James E. Loukides

Bio: James E. Loukides is an academic researcher. The author has contributed to research in topics: Mexiletine & Effective refractory period. The author has an hindex of 4, co-authored 6 publications receiving 952 citations.

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Abstract: Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB. Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour.

Comparative electropharmacology of mexiletine, lidocaine and quinidine in a canine Purkinje fiber model

Abstract: Although said to be lidocaine-like, there is evidence that mexiletine has some properties similar to those of quinidine. To evaluate the relationship between the effects of these three drugs we analyzed their effects on action potentials of Purkinje fibers from canine false tendons. Experiments with each drug were done on single preparations from each of six dogs over the concentration range 0.31 to 10.0 X 10(-5) M. Lidocaine shortened action potential duration and effective refractory period with a log concentration-response relationship. The maximum velocity of phase "0" (Vmax) was unaffected at low concentrations and only slightly depressed at high concentrations. Quinidine also shortened action potential duration and effective refractory period but the effect levelled off at midrange and was reversed at higher concentrations. Quinidine depressed Vmax throughout the concentration range studied. Mexiletine shortened action potential duration with a log concentration response relationship. Effective refractory period was shortened at low concentrations but the effect levelled off and then reversed at higher concentrations of the drug. Mexiletine had no effect on Vmax at the lower end of the concentration curve but did suppress this parameter at higher concentrations. Mexiletine resembled lidocaine in its effect on Vmax and action potential duration whereas the effects of quinidine on these two parameters were distinct. On the other hand, the effects of mexiletine on effective refractory period were more akin to quinidine than lidocaine.

A comparison of the cellular electrophysiology of mexiletine and sotalol, singly and combined, in canine Purkinje fibers.

Abstract: To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1-100 microM), sotalol (3.1-400 microM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 microM of one drug combined with 3.1, 12.5, and 50 microM of the other. Mexiletine caused a concentration dependent depression of Vmax, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 microM, sotalol depressed Vmax slightly. Increasing the stimulation frequency did not result in further Vmax depression. The addition of sotalol did not alter the Vmax depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.

Effects of simultaneous administration of mexiletine and quinidine on the electrophysiologic parameters of canine Purkinje fibers

Abstract: The electropharmacologic effects of an equimolar combination of mexiletine and quinidine on canine Purkinje action potential parameters were compared with the effects of either drug alone in concentrations ranging from 0.31 to 5.0 X 10(-5) M. Six separate experiments were performed with mexiletine alone, quinidine alone, and the combination. At low concentrations, all three shortened action potential duration (APD) and effective refractory period (ERP) to the same degree; however, the combination depressed Vmax to the same extent as did solutions containing twice the concentration of quinidine alone even though mexiletine alone, in these concentrations, had no effect on the maximum rate of depolarization of phase 0 of the action potential Vmax. In higher concentrations, the combination depressed Vmax and prolonged the ERP to values midway between that achieved by the two drugs separately. Although increasing concentrations of mexiletine alone progressively shortened APD, the combination prolonged this parameter to values similar to those seen with twice the concentration of quinidine alone. The electropharmacologic effects of mexiletine and quinidine in combination are not simply additive and cannot be entirely predicted on the basis of a knowledge of their effects in isolation.

TREM2 Variants in Alzheimer's Disease

Abstract: BACKGROUND: Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS: We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS: We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS: Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of β-secretase

Abstract: BACE is an enzyme necessary for the generation of neurotoxic amyloid-β in Alzheimer's disease. Claes Wahlestedt and his colleagues identify a noncoding RNA that is upregulated in the brains of individuals with Alzheimer's disase. This noncoding RNA increases expression of BACE, driving amyloid-β generation and possibly disease progression.

Signaling Mechanisms Linking Neuronal Activity to Gene Expression and Plasticity of the Nervous System

Abstract: Sensory experience and the resulting synaptic activity within the brain are critical for the proper development of neural circuits. Experience-driven synaptic activity causes membrane depolarization and calcium influx into select neurons within a neural circuit, which in turn trigger a wide variety of cellular changes that alter the synaptic connectivity within the neural circuit. One way in which calcium influx leads to the remodeling of synapses made by neurons is through the activation of new gene transcription. Recent studies have identified many of the signaling pathways that link neuronal activity to transcription, revealing both the transcription factors that mediate this process and the neuronal activity-regulated genes. These studies indicate that neuronal activity regulates a complex program of gene expression involved in many aspects of neuronal development, including dendritic branching, synapse maturation, and synapse elimination. Genetic mutations in several key regulators of activity-dependent transcription give rise to neurological disorders in humans, suggesting that future studies of this gene expression program will likely provide insight into the mechanisms by which the disruption of proper synapse development can give rise to a variety of neurological disorders.