Genetic and Environmental Factors in Parkinson's Disease Converge on Immune Function and Inflammation.

Idiopathic Parkinson's disease (iPD) is a movement disorder characterized by the degeneration of dopaminergic neurons and aggregation of the protein α-synuclein. Patients with iPD vary in age of symptom onset, rate of progression, severity of motor and non-motor symptoms, and extent of central and peripheral inflammation. Genetic and environmental factors are believed to act synergistically in iPD pathogenesis. We propose that environmental factors (pesticides and infections) increase the risk for iPD via the immune system and that the role of PD risk genes in immune cells is worthy of investigation. This review highlights the major PD-relevant genes expressed in immune cells and key environmental factors that activate immune cells and, alone or in combination with other factors, may contribute to iPD pathogenesis. By reviewing these interactions, we seek to enable the future development of immunomodulatory approaches to prevent or delay onset of iPD. © 2020 International Parkinson and Movement Disorder Society.

The second generation mixed lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced nigral dopaminergic neuron loss.

Dopaminergic neurons express mixed lineage kinases which regulate the expression of cell death genes. In Parkinson's disease, cell death via apoptosis is prevalent, and previous work testing mixed lineage kinase inhibitors in animal models suggested the inhibitors had some neuroprotective potential. CLFB-1134 is a new, brain-penetrant inhibitor specific for MLK3, tested here in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of dopaminergic depletion and nigral neuron death in mice. After ensuring that treatment with CLFB-1134 did not alter conversion of MPTP to MPP+, we demonstrated CLFB-1134's inhibition of MLK3 and neuroprotective efficacy. Specifically we evaluated the integrity of the nigrostriatal dopamine system following MPTP by assessing protein expression, high performance liquid chromatography, and immunohistology with stereology. We found that CLFB-1134 achieves protection of striatal dopaminergic terminals and nigral cell bodies when dosed simultaneously or following MPTP treatment. By preventing phosphorylation of JNK and other downstream targets of MLK3, CLFB-1134 protects against the neurotoxin MPTP. Inhibition of MLK3 may be a valid target for future work investigating treatment of Parkinson's disease.

Evolving management strategies in esophageal perforation: surgeons using nonoperative techniques to improve outcomes.

BACKGROUND: Management of acute esophageal perforation continues to evolve. We hypothesized that treatment of these patients at a tertiary referral center is more important than beginning treatment within 24 hours, and that the evolving application of nonsurgical treatment techniques by surgeons would produce improved outcomes. STUDY DESIGN: Demographics and outcomes of patients treated for esophageal perforation from 1989 to 2009 were recorded in an Institutional Review Board-approved database. Retrospective outcomes assessment was done for 5 separate time spans, including timing and type of treatment, length of stay (LOS), complications, and mortality. RESULTS: Eighty-one consecutive patients presented with acute esophageal perforation. Their mean age was 64 years, and 55 patients (68%) had American Society of Anesthesiologists levels 3 to 5; 59% of the study population was referred from other hospitals; 48 patients (59%) were managed operatively, 33 (41%) nonoperatively, and 10 patients with hybrid approaches involving a combination of surgical and interventional techniques; 57 patients (70%) were treated <24 hours and 24 (30%) received treatment >24 hours after perforation. LOS was lower in the early-treatment group; however, there was no difference in complications or mortality. Nonoperative therapy increased from 0% to 75% over time. Nonsurgical therapy was more common in referred cases (48% vs 30%) and in the >24 hours treatment group (46% vs 38%). Over the period of study, there were decreases in complications (50% to 33%) and LOS (18.5 to 8.5 days). Mortality for the entire series involved 3 patients (4%): 2 operative and 1 nonoperative. CONCLUSIONS: Results from our series indicate that referral to a tertiary care center is as important as treatment within 24 hours. An experienced surgical management team using a diversified approach, including selective application of nonoperative techniques, can expect to shorten LOS and limit complications and mortality.