Treatment of congenital Langerhans cell histiocytosis with cobimetinib

We report a case of congenital multisystem Langerhans cell histiocytosis with cutaneous and hematopoietic involvement. After the failure of first-line (vinblastine and prednisolone) and second-line (vincristine and cytarabine) therapies, treatment with cobimetinib, a mitogen-activated protein kinase (MEK) inhibitor, led to the remission of disease and a sustained response after 11 months of ongoing treatment. Protein kinase inhibitors targeting BRAF or MEK could represent a promising future therapeutic option, also in children with LCH.     

Focal myositis presenting as pseudothrombophlebitis of the neck in a patient with mixed connective tissue disease

This report describes a case of focal myositis in a patient with mixed connective tissue disease. The patient presented with diffuse neck swelling and pseudothrombophlebitis of the left internal jugular vein. Other clinical features included a high fever, elevated erythrocyte sedimentation rate, and prompt improvement after administration of high-dose intravenous corticosteroid therapy. Criteria for polymyositis were absent, serum levels of creatine kinase remained normal, and there was no sign of recurrence during 3 years of followup. Results of immunoprecipitation for anti–Jo-1 and other myositis-specific autoantibodies remained negative in serial serum samples obtained before, during, and after the episode.     

Quantitative assessment of consciousness during anesthesia without EEG data

Assessing the depth of anesthesia (DoA) is a daily challenge for anesthesiologists. The best assessment of the depth of anesthesia is commonly thought to be the one made by the doctor in charge of the patient. This evaluation is based on the integration of several parameters including epidemiological, pharmacological and physiological data. By developing a protocol to record synchronously all these parameters we aim at having this evaluation made by an algorithm. Our hypothesis was that the standard parameters recorded during anesthesia (without EEG) could provide a good insight into the consciousness level of the patient. We developed a complete solution for high-resolution longitudinal follow-up of patients during anesthesia. A Hidden Markov Model (HMM) was trained on the database in order to predict and assess states based on four physiological variables that were adjusted to the consciousness level: Heart Rate (HR), Mean Blood Pressure (MeanBP) Respiratory Rate (RR), and AA Inspiratory Concentration (AAFi) all without using EEG recordings. Patients undergoing general anesthesia for hernial inguinal repair were included after informed consent. The algorithm was tested on 30 patients. The percentage of error to identify the actual state among Awake, LOC, Anesthesia, ROC and Emergence was 18%. This protocol constitutes the very first step on the way towards a multimodal approach of anesthesia. The fact that our first classifier already demonstrated a good predictability is very encouraging for the future. Indeed, this first model was merely a proof of concept to encourage research ways in the field of machine learning and anesthesia.

     

Physiological and anatomical evidence for an inhibitory trigemino-oculomotor pathway in the cat

During blink down‐phase, the levator palpebrae superioris (levator) muscle is inactivated, allowing the orbicularis oculi muscle to act. For trigeminal reflex blinks, the excitatory connections from trigeminal sensory nuclei to the facial nucleus have been described, but the pathway whereby the levator is turned off have not. We examined this question by use of both physiological and anatomical approaches in the cat. Intracellular records from antidromically activated levator motoneurons revealed that periorbital electrical stimulation produced bilateral, long latency inhibitory postsynaptic potentials (IPSPs). Central electrical stimulation of the principal trigeminal nucleus produced shorter latency IPSPs. Intracellular staining revealed that these motoneurons reside in the caudal central subdivision and have 10 or more poorly branched dendrites, which extend bilaterally into the surrounding supraoculomotor area. Axons penetrated in this region could be activated from periorbital and central electrodes. Neurons labeled from tracer injections into the caudal oculomotor complex were distributed in a crescent‐shaped band that lined the ventral and rostral aspects of the pontine trigeminal sensory nucleus. Double‐label immunohistochemical procedures demonstrated that these cells were not tyrosine hydroxylase‐positive cells in the Kölliker‐Fuse area. Instead, supraorbital nerve afferents displayed a similar crescent‐shaped distribution, suggesting they drive these trigemino‐oculomotor neurons. Anterograde labeling of the trigemino‐oculomotor projection indicates that it terminates bilaterally, in and above the caudal central subdivision. These results characterize a trigemino‐oculomotor pathway that inhibits levator palpebrae motoneurons in response to blink‐producing periorbital stimuli. The bilateral distributions of trigemino‐oculomotor afferents, levator motoneurons, and their dendrites supply a morphological basis for conjugate lid movements. J. Comp. Neurol. 520:2218–2240, 2012. © 2012 Wiley Periodicals, Inc.     

Possible cues driving context-specific adaptation of optocollic reflex in pigeons (Columba livia)

Context-specific adaptation (Shelhamer M, Clendaniel R. Neurosci Lett 332: 200-204, 2002) explains that reflexive responses can be maintained with different "calibrations" for different situations (contexts). Which context cues are crucial and how they combine to evoke context-specific adaptation is not fully understood. Gaze stabilization in birds is a nice model with which to tackle that question. Previous data showed that when pigeons (Columba livia) were hung in a harness and subjected to a frontal airstream provoking a flying posture ("flying condition"), the working range of the optokinetic head response [optocollic reflex (OCR)] extended toward higher velocities compared with the "resting condition." The present study was aimed at identifying which context cues are instrumental in recalibrating the OCR. We investigated that question by using vibrating stimuli delivered during the OCR provoked by rotating the visual surroundings at different velocities. The OCR gain increase and the boost of the fast phase velocity observed during the "flying condition" were mimicked by body vibration. On the other hand, the newly emerged relationship between the fast-phase and slow-phase velocities in the "flying condition" was mimicked by head vibration. Spinal cord lesion at the lumbosacral level decreased the effects of body vibration, whereas lesions of the lumbosacral apparatus had no effect. Our data suggest a major role of muscular proprioception in the context-specific adaptation of the stabilizing behavior, while the vestibular system could contribute to the context-specific adaptation of the orienting behavior. Participation of an efferent copy of the motor command driving the flight cannot be excluded.     

