF) levels of ACTH and beta-endorphin (beta-EP) were measured in 6 children (4-8 months) affected by infantile spasms with hypsarhythmia, an idiopathic early onset encephalopathy, and in 8 age-matched controls. beta-EP levels in the patients (76.3 +/- 14.7 fmol/ml, M +/- SD) did not differ from those in controls (109.8 +/- 42.7) while babies with epileptic encephalopathy showed reduced ACTH levels in the CSF (3.8 +/- 1.5) as compared to controls (9.0 +/- 3.7, p less than 0.01). This resulted in an increased beta-EP/ACTH ratio. Another patient previously treated with ACTH showed a normal CSF level of ACTH (9.0) with a normal beta-EP/ACTH ratio while in clinical and EEG remission. These results are consistent with the hypothesis that some infantile seizures unrelated to brain injuries could originate from an ACTH deficiency at central level and/or an imbalance of neuropeptidergic pathways.     

Role of I-J in neonatal suppression

Spleen cells from neonatal mice belonging to strains with the I-J-b or I-J-k genotype, were treated with anti-I-Jb or anti-I-Jk antibody and complement. This reduces their suppressor cell activity as demonstrated by a decrease in the ability to suppress the mixed-lymphocyte reactivity of adult spleen cells. Injection of anti-I-J antibody into neonatal mice also reduces splenic suppressor cell activity prematurely. The removal of suppressor cells from neonatal spleen does not result in an immediate increase in mixed-lymphocyte reactivity (cell-mediated immunity) but does hasten the development of mixed-lymphocyte reactivity in the young mice. The results are discussed in light of the hypothesis that suppressor cells inhibit the function of immunocompetent cells in the neonatal mouse and control the development of immunocompetence.     

Dynamics of epileptic seizures: Evolution, spreading, and suppression

Dynamical properties of epileptic seizures are investigated using a recent compact continuum model for electric activity of the brain. Large amplitude limit cycles resembling electroencephalograms during epilepsy emerge when the system loses linear stability. Seizures that are confined to an onset area, or spread synchronously to other areas via spatial coupling, are studied and argued to be associated with clinical partial and secondarily generalized seizures, respectively. Suppression of such seizures is also demonstrated, which implies potential for future clinical applications.     

Opioid-mediated suppression of cultured peripheral blood mononuclear cell respiratory burst activity

Opiate addiction and stress have been associated with altered immune responses. In this study, we evaluated the influence of morphine and the stress responsive opioid peptide beta-endorphin (beta-END) on O-2 and H2O2 production by cultured human peripheral blood mononuclear cells. Exposure of these cells during 48 hr of culture to morphine and beta-END at pharmacologically (10(-8) M) and physiologically (10(-12) M) relevant concentrations, respectively, markedly suppressed peripheral blood mononuclear cell O-2 and H2O2 release in response to the respiratory burst stimuli opsonized zymosan and phorbol myristate acetate. Both opioids also induced a minimal, but statistically significant, increase in resting O-2 and H2O2 generation. The modulatory effects of morphine and beta-END on peripheral blood mononuclear cell oxygen metabolism appeared to involve a classical opioid receptor, because opioid activity was blocked by naloxone and was not observed with N-acetylated-beta-END. Using purified lymphocyte and monocyte preparations, we determined that although opioids directly increase monocyte-resting oxygen metabolism, lymphocytes are the primary target cell in opioid-mediated suppression of monocyte respiratory burst activity. The release of a suppressive product from opioid-triggered lymphocytes was inhibited by cyclosporine. Based on the results of this study, we propose that opioid-mediated suppression of mononuclear phagocyte respiratory burst activity is another factor to be considered in the immunodeficiency of opiate addiction and stress.     

A model of feedback control for the charge-balanced suppression of epileptic seizures

Here we present several refinements to a model of feedback control for the suppression of epileptic seizures. We utilize a stochastic partial differential equation (SPDE) model of the human cortex. First, we verify the strong convergence of numerical solutions to this model, paying special attention to the sharp spatial changes that occur at electrode edges. This allows us to choose appropriate step sizes for our simulations; because the spatial step size must be small relative to the size of an electrode in order to resolve its electrical behavior, we are able to include a more detailed electrode profile in the simulation. Then, based on evidence that the mean soma potential is not the variable most closely related to the measurement of a cortical surface electrode, we develop a new model for this. The model is based on the currents flowing in the cortex and is used for a simulation of feedback control. The simulation utilizes a new control algorithm incorporating the total integral of the applied electrical potential. Not only does this succeed in suppressing the seizure-like oscillations, but it guarantees that the applied signal will be charge-balanced and therefore unlikely to cause cortical damage.     

