Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis

<p>Abstract</p> <p>Background</p> <p>Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use. Contraindications include a history of certain neurological conditions that might increase the risk of seizure and other adverse events. The precise pathophysiological mechanism by which mefloquine might predispose those with such a history to seizure remains unclear.</p> <p>Presentation of the hypothesis</p> <p>Studies have demonstrated that mefloquine at doses consistent with chemoprophylaxis accumulates at high levels in brain tissue, which results in altered neuronal calcium homeostasis, altered gap-junction functioning, and contributes to neuronal cell death. This paper reviews the scientific evidence associating mefloquine with alterations in neuronal function, and it suggests the novel hypothesis that among those with the prevalent EPM1 mutation, inherited and mefloquine-induced impairments in neuronal physiologic safeguards might increase risk of GABAergic seizure during mefloquine chemoprophylaxis.</p> <p>Testing and implications of the hypothesis</p> <p>Consistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1. Recommendations and directions for future research are presented.</p

Gap junctions in olfactory neurons modulate olfactory sensitivity

<p>Abstract</p> <p>Background</p> <p>One of the fundamental questions in olfaction is whether olfactory receptor neurons (ORNs) behave as independent entities within the olfactory epithelium. On the basis that mature ORNs express multiple connexins, I postulated that gap junctional communication modulates olfactory responses in the periphery and that disruption of gap junctions in ORNs reduces olfactory sensitivity. The data collected from characterizing connexin 43 (Cx43) dominant negative transgenic mice OlfDNCX, and from calcium imaging of wild type mice (WT) support my hypothesis.</p> <p>Results</p> <p>I generated OlfDNCX mice that express a dominant negative Cx43 protein, Cx43/β-gal, in mature ORNs to inactivate gap junctions and hemichannels composed of Cx43 or other structurally related connexins. Characterization of OlfDNCX revealed that Cx43/β-gal was exclusively expressed in areas where mature ORNs resided. Real time quantitative PCR indicated that cellular machineries of OlfDNCX were normal in comparison to WT. Electroolfactogram recordings showed decreased olfactory responses to octaldehyde, heptaldehyde and acetyl acetate in OlfDNCX compared to WT. Octaldehyde-elicited glomerular activity in the olfactory bulb, measured according to odor-elicited <it>c-fos </it>mRNA upregulation in juxtaglomerular cells, was confined to smaller areas of the glomerular layer in OlfDNCX compared to WT. In WT mice, octaldehyde sensitive neurons exhibited reduced response magnitudes after application of gap junction uncoupling reagents and the effects were specific to subsets of neurons.</p> <p>Conclusions</p> <p>My study has demonstrated that altered assembly of Cx43 or structurally related connexins in ORNs modulates olfactory responses and changes olfactory activation maps in the olfactory bulb. Furthermore, pharmacologically uncoupling of gap junctions reduces olfactory activity in subsets of ORNs. These data suggest that gap junctional communication or hemichannel activity plays a critical role in maintaining olfactory sensitivity and odor perception.</p

The “conscious pilot”—dendritic synchrony moves through the brain to mediate consciousness

Cognitive brain functions including sensory processing and control of behavior are understood as “neurocomputation” in axonal–dendritic synaptic networks of “integrate-and-fire” neurons. Cognitive neurocomputation with consciousness is accompanied by 30- to 90-Hz gamma synchrony electroencephalography (EEG), and non-conscious neurocomputation is not. Gamma synchrony EEG derives largely from neuronal groups linked by dendritic–dendritic gap junctions, forming transient syncytia (“dendritic webs”) in input/integration layers oriented sideways to axonal–dendritic neurocomputational flow. As gap junctions open and close, a gamma-synchronized dendritic web can rapidly change topology and move through the brain as a spatiotemporal envelope performing collective integration and volitional choices correlating with consciousness. The “conscious pilot” is a metaphorical description for a mobile gamma-synchronized dendritic web as vehicle for a conscious agent/pilot which experiences and assumes control of otherwise non-conscious auto-pilot neurocomputation

Novel Methods for Surface EMG Analysis and Exploration Based on Multi-Modal Gaussian Mixture Models

<div><p>This paper introduces a new method for data analysis of animal muscle activation during locomotion. It is based on fitting Gaussian mixture models (GMMs) to surface EMG data (sEMG). This approach enables researchers/users to isolate parts of the overall muscle activation within locomotion EMG data. Furthermore, it provides new opportunities for analysis and exploration of sEMG data by using the resulting Gaussian modes as atomic building blocks for a hierarchical clustering. In our experiments, composite peak models representing the general activation pattern per sensor location (one sensor on the long back muscle, three sensors on the gluteus muscle on each body side) were identified per individual for all 14 horses during walk and trot in the present study. Hereby we show the applicability of the method to identify composite peak models, which describe activation of different muscles throughout cycles of locomotion.</p></div

Response of glacial landscapes to spatial variations in rock uplift rate

The kinematics of the human hand is optimal with respect to force distribution during pinch as well as power grasp, reducing the tissue strain when exerting forces through opposing fingers and optimising contact faces. Quantifying this optimality is of key importance when constructing biomimetic robotic hands, but understanding the exact human finger motion is also an important asset in, e.g., tracking finger movement during manipulation. The goal of the method presented here is to determine the precise orientations and positions of the axes of rotation of the finger joints by using suitable magnetic resonance imaging (MRI) images of a hand in various postures. The bones are segmented from the images, and their poses are estimated with respect to a reference posture. The axis orientations and positions are fitted numerically to match the measured bone motions. Eight joint types with varying degrees of freedom are investigated for each joint, and the joint type is selected by setting a limit on the rotational and translational mean discrepancy. The method results in hand models with differing accuracy and complexity, of which three examples, ranging from 22 to 33 DoF, are presented. The ranges of motion of the joints show some consensus and some disagreement with data from literature. One of the models is published as an implementation for the free OpenSim simulation environment. The mean discrepancies from a hand model built from MRI data are compared against a hand model built from optical motion capture data

Pelizaeus–Merzbacher-like disease is caused not only by a loss of connexin47 function but also by a hemichannel dysfunction

Autosomal recessive mutations in the GJA12/GJC2 gene encoding the gap junction protein connexin47 (C × 47) cause a form of Pelizaeus–Merzbacher-like disease (PMLD) with hypomyelination, nystagmus, impaired psychomotor development and progressive spasticity. We investigated the functional consequences of four C × 47 missense mutations (G149S, G236R, T265A, and T398I) and one C × 47 complex mutation (A98G_V99insT) by immunoblot analysis and immunocytochemistry in transfected communication-incompetent HeLa cells and in OLI-neu cells. All studied C × 47 mutants, except G236R, generated stable proteins in transfected HeLa cells and OLI-neu cells. The mutants T265A and A98G_V99insT were retained in the ER, T398I formed gap junctional plaques at the plasma membrane, and G149S showed both, structures at the plasma membrane and ER localization. Two-microelectrode voltage clamp analyses in Xenopus laevis oocytes injected with wild-type and mutant C × 47 cRNA revealed reduced hemichannel currents for G236R, T265A, and A98G_V99insT. In contrast, T398I revealed hemichannel currents comparable to wild-type. For C × 47 mutant T398I, our results indicate a defect in hemichannel function, whereas C × 47 mutants G149S, G236R, T265A, and A98G_V99insT are predicted to result in a loss of C × 47 hemichannel function. Thus, PMLD is likely to be caused by two different disease mechanisms: a loss of function and a dysfunction