In the present study, the hypothesis that sex-related differences in glutamate-evoked rat masseter muscle afferent discharge may result from estrogen-related modulation of peripheral N-methyl-d-aspartate (NMDA) receptor activity and/or expression was tested by examining afferent fiber discharge in response to masseter injection of NMDA and the expression of NR2A/B subunits by masseter ganglion neurons in male and female rats. The results showed that injection of NMDA into the masseter muscle evoked discharges in putative mechanonociceptive afferent fibers and increased blood pressure that was concentration-dependent, however, a systemic action of NMDA appeared responsible for increased blood pressure. NMDA-evoked afferent discharge was significantly greater in female than in male rats, was positively correlated with plasma estrogen levels in females and was significantly greater in ovariectomized female rats treated with a high dose (5 mug/day) compared with a low dose (0.5 mug/day) of estrogen. Pre-treatment of high dose estrogen-treated-ovariectomized female rats with the Src tyrosine kinase inhibitor PP2 did not affect NMDA-evoked afferent discharge. NMDA-evoked afferent discharge was attenuated by the antagonists ketamine and ifenprodil, which is selective for NR2B containing NMDA receptors. Fewer masseter ganglion neurons expressed the NR2A (16%) subunit as compared with the NR2B subunit (38%), which was expressed at higher frequencies in intact female (46%) and high dose estrogen-treated ovariectomized female (60%) rats than in male (31%) rats. Taken together, these results suggest that sex-related differences in NMDA-evoked masseter afferent discharge are due, at least in part, to an estrogen-mediated increase in expression of peripheral NMDA receptors by masseter ganglion neurons in female rats.

HDAC6 plays a central role in the recruitment of protein aggregates for lysosomal degradation and is a promising target for combination therapy with proteasome inhibitors in multiple myeloma. Pharmacologically displacing ubiquitin from the zinc-finger ubiquitin-binding domain (ZnF-UBD) of HDAC6 is an underexplored alternative to catalytic inhibition. Here, we present the discovery of an HDAC6 ZnF-UBD-focused chemical series and its progression from virtual screening hits to low micromolar inhibitors. A carboxylate mimicking the C-terminal extremity of ubiquitin, and an extended aromatic system stacking with W1182 and R1155, are necessary for activity. One of the compounds induced a conformational remodeling of the binding site where the primary binding pocket opens up onto a ligand-able secondary pocket that may be exploited to increase potency. The preliminary structure-activity relationship accompanied by nine crystal structures should enable further optimization into a chemical probe to investigate the merit of targeting the ZnF-UBD of HDAC6 in multiple myeloma and other diseases.

Background Atrial fibrillation (AF) ablation is a complex procedure, generally requiring at least one overnight hospital stay. We investigated the safety and feasibility of early mobilization and same‐day discharge following streamlined peri‐ablation management for AF. Methods From 2014, we offered same‐day discharge to selected patients who underwent uncomplicated AF ablation on the morning lists, with ultrasound‐guided femoral access, uninterrupted warfarin or minimal interruption in novel oral anticoagulants, and reversal of intraprocedural heparin with protamine. Patients were discharged 6‐8 h postprocedure and offered access to a dedicated nurse helpline. Results Of 1599 AF ablation cases performed from April 2014 to March 2017, 811 (50.7%) were performed on the morning lists and 169/811 (20.8%) were discharged on the same day. Excluding 26 research cases, 1/143 (0.7%) had transient right phrenic nerve palsy and five (3.5%) cases experienced minor problems that did not preclude same‐day discharge; three (2.1%) needed rehospitalization postdischarge: one for pericarditic chest pain and two for nausea/vomiting. Compared to 642 overnight cases, day‐case procedures were shorter, more likely to be redos, to be performed under sedation rather than general anesthesia, and less likely to involve linear lesions and electrical cardioversion. There were no significant differences in patient age, gender, body mass index, CHA2DS2‐VASc, in preprocedural anticoagulation regimen (warfarin vs novel anticoagulants vs no anticoagulation) and in choice of ablation method (cryoballoon vs radiofrequency). Conclusions Selective same‐day discharge after AF ablation is safe and feasible using a streamlined peri‐procedural care protocol. Wider adoption can potentially reduce health‐care costs while improving patient experience.

There is evidence that elevated tissue concentrations of glutamate may contribute to pain and sensitivity in certain musculoskeletal pain conditions. In the present study the food additive monosodium glutamate (MSG) was injected intravenously into rats to determine whether it could significantly elevate interstitial concentrations of glutamate in the masseter muscle and whether MSG administration could excite and/or sensitize slowly conducting masseter afferent fibers through Nmethyl-D-aspartate (NMDA) receptor activation. The interstitial concentration of glutamate after systemic injection of isotonic phosphate-buffered saline (control) or MSG (10 and 50 mg/kg) was measured with a glutamate selective biosensor. The pre-injection baseline interstitial concentration of glutamate in the rat masseter muscle was 24±11 μM. Peak interstitial concentration after injection of 50 mg/kg MSG was 63±18 μM and remained elevated above baseline for ~18 minutes In vivo single unit recording experiments were undertaken to assess the effect of MSG (50 mg/kg) on masseter afferent fibers. Injection of MSG evoked a brief discharge in one afferent fiber, and significantly decreased (~25%) the average afferent mechanical threshold (n=10) during the first 5 min after injection of MSG. Intravenous injection of ketamine (1 mg/kg), 5 minutes prior to MSG, prevented the MSG-induced decreases in the mechanical threshold of masseter afferent fibers. The present results indicate that a 2-3 fold elevation in interstitial glutamate levels in the masseter muscle is sufficient to excite and induce afferent mechanical sensitization through NMDA receptor activation. These findings suggest that modest elevations of interstitial glutamate concentration could alter musculoskeletal pain sensitivity in humans.