Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination.

Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.

Financial implications of laparoscopic hot gallbladder service in a nontertiary District General Hospital.

INTRODUCTION: The service of providing index admission laparoscopic cholecystectomy (IALC), as recommended by NIC guidelines, often falls short in nontertiary centres because of a combination of limited resources and financial constraints. METHODS: This retrospective study in a single-centre District General Hospital included 50 patients, eligible to undergo IALC, and calculated potential savings from performing IALC on the day of admission by considering admission tariffs, bed, and operating costs. RESULTS: The IALC was provided in 19 patients (38%), with a mean delay from admission to operation of (median) 3 days. Mean surplus tariff was £1421 and £1571 in IALC and non-IALC groups, respectively. Performing immediate IALC (on the day of admission) for acute cholecystitis (AC) is predicted to increase mean surplus tariff to £2132 per patient, raising total predicted annual surplus by £53 000. Immediate IALC is also predicted to reduce waiting time for day-case LC by freeing up 53 day-case slots, attracting additional £95 600 annually, along with freeing up many inpatient bed days. CONCLUSIONS: This study demonstrates that reduction of preoperative stay in AC by expediting operations in every eligible patient promises significant surplus revenue. Additional advantages include reducing inpatient bed days and freeing up operating lists that are otherwise taken up by patients for interval cholecystectomy.