In the present study, intraplantar carageenan induced increased mechanical allodynia, phosphorylation of PKB/Akt and GluR1 ser 845 (PKA site) as well as GluR1, but not GluR2 movement into neuronal membranes. This change in membrane GluR1/GluR2 ratio is indicative of Ca ++ permeable AMPA receptor insertion. Pain behavior was reduced and biochemical changes blocked by spinal pretreatment, but not post-treatment, with a tumor necrosis factor (TNF) antagonist, Etanercept (100µg). Pain behavior was also reduced by spinal inhibition of phosphatidylinositol 3-kinase (PI-3K) (wortmannin; 1 and 5µg) and LY294002; 50 and 100µg) and Akt (Akt inhibitor IV; 3µg). Phosphorylated Akt was found exclusively in neurons in grey matter and in oligodendrocytes in white matter. Interestingly, this increase was seen first in superficial dorsal horn and α-motor neurons (peak 45 min) and later (peak 2 h post-injection) in deep dorsal horn neurons. Akt and GluR1 phosphorylation, AMPA receptor trafficking and mechanical allodynia were all TNF dependent. Whether phosphorylation of Akt and GluR1 are in series or in parallel or upstream of pain behavior remains to be determined. Certainly, TNF mediated GluR1 trafficking appears to play a major role in inflammatory pain and TNF mediated effects such as these could represent a path by which glia contribute to neuronal sensitization (spinal LTP) and pathological pain.

Patients with advanced-stage laryngeal SCC with T3 and T4a tumors, N0 neck disease, or supraglottic primaries have the greatest chance of survival when treated with primary surgery. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1380-1386, 2016.

IMPORTANCE Patients with cleft palate and other causes of velopharyngeal insufficiency (VPI) suffer adverse effects on social interactions and communication. Measurement of these patient-reported outcomes is needed to help guide surgical and nonsurgical care.OBJECTIVES To further validate the VPI Effects on Life Outcomes (VELO) instrument, measure the change in quality of life (QOL) after speech surgery, and test the association of change in speech with change in QOL. DESIGN, SETTING, AND PARTICIPANTSProspective descriptive cohort including children and young adults undergoing speech surgery for VPI in a tertiary academic center. Participants completed the validated VELO instrument before and after surgical treatment. MAIN OUTCOMES AND MEASURESThe main outcome measures were preoperative and postoperative VELO scores and the perceptual speech assessment of speech intelligibility. The VELO scores are divided into subscale domains. Changes in VELO after surgery were analyzed using linear regression models. VELO scores were analyzed as a function of speech intelligibility adjusting for age and cleft type. The correlation between speech intelligibility rating and VELO scores was estimated using the polyserial correlation.RESULTS Twenty-nine patients (13 males and 16 females) were included. Mean (SD) age was 7.9 (4.1) years (range, 4-20 years). Pharyngeal flap was used in 14 (48%) cases, Furlow palatoplasty in 12 (41%), and sphincter pharyngoplasty in 1 (3%). The mean (SD) preoperative speech intelligibility rating was 1.71 (1.08), which decreased postoperatively to 0.79 (0.93) in 24 patients who completed protocol (P < .01). The VELO scores improved after surgery (P<.001) as did most subscale scores. Caregiver impact did not change after surgery (P = .36). Speech Intelligibility was correlated with preoperative and postoperative total VELO score (P < .01) and to preoperative subscale domains (situational difficulty [VELO-SiD, P = .005] and perception by others [VELO-PO, P = .05]) and postoperative subscale domains (VELO-SiD [P = .03], VELO-PO [P = .003]). Neither the VELO total nor subscale score change after surgery was correlated with change in speech intelligibility.CONCLUSIONS AND RELEVANCE Speech surgery improves VPI-specific quality of life. We confirmed validation in a population of untreated patients with VPI and included pharyngeal flap surgery, which had not previously been included in validation studies. The VELO instrument provides patient-specific outcomes, which allows a broader understanding of the social, emotional, and physical effects of VPI.LEVEL OF EVIDENCE 2.

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