Reduction of self-mutilating behavior and improved oromotor function in a patient with Lesch-Nyhan syndrome following botulinum toxin injection: A case report.

Lesch-Nyhan syndrome is a genetic metabolic disorder often involving dystonia and self-mutilating behavior. This case report describes a 13-year-old boy with Lesch-Nyhan syndrome and self-mutilating behavior who received botulinum toxin injections to his bilateral masseter muscles after failing multiple other treatments. Following injections, the patient had reduction in self-biting, along with improvements in speech, mastication and feeding observed in speech therapy. Botulinum toxin injections to the masseters may help to improve oromotor function and reduce self-mutilating behaviors in children with Lesch-Nyhan syndrome who have failed more conservative treatments, providing opportunity for improved functional status and patient safety. Further investigation is indicated to establish optimal dosing. Additionally, the mechanism for the reduction of self-mutilating behavior is unclear and justifies additional investigation.

Cell-Based High-Throughput Luciferase Reporter Gene Assays for Identifying and Profiling Chemical Modulators of Endoplasmic Reticulum Signaling Protein, IRE1.

Endoplasmic reticulum (ER) stress activates three distinct signal transducers on the ER membrane. Inositol-requiring protein 1 (IRE1), the most conserved signal transducer, plays a key role in ER stress-mediated signaling. During ER stress, IRE1 initiates two discrete signaling cascades: the "adaptive" signaling cascade mediated by the XBP1 pathway and the "alarm" signaling cascade mediated by stress-activated protein kinase pathways. Fine-tuning of the balance between the adaptive and alarm signals contributes significantly to cellular fate under ER stress. Thus, we propose that the design of high-throughput screening (HTS) assays to selectively monitor IRE1 mediated-signaling would be desirable for drug discovery. To this end, we report the generation of stable human neural cell lines and development of cell-based HTS luciferase (Luc) reporter gene assays for the identification of pathway-specific chemical modulators of IRE1. We implemented a cell-based Luc assay using a chimeric CHOP-Gal4 transcription factor in 384-well format for monitoring IRE1 kinase-mediated p38MAPK activation and an unfolded response pathway element (URPE)-Luc cell-based assay in 1536-well format for monitoring IRE1's RNase-mediated activation of XBP1. Chemical library screening was successfully conducted with both the CHOP/Gal4-Luc cells and UPRE-Luc engineered cells. The studies demonstrate the feasibility of using these HTS assays for discovery of pathway-selective modulators of IRE1.

Motor learning during poststroke gait rehabilitation: a case study.

INTRODUCTION: To develop more effective gait rehabilitation strategies, it is important to understand the time course of motor learning that underlies improvements achieved with gait training. The purpose of this case study was to evaluate motor learning through the measurement of within-session and across-session changes in gait biomechanics during the first and sixth weeks of a 6-week clinical gait training program. CASE DESCRIPTION: A 47-year-old man with poststroke left hemiparesis participated in the study (15.5 months poststroke, lower extremity Fugl-Meyer score of 12). INTERVENTION: The subject participated in 6 weeks of training with 3 sessions per week, comprising fast treadmill walking and functional electrical stimulation to plantar and dorsiflexors. In one training session during the first and sixth weeks, paretic propulsion and swing phase knee flexion were measured during a pretest (before the training session), posttest (after the training session), and retention test (48 hours after training). OUTCOMES: After 6 week of training, the subject's gait speed increased from 0.38 to 0.57 m/s; there was a 55.4% improvement in paretic propulsion and 25% increase in swing phase knee flexion. Examination of change scores revealed greater within-session gains and greater retention during the first versus sixth weeks of gait training for both paretic propulsion and knee flexion. DISCUSSION: We demonstrate the feasibility and advantage of using within- and across-session changes for evaluating motor learning during clinical gait rehabilitation. An understanding of the time course of motor learning that underlies gait training can guide the development of novel strategies and dosing regimens to increase the efficacy of each session of gait rehabilitation. VIDEO ABSTRACT AVAILABLE: (See Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A72, for more insights from the authors.).

Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and ß-arrestin2 with antinociceptive activity.

Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics oxantel pamoate and pyrantel pamoate; the psychoactive compounds hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a G(i/o)-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of ß-arrestin2 to GPR35, and internalization of GPR35. In mice, it attenuates visceral pain perception, indicating an antinociceptive effect, possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35-associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent.

'Where are the lesbians in Chaucer?' Lack, opportunity and female homoeroticism in Medieval Studies today.

This article explores the study of lesbians in the Middle Ages and proposes that the unstable construct of lesbian poses a problem for traditional Medieval Studies that can lead to the development in Medieval Studies of more nuanced and productive theorizing.