Rare, generally pediatric oligodendroglioma-like neoplasms with extensive leptomeningeal dissemination have been interpreted variably as glial, oligodendroglial or glioneuronal. The clinicopathologic features have not been fully characterized. We studied 36 patients, 12 females and 24 males with a median age of 5 years (range 5 months-46 years). MRI demonstrated leptomeningeal enhancement, frequently with cystic or nodular T2 hyperintense lesions within the spinal cord/brain along the subpial surface. A discrete intraparenchymal lesion, usually in the spinal cord, was found in 25 (of 31) (81 %). Tumors contained oligodendroglioma-like cells with low-mitotic activity (median 0 per 10 high power fields, range 0-4), and rare ganglion/ganglioid cells in 6 cases (17 %). Tumors were mostly low-grade, with anaplastic progression in 8 (22 %). Immunohistochemistry demonstrated strong reactivity for OLIG2 (7 of 9) (78 %), and moderate/strong S100 (11 of 12) (92 %), GFAP (12 of 31) (39 %) and synaptophysin (19 of 27) (70 %). NeuN, EMA, and mutant IDH1 (R132H) protein were negative. Median MIB1 labeling index was 1.5 % (range <1-30 %). FISH (n = 13) or SNP array (n = 2) demonstrated 1p loss/intact 19q in 8 (53 %), 1p19q co-deletion in 3 (20 %), and no 1p or 19q loss in 4 (27 %). Clinical follow-up (n = 24) generally showed periods of stability or slow progression, but a subset of tumors progressed to anaplasia and behaved more aggressively. Nine patients (38 %) died 3 months-21 years after diagnosis (median total follow-up 5 years). We report a series of a neoplasm with distinct clinicopathologic and molecular features. Although most progress slowly, a significant fraction develop aggressive features.
Electrical stimulation of the brainstem in paralysed decerebrate cats evokes a centrally generated pattern of motor output (fictive locomotion) that has many of the characteristics of overground locomotion in adult quadripedal mammals (see Rossignol, 1996). During fictive locomotion, motoneurones innervating limb muscles receive alternating excitatory and inhibitory synaptic currents from the central pattern generator (CPG) for locomotion (Jordan, 1983). These result in the rhythmic fluctuations of membrane potential (locomotor drive potentials, LDPs) that underlie the patterned activation of motoneurones during locomotion. The transformation of rhythmic excitatory drive into trains of action potentials is governed by the passive and active membrane properties of motoneurones. It is now known that some of these properties are altered during locomotion. For example, the post-spike afterhyperpolarization (AHP) is reduced in motoneurones during fictive locomotion (Brownstone et al. 1992;Schmidt, 1994) and there is the appearance of a voltagedependent excitatory current (Brownstone et al. 1994). This voltage-dependent excitation results in non-linear responses of motoneurones to depolarizing currents, which may facilitate the recruitment of motoneurones, or augment motoneuronal output evoked by reflex or central excitation (Brownstone et al. 1994;McCrea et al. 1997;Bennett et al. 1998). These changes in motoneurone membrane properties result in increased motoneuronal firing in response to intracellular current injection during fictive locomotion (Brownstone et al. 1992;. The fictive locomotor state thus appears to include processes that increase the excitability of hindlimb motoneurones.The membrane potential at which action potentials are initiated in response to sufficient depolarizing currents (the voltage threshold, V th ) is not a fixed value in motoneurones. For example, V th tends to be higher (more depolarized) in higher rheobase motoneurones (Gustafsson & Pinter, 1984) 1. Experiments were conducted on decerebrate adult cats to examine the effect of brainstemevoked fictive locomotion on the threshold voltage (V th ) at which action potentials were initiated in hindlimb motoneurones. Measurements of the voltage threshold of the first spike evoked by intracellular injection of depolarizing ramp currents or square pulses were compared during control and fictive locomotor conditions. The sample of motoneurones included flexor and extensor motoneurones, and motoneurones with low and high rheobase currents.2. In all 38 motoneurones examined, action potentials were initiated at more hyperpolarized membrane potentials during fictive locomotion than in control conditions (mean hyperpolarization _8.0 ± 5.5 mV; range _1.8 to _26.6 mV). Hyperpolarization of V th occurred immediately at the onset of fictive locomotion and recovered in seconds (typically < 60 s) following the termination of locomotor activity.3. The V th of spikes occurring spontaneously without intracellular current injection was also reduced during loc...
Chronic traumatic encephalopathy (CTE) has been described mainly in professional athletes and military personnel and is characterized by deposition of hyperphosphorylated tau at the depths of cortical sulci and around blood vessels. To assess CTE-like changes in a routine neuropathology service, we prospectively examined 111 brains (age 18-60 years). The presence of tau-immunoreactive deposits was staged using guidelines described by others and was correlated with the medical history. 72/111 cases were negative for CTE-like changes; 34/111 were CTE stage <1; 3/111 were CTE stage 1; and 2/111 were CTE stage 2. The combined history of head injury and alcohol and/or drug abuse was a significant predictor of any CTE-like changes. Age was also a significant predictor; most with any CTE-like changes were >40 years old. CTE-like changes were not identified at sites of contusion. Among a separate group studied retrospectively, we identified 4 cases that met full criteria for CTE. We conclude that CTE-like findings are not confined to professional athletes; the risk factors of head injury and substance abuse are similar in the routine population. However, the significance of very small hyperphosphorylated tau deposits remains to be determined. In addition, the absence of typical CTE-like deposits near contusion sites keeps open the question of pathogenesis.
