Biophysical Modeling of Dopaminergic Denervation Landscapes in the Striatum Reveals New Therapeutic Strategy.

Parkinson's disease (PD) results from a loss of dopaminergic neurons. What triggers the break-down of neuronal signaling, and how this might be compensated, is not understood. The age of onset, progression and symptoms vary between patients, and our understanding of the clinical variability remains incomplete. In this study, we investigate this, by characterizing the dopaminergic landscape in healthy and denervated striatum, using biophysical modeling. Based on currently proposed mechanisms, we model three distinct denervation patterns, and show how this affect the dopaminergic network. Depending on the denervation pattern, we show how local and global differences arise in the activity of striatal neurons. Finally, we use the mathematical formalism to suggest a cellular strategy for maintaining normal dopamine (DA) signaling following neuronal denervation. This strategy is characterized by dual enhancement of both the release and uptake capacity of DA in the remaining neurons. Overall, our results derive a new conceptual framework for the impaired dopaminergic signaling related to PD and offers testable predictions for future research directions.

Early postoperative recovery after peri-acetabular osteotomy: A double-blind, randomised single-centre trial of 48 vs. 8 mg dexamethasone.

BACKGROUND: Peri-acetabular osteotomy is the joint-preserving treatment of choice in young adults with hip dysplasia but is associated with intense pain and high opioid consumption postoperatively. OBJECTIVES: To investigate whether 48 mg of pre-operative dexamethasone was superior to a standard dose of 8 mg on reducing pain in the immediate postoperative phase. DESIGN: A randomised, double-blind trial. SETTING: Single-centre, primary facility. May 2017 to August 2019. PATIENTS: At least 18 years undergoing peri-acetabular osteotomy. INTERVENTIONS: Patients were randomised 1 : 1 to 48 or 8 mg dexamethasone intravenous (i.v.) as a single pre-operative injection. All patients received a standardised peri-operative protocol, including pre-operative acetaminophen and gabapentin, total i.v. anaesthesia and local anaesthetic catheter based wound administration. MAIN OUTCOME MEASURE: Number of patients with moderate/severe pain [>3 on a numeric rating scale (NRS)] in the immediate postoperative phase. RESULTS: Sixty-four patients (32 in each group) were included, and their data analysed. At some point from tracheal extubation until transfer to the ward, the NRS was more than 3 in 75% (24/32) of the 48 mg group and in 66% (21/32) in the 8 mg group, odds ratio 1.571 (95% CI, 0.552 to 4.64), P = 0.585. Patients in the 48 mg group received less opioid [cumulative rescue analgesics, oral morphine equivalents (OMEQ)] during postoperative days 0-4: median [IQR] OMEQ was 36 [15 to 85] mg vs. 79 [36 to 154] mg in the 48 and 8 mg group, respectively, P = 0.034. There were no statistically significant differences regarding complications, rate of infections or readmissions. CONCLUSION: Forty-eight milligram of dexamethasone did not reduce pain in the immediate postoperative phase compared with an 8 mg dose. We observed insignificantly lower pain scores and significantly lower cumulated opioid requirements in the 48 mg group during the first four postoperative days. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03161938, EudraCT (2017-000544-1).