Inflammatory agonist stimulation and signal pathway of oxidative burst in neonatal chicken heterophils

Heterophils are the predominant polymorphonuclear leukocytes (PMNs) in poultry. The oxidative burst of activated heterophils, which generates reactive oxygen species (ROS), is one of the first line cellular defenses against invading microorganisms. In this report, the oxidative response of heterophils from neonatal chicks to in vitro stimulation by various inflammatory agonists was investigated using a fluorescence microplate assay. Both non-opsonized formalin-killed Salmonella enteritidis and Staphylococcus aureus were able to stimulate heterophil oxidative burst. The phorbol myristate acetate (PMA) was the most potent stimulant for the chicken heterophil oxidative response, whereas, the bacterial cell surface components lipopolysaccharide (LPS) and lipoteichoic acid (LTA) were less effective. Protein kinase C (PKC) is an essential signaling component regulating heterophil oxidative response to stimulation by PMA, LPS, LTA and S. enteritidis. However, inhibition of PKC did not affect the oxidative response to stimulation by S. aureus, suggesting differential signaling pathway responsible for the activation of oxidative burst by Gram-negative S. enteritidis and Gram-positive S. aureus. Inhibition of mitogen activated protein (MAP) kinase p38 and extracellular response kinase (ERK) by SB 203580 and PD 098059, respectively, did not inhibit activated oxidative burst.     

The Microelectrophoretic Behaviour of Plant Mitochondria compared with Rat Mitochondria

‘Heavy’ mitochondrial preparations of bean, cauliflower,and rat liver have been found to give unimodal distributionfor electrophoretic mobility against number of particles. ThepH-mean mobility curves were similar in form and consistentwith the mitochondrial surfaces being lipoproteins. de Duve (1959) separated ‘heavy’ and ‘light’(lysosome-rich) mitochondrial fractions from rat liver. Microelectrophoreticstudies on similar ‘heavy’ and ‘light’mitochondrial preparations from rat liver have shown the latterto consist mostly of mitochondria with some faster-moving particlestentatively identified with de Duve's lysosomes. ‘Light’mitochondrial preparations of bean showed no evidence of particlesadditional to mitochondria.     

Hyperinfective strongyloidiasis: Strongyloides stercoralis undergoes an autoinfective burst in neonatal gerbils

One of the unusual aspect of the life cycle of Strongyloides stercoralis is the occurrence of autoinfective third-stage larvae (L3a). These are the causative agents of severe hyperinfective strongyloidiasis. When 6-wk-old gerbils are infected with 1,000 infective third-stage larvae (L3i), no L3a are seen during the course of the infection. However, in neonatal gerbils (1-13 days of age) infected with 1,000 L3i, a burst of autoinfection takes place between 15 and 30 days postinfection (PI). Only occasional L3a can be found in neonatally infected gerbils after 4 wk PI. This autoinfective burst is not seen in neonatal gerbils infected with 200 L3i.     

d-serine regulation of the timing and architecture of the inspiratory burst in neonatal mice

d-serine, released from mouse medullary astrocytes in response to increased CO₂ levels, boosts the respiratory frequency to adapt breathing to physiological demands. We analyzed in mouse neonates, the influence of d-serine upon inspiratory/expiratory durations and the architecture of the inspiratory burst, assessed by pwelch's power spectrum density (PSD) and continuous wavelet transform (CWT) analyses. Suction electrode recordings were performed in slices from the ventral respiratory column (VRC), site of generation of the respiratory rhythm, and in brainstem-spinal cord (en bloc) preparations, from the C5 ventral roots, containing phrenic fibers that in vivo innervate and drive the diaphragm, the main inspiratory muscle.In en bloc and slice preparations, d-serine (100 μM) reduced the expiratory, but not the inspiratory duration, and increased the frequency and the regularity of the respiratory rhythm. In en bloc preparations, d-serine (100 μM) also increased slightly the amplitude of the integrated inspiratory burst and the area under the curve of the integrated inspiratory burst, suggesting a change in the recruitment or the firing pattern of neurons within the burst. Time-frequency analyses revealed that d-serine changed the burst architecture of phrenic roots, widening their frequency spectrum and shifting the position of the core of firing frequencies towards the onset of the inspiratory burst. At the VRC, no clear d-serine induced changes in the frequency-time domain could be established. Our results show that d-serine not only regulates the timing of the respiratory cycle, but also the recruitment strategy of phrenic motoneurons within the inspiratory burst.     