Brownstone RM, Krawitz S, Jordan LM. Reversal of the late phase of spike frequency adaptation in cat spinal motoneurons during fictive locomotion. J Neurophysiol 105: 1045-1050, 2011. First published December 22, 2010 doi:10.1152/jn.00411.2010.-In spinal motoneurons, late spike frequency adaptation (SFA) is defined as the slowing of the firing rate over tens of seconds and can be seen during sustained or intermittent current injection. Although the function of late SFA is not known, it may result in a decrease in force production over time, or muscle fatigue. Because locomotion can persist for long periods of time without fatigue, late SFA was studied using intracellular recordings from adult cat motoneurons during fictive locomotion. Of eight lumbar motoneurons studied, all showed late adaptation during control conditions, but none demonstrated late adaptation during locomotor activity. The most consistent properties that correlated with the presence or absence of late SFA were those related to availability of fast, inactivating sodium channels, particularly action potential rate of rise. Evidence of the reversal of late SFA during locomotion was present for several minutes following locomotor trials, consistent with the suggestion that SFA is modulated through slow metabotropic pathways. The abolition of late adaptation in spinal motoneurons during fictive locomotion is an example of a statedependent change in the "intrinsic" properties of mammalian motoneurons. This change contributes to increased excitability of motoneurons during locomotion and results in robust firing during sustained locomotion.
The multikinase inhibitor and FDA-approved drug dovitinib (Dov) crosses the blood–brain barrier and was recently used as single drug application in clinical trials for GB patients with recurrent disease. The Dov-mediated molecular mechanisms in GB cells are unknown. We used GB patient cells and cell lines to show that Dov downregulated the stem cell protein Lin28 and its target high-mobility group protein A2 (HMGA2). The Dov-induced reduction in pSTAT3Tyr705 phosphorylation demonstrated that Dov negatively affects the STAT3/LIN28/Let-7/HMGA2 regulatory axis in GB cells. Consistent with the known function of LIN28 and HMGA2 in GB self-renewal, Dov reduced GB tumor sphere formation. Dov treatment also caused the downregulation of key base excision repair factors and O6-methylguanine-DNA-methyltransferase (MGMT), which are known to have important roles in the repair of temozolomide (TMZ)-induced alkylating DNA damage. Combined Dov/TMZ treatment enhanced TMZ-induced DNA damage as quantified by nuclear γH2AX foci and comet assays, and increased GB cell apoptosis. Pretreatment of GB cells with Dov (‘Dov priming’) prior to TMZ treatment reduced GB cell viability independent of p53 status. Sequential treatment involving ‘Dov priming’ and alternating treatment cycles with TMZ and Dov substantially reduced long-term GB cell survival in MGMT+ patient GB cells. Our results may have immediate clinical implications to improve TMZ response in patients with LIN28+/ HMGA2+ GB, independent of their MGMT methylation status.
The excitability of lumbar motoneurons in the cat is increased during fictive locomotion induced by stimulation of the mesencephalic locomotor region (MLR). This change in excitability has previously been demonstrated experimentally. During fictive locomotion: (1) the afterhyperpolarization (AHP) is reduced 1,2 and (2) the voltage threshold for production of an action potential is lowered 3 . The excitability of motoneurons is determined by intrinsic properties of the cells that are modulated by the premotoneuronal locomotor network. In this computer simulation study we focus on the lowering of the voltage threshold for an action potential and the accompanying reduction of the AHP. The purpose of this paper is to explore the potential ionic conductances responsible for the increase in motoneuron excitability during fictive locomotion. COMPUTER MODELA single cell model with three compartments (initial segment, soma and dendrite) was built using the GENESIS software (FIG. 1A). The active ionic currents were taken from Traub 4 , Jones and Bawa 5 and Takahashi 6 . Ramp current was injected into the soma following a reduction of 70% of the g K(AHP) that was used to simulate the reduction of AHP during fictive locomotion. Membrane potential of the soma compartment was solved to investigate the relationship between voltage threshold and varying specific conductances in the soma and initial segment. RESULTSDecreasing somatic conductance of various potassium channels and increasing somatic conductance of the sodium channel readily produced changes in current threshold, but changes in voltage threshold were small and were accompanied by gross changes in the action potential shape. Increasing g Na by 100% in the initial segment (FIG. 2) produced a lowering of the voltage threshold in soma by 6.7 mV (compared to a mean value of 6.3±3.9 recorded in the cat experiments) while the size and shape of the somatic action potential were minimally affected (FIG. 2C), as in the experimental results. Alternatively, decreasing g K(DR) by 60% in the initial segment was also able to produce a lowering of the voltage threshold in the soma by 6.4 mV, but this caused a change in shape of the repolarization phase of the somatic action potential (FIG. 2D). a
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