The neurodegenerative effects of Parkinson’s disease (PD) are marked by a selective loss of dopaminergic (DA) neurons. Epidemiological studies suggest that chronic exposure to the pesticide paraquat may increase the risk for PD and DA cell loss. However, combined exposure with additional fungicide(s) including maneb and/or ziram may be required for pathogenesis. To explore potential pathogenic mechanisms, we have developed a Drosophila model of chronic paraquat exposure. We find that while chronic paraquat exposure alone decreased organismal survival and motor function, combined chronic exposure to both paraquat and maneb was required for DA cell death in the fly. To initiate mechanistic studies of this interaction, we used additional genetic reagents to target the ubiquitin proteasome system, implicated in some rare familial forms of PD and the toxic effects of ziram. Genetic inhibition of E1 ubiquitin ligase, but not the proteasome itself, increased DA cell death in combination with maneb but not paraquat. These studies establish a model for long-term exposure to multiple pesticides, and support the idea that pesticide interactions relevant to PD may involve inhibition of protein ubiquitination.

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Background Currently, over half of drug overdose deaths are due to opioids. Opioid alternatives may be prescribed to help curb the opioid epidemic. However, little is known about their efficacy for acute postoperative pain. Methods We studied patients who underwent low-risk outpatient surgery. Perioperatively, all patients were started on an anti-inflammatory bundle consisting of multimodal pain remedies. Opioids were available to the patients postoperatively. Pain scores and opioid use were recorded. Results Over 18 months, 120 patients underwent low-risk outpatient surgery and all used the anti-inflammatory bundle. All patients had a significant decrease in postoperative pain scores (p = 0.001). There was no significant difference in postoperative pain scores between those who followed the anti-inflammatory bundle alone and those who also used opioids (mean 2.2 vs 3.1/10). Twenty-five (21%) patients were using opioids preoperatively and 50 (42%) postoperatively. Of those using opioids preoperatively, six (24%) patients used the anti-inflammatory bundle alone and avoided opioids postoperatively. Conclusions For 58% of our patients, an anti-inflammatory bundle alone provided adequate pain control after a low-risk outpatient operation, such as hernia repair. Our practice uses the anti-inflammatory bundle for all patients. Our goal is to reduce both the need for opioids and the surgeon’s contribution to the opioid epidemic.