A chronic neuroinflammatory event mediated by persistent microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson's disease (PD). Identification of key targets contributing to sustained microglia activation and the regulation of these targets could provide potential treatments to halt disease progression. In this study, we show that microglial Kv1.3, a voltage‐gated potassium channel, was highly upregulated in aggregated α‐synuclein (αSyn)‐stimulated primary microglia cultures, animal models of PD, as well as in human PD postmortem samples. Importantly, patch‐clamp electrophysiological studies confirm that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. We further demonstrate that Fyn, a non‐receptor tyrosine kinase, modulated the transcriptional upregulation of microglial Kv1.3. Using multiple state‐of‐the‐art techniques, including DuoLink PLA technology, we show that Fyn directly binds to Kv1.3 and post‐translationally modified its channel activity. Furthermore, we demonstrate the functional relevance of Kv1.3 with respect to neuroinflammation by using Kv1.3 knockout (KO) microglia and the Kv1.3‐specific pharmacological inhibitor PAP‐1. Kv1.3 KO microglial cells treated with aggregated αSyn produced fewer pro‐inflammatory cytokines. PAP‐1 significantly attenuated aggregated αSyn‐induced inflammation in both a microglial cell line and primary microglia, thus highlighting Kv1.3's importance in inflammation. Oral administration of PAP‐1 significantly inhibited MPTP‐induced neurodegeneration and inflammation in vivo. PAP‐1 also significantly reversed behavioral deficits and dopamine loss in MitoPark mice, a progressive model of PD. Our results collectively show that the Fyn‐dependent Kv1.3 channel plays an important role in inflammation in PD and has potential therapeutic implications. Support or Funding Information ES026892, NS088206, NS100090, Llyod Chair This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Control of LPR may be an essential component in the successful management of OME in pediatric patients. Pepsin/pepsinogen analysis in effusions of children, using ELISA, can be considered a reliable marker for assessment of reflux in children with OME.

The organophosphate (OP) pesticide chlorpyrifos (CPF), used in agricultural settings, induces developmental and neurological impairments. Recent studies using in vitro cell culture models have reported CPF exposure to have a positive association with mitochondria-mediated oxidative stress response and dopaminergic cell death; however, the mechanism by which mitochondrial reactive oxygen species (ROS) contribute to dopaminergic cell death remains unclear. Therefore, we hypothesized that STAT1, a transcription factor, causes apoptotic dopaminergic cell death via mitochondria-mediated oxidative stress mechanisms. Here we show that exposure of dopaminergic neuronal cells such as N27 cells (immortalized murine mesencephalic dopaminergic cells) to CPF resulted in a dose-dependent increase in apoptotic cell death as measured by MTS assay and DNA fragmentation. Similar effects were observed in CPF-treated human dopaminergic neuronal cells (LUHMES cells), with an associated increase in mitochondrial dysfunction. Moreover, CPF (10 μM) induced time-dependent increase in STAT1 activation coincided with the collapse of mitochondrial transmembrane potential, increase in ROS generation, proteolytic cleavage of protein kinase C delta (PKCδ), inhibition of the mitochondrial basal oxygen consumption rate (OCR), with a concomitant reduction in ATP-linked OCR and reserve capacity, increase in Bax/Bcl-2 ratio and enhancement of autophagy. Additionally, by chromatin immunoprecipitation (ChIP), we demonstrated that STAT1 bound to a putative regulatory sequence in the NOX1 and Bax promoter regions in response to CPF in N27 cells. Interestingly, overexpression of non-phosphorylatable STAT1 mutants (STAT1Y701F and STAT1S727A) but not STAT1 WT construct attenuated the cleavage of PKCδ and ultimately cell death in CPF-treated cells. Furthermore, small interfering RNA knockdown demonstrated STAT1 to be a critical regulator of autophagy and mitochondria-mediated proapoptotic cell signaling events after CPF treatment in N27 cells. Finally, oral administration of CPF (5 mg/kg) in postnatal rats (PNDs 27-61) induced motor deficits, and nigrostriatal dopaminergic neurodegeneration with a concomitant induction of STAT1-dependent proapoptotic cell signaling events. Conversely, co-treatment with mitoapocynin (a mitochondrially-targeted antioxidant) and CPF rescued motor deficits, and restored dopaminergic neuronal survival via abrogation of STAT1-dependent proapoptotic cell signaling events. Taken together, our study identifies a novel mechanism by which STAT1 regulates mitochondria-mediated oxidative stress response, PKCδ activation and autophagy. In this context, the phosphorylation of Tyrosine 701 and Serine 727 in STAT1 was found to be essential for PKCδ cleavage. By attenuating mitochondrial-derived ROS, mitoapocynin may have therapeutic applications for reversing CPF-induced dopaminergic neurotoxicity and associated neurobehavioral deficits as well as neurodegenerative diseases.

Aspiration and tube drainage have no significant difference in treating patients with first episode of PSP regarding recurrence. Aspiration reduced hospitalization days when compared with tube drainage. Thoracotomy with mechanical pleurodesis and VATS with or without pleurodesis are not significantly different in preventing recurrence in patients with recurrent or persistent PSP. VATS alone reduced complications compared with others treatments except for thoracotomy with abrasion.

Abstract. Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. It affects the locomotor system, leading to a final severe disability through degeneration of dopaminergic neurons. Despite several therapeutic approaches used, no treatment has been proven to be effective; however, cell therapy may be a promising therapeutic method. In addition, the use of the intranasal (IN) route has been advocated for delivering various therapies to the brain. In the present study, the IN route was used for administration of mesenchymal stem cells (MSCs) in a mouse model of PD, with the aim to evaluate IN delivery as an alternative route for cell based therapy administration in PD. The PD model was developed in C57BL/6 mice using intraperitoneal rotenone administration for 60 consecutive days. MSCs were isolated from the mononuclear cell fraction of pooled bone marrow from C57BL/6 mice and incubated with micrometer-sized iron oxide (MPIO) particles. For IN administration, we used a 20 µl of 5x10 5 cell suspension. Neurobehavioral assessment of the mice was performed, and after sacrifice, brain sections were stained with Prussian blue to detect the MPIO-labeled MSCs. In addition, immunohistochemical evaluation was conducted to detect tyrosine hydroxylase (TH) antibodies in the corpus striatum and dopaminergic neurons in the substantia nigra pars compacta (SNpc). The neurobehavioral assessment revealed progressive deterioration in the locomotor functions of the rotenone group, which was improved following MSC administration. Histopathological evaluation of brain sections in the rotenone+MSC group revealed successful delivery of MSCs, evidenced by positive Prussian blue staining. Furthermore, rotenone treatment led to significant decrease in dopaminergic neuron number in SNpc, as well as similar decrease in the corpus striatum fiber density. By contrast, in animals receiving IN administration of MSCs, the degeneration caused by rotenone treatment was significantly counteracted. In conclusion, the present study validated that IN delivery of MSCs may be a potential safe, easy and cheap alternative route for stem cell treatment in neurodegenerative disorders.