Prion protein and the transmissible spongiform encephalopathies

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that occur in a wide variety of mammals. In humans, TSE diseases include kuru, sporadic and iatrogenic Creutzfeldt-Jakob disease (CJD), Gerstmann-Str?ussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). So far, TSE diseases occur only rarely in humans; however, scrapie is a widespread problem in sheep, and the recent epidemic of bovine spongiform encephalopathy (BSE or mad cow disease) has seriously affected the British cattle industry. Of special concern is the recent appearance of a new variant of CJD in humans that is suspected of being caused by infections from BSE-infected cattle products. In all these diseases, an abnormal form of a host protein, prion protein (PrP), is essential for the pathogenic process. The relationship of this protein to the transmissible agent is currently the subject of great interest and controversy and is the subject of this review.     

Mitochondria and apoptosis

Apoptosis is a coordinated sequence of events culminating in the death of the cell. Many of these biochemical processes are regulated by the mitochondria, including the release of proapoptotic molecules in addition to the caspase-activating cofactor, cytochrome c. Pro- and antiapoptotic members of the Bcl-2 family regulate mitochondrial participation in cell death. Current models explaining cytochrome c release are discussed in light of mitochondrial structure and physiology.     

Mitochondria and Aging

Cover illustration: Mitochondria and Aging, a special issue edited by Professor Heinz D. Osiewacz (Frankfurt, Germany), devoted to aging research and the involvement of mitochondria “from models to humans”. Depicted are a 3D section of a human cell with mitochondria shown in red (© NIH, see http://ghr.nlm.nih.gov/handbook/illustrations/cellmitochondria) and from top to bottom: micrograph of mitochondria from the model organism Podospora anserina (© C. Scheckhuber, see p. 781), hand with pill (© Photodisc Inc.) and the worm Caenorhabditis elegans with typical senescent morphology (© B. Braeckman, see p. 803).     

Mitochondria and Neurodegeneration

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question “is mitochondrial dysfunction a necessary step in neurodegeneration?” is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.     

Mitochondria and neuroplasticity

The production of neurons from neural progenitor cells, the growth of axons and dendrites and the formation and reorganization of synapses are examples of neuroplasticity. These processes are regulated by cell-autonomous and intercellular (paracrine and endocrine) programs that mediate responses of neural cells to environmental input. Mitochondria are highly mobile and move within and between subcellular compartments involved in neuroplasticity (synaptic terminals, dendrites, cell body and the axon). By generating energy (ATP and NAD⁺), and regulating subcellular Ca²⁺ and redox homoeostasis, mitochondria may play important roles in controlling fundamental processes in neuroplasticity, including neural differentiation, neurite outgrowth, neurotransmitter release and dendritic remodelling. Particularly intriguing is emerging data suggesting that mitochondria emit molecular signals (e.g. reactive oxygen species, proteins and lipid mediators) that can act locally or travel to distant targets including the nucleus. Disturbances in mitochondrial functions and signalling may play roles in impaired neuroplasticity and neuronal degeneration in Alzheimer''s disease, Parkinson''s disease, psychiatric disorders and stroke.     

Mitochondria and arrhythmias

Mitochondria are essential to providing ATP, thereby satisfying the energy demand of the incessant electrical activity and contractile action of cardiac muscle. Emerging evidence indicates that mitochondrial dysfunction can adversely affect cardiac electrical functioning by impairing the intracellular ion homeostasis and membrane excitability through reduced ATP production and excessive reactive oxygen species (ROS) generation, resulting in increased propensity to cardiac arrhythmias. In this review, the molecular mechanisms linking mitochondrial dysfunction to cardiac arrhythmias are discussed with an emphasis on the impact of increased mitochondrial ROS on the cardiac ion channels and transporters that are critical to maintaining normal electromechanical functioning of the cardiomyocytes. The potential of using mitochondria-targeted antioxidants as a novel antiarrhythmia therapy is highlighted.