Increased striatal gray matter densities in patients with schizophrenia and substance use disorder: a voxel-based morphometry study

We sought to investigate the link between substance abuse and increased striatal gray matter densities (GMD) in schizophrenia, using voxel-based morphometry (VBM). Increased striatal GMD were found in patients with schizophrenia and substance use disorder (n=12), but not schizophrenia only patients (n=11), compared to healthy volunteers (n=15).     

Electrophysiological evidence that a subset of midbrain dopamine neurons integrate the reward signal induced by electrical stimulation of the posterior mesencephalon

This study was aimed at determining whether midbrain dopamine (DA) neurons are trans-synaptically activated by rewarding electrical stimulation applied near the midline in the posterior mesencephalon (PM), and in the affirmative, whether the increase in firing was proportional to the rewarding effectiveness of the stimulation. Experiments were performed on male Long–Evans rats trained to lever press to obtain 400 ms trains of cathodal rectangular pulses. Following the training period, curves relating the rates of responding to the stimulation frequencies were determined at two current intensities and reward thresholds were calculated for each animal. Each animal was then anesthetized with urethane (1.2 g/kg, i.p.) and firing rate of DA neurons were recorded before, during, and after each of 50 trains (1 train/3 s) of stimulation to the PM using stimulation parameters that either sustained near threshold responding (rewarding), or failed to sustain responding (non-rewarding), in the behavioral tests. A total of 24 DA cells were recorded from 13 behaviorally trained animals, and of these, 17 (71%) responded to rewarding stimulation by an increase in firing, five (21%) were unresponsive and two (8%) were inhibited. In 12 of the 17 cells that were activated, the increase in firing was proportional to the rewarding effectiveness of the stimulation rather than the total strength of the stimulation. These results provide evidence that a subset of midbrain DA neurons are trans-synaptically activated by rewarding PM stimulation and constitute a second, or subsequent, stage of the reward-relevant pathway that integrates the PM reward signal.     

Novel approaches to gastrointestinal stromal tumors resistant to imatinib and sunitinib

Gastrointestinal stromal tumors (GIST) are rare tumors of mesenchymal origin that may arise anywhere along the gastrointestinal tract or in the peritoneum. In most cases, GIST harbor mutations of KIT or PDGFRA. Imatinib mesylate (IM), a small-molecule tyrosine kinase inhibitor developed for the treatment of chronic myeloid leukemia, has been shown to be active against these mutations and has significant activity in patients with metastatic GIST. However, resistance to IM emerges after a median of 24 months of treatment. Sunitinib malate (SU) has been approved for the treatment of patients with IM-resistant advanced GIST, but the median progression-free survival in this setting is only 6 months. This article reviews the current knowledge regarding IM and SU resistance in GIST, as well as the available options for the management of GIST resistant to IM and SU.     

Blockade of 5-HT2a receptors reduces haloperidol-induced attenuation of reward.

Previous studies have shown that effective antipsychotic medications attenuate reward, an effect that is generally attributed to their effectiveness at blocking the dopamine D2-like receptors. As blockade of the serotonin type 2a (5-HT2a) receptors is a common property of the newer antipsychotics, the present study compared the effect of haloperidol, clozapine, and M100907 (a selective 5-HT2a antagonist) and the combined effect of haloperidol and M100907 treatment on brain stimulation reward (BSR). Experiments were performed on male Sprague-Dawley rats trained to produce an operant response to obtain electrical stimulation in the lateral hypothalamus. Measures of reward threshold were determined in different groups of rats using the curve-shift method using fixed current intensity and variable frequency before and at different times after injection of haloperidol (0.01, 0.05, 0.1, and 0.25 mg/kg), clozapine (1, 7.5, 15, and 30 mg/kg), M100907 (0.033, 0.1, and 0.3 mg/kg), or their vehicle. The effect of M100907 (0.3 mg/kg) on the attenuation of BSR by a sub- and suprathreshold dose of haloperidol was studied in another group of rats. Clozapine produced a dose-orderly increase in reward threshold with a mean maximal increase of 50%; at high doses, clozapine induced cessation of responding in several animals at different time periods. Haloperidol induced a dose-dependent increase in reward threshold, with the mean maximal increase (75%) being observed at the highest dose; it also produced a dose-dependent reduction of maximum rates of responding. M100907 failed to alter reward at any of the doses tested and had no effect on the subthreshold dose (0.01 mg/kg) of haloperidol. But when combined with a suprathreshold dose of haloperidol, M100907 reduced the reward-attenuating effect of haloperidol. These results show that 5-HT2a receptors are unlikely to constitute a component of the reward-relevant pathway activated by lateral hypothalamic stimulation. However, blockade of 5-HT2a receptors may account for the relatively lower level of reward attenuation produced by clozapine, and predict that antipsychotic medications that have a high affinity for the 5-HT2a receptor may be less likely to induce dysphoria.