Endoplasmic Reticulum (ER) stress has been linked to insulin resistance in multiple tissues but the role of ER stress in skeletal muscle has not been explored. ER stress has also been reported to increase tribbles 3 (TRB3) expression in multiple cell lines. Here, we report that high fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases TRB3 and ER stress markers in skeletal muscle. Overexpression of TRB3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signaling. Incubation of C2C12 cells and mouse skeletal muscle with ER stressors thapsigargin and tunicamycin increases TRB3 and impairs insulin signaling and glucose uptake, effects reversed in cells overexpressing RNAi for TRB3 and in muscles from TRB3 knockout mice. Furthermore, TRB3 knockout mice are protected from high fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that TRB3 mediates ER stress-induced insulin resistance in skeletal muscle.
Background Botulinum toxin injections are effective in relieving focal spasticity resulting from upper motor neuron injuries. Doses approved in the United States for onabotulinumtoxinA and incobotulinumtoxinA are up to 400 units, yet higher doses are often used. Objective To determine differences in risk of adverse events when using higher (>600 units) as compared to lower doses within clinically applicable categories; the difference in adverse events between types of botulinum toxin‐A, and any association of the injection of cervical muscles with increased risk for adverse events. Design and Setting Retrospective analysis of injections performed over a 3‐year period at a freestanding rehabilitation hospital network. Participants Persons with spasticity or dystonia undergoing ona‐ and/or incobotulinumtoxinA injections. Interventions Not applicable. Main Outcome Measures Adverse events for injections were divided into the three dose ranges (≤400 units, 401‐600 units, or > 600 units). Results 889 injections in 342 patients met inclusion criteria with 65% ≤400 units, 21% 401‐600 units, and 14% >600 units. Adverse events were not significantly increased in doses of 401‐600 units relative to ≤400 units (OR 0.97, 95% CI 0.31, 2.98). Doses of toxin over 600 units were associated with significantly increased relative risk of adverse events (OR 2.98, 95% CI 1.12, 8.13). There were no significant differences between adverse event rates for onabotulinumtoxinA or incobotulinumtoxinA (P >.99). Inclusion of cervical muscles in isolation did significantly increase the risk of adverse events (OR 4.21, 95% CI 1.15, 15.46). Conclusion Risk for adverse events were not significantly increased in doses of ona‐ and/or incobotulinumtoxinA up to 600 units, suggesting that the current 400 units upper bound of approved dose may need to be reexamined. Doses above 600 units were found to increase the rate of adverse effects and clinical benefit versus risk should be taken into account. Level of Evidence III.
We present a case of a 71-year-old man with Clostridium difficile infection who underwent fecal transplantation. The patient was found to have a predominantly demyelinating sensorimotor peripheral polyneuropathy upon electrodiagnostic testing. To our knowledge, only one case of peripheral neuropathy after fecal transplantation has previously been reported. Although the exact cause of this patient's neuropathy cannot be confirmed, it has been speculated that the pathophysiology is an immune-mediated process. Given the increasing incidence of C difficile infections and the emergence of fecal transplantation as treatment, it is important to note that peripheral neuropathy is a potential adverse complication.
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