Faculty Bibliography

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation.

CONTEXT: Fatigue is the most common symptom in oncology patients during chemotherapy (CTX). Little is known about the predictors of interindividual variability in initial levels and trajectories of morning fatigue severity in these patients. OBJECTIVES: An evaluation was done to determine which demographic, clinical, and symptom characteristics were associated with initial levels as well as the trajectories of morning fatigue and to compare findings with our companion paper on evening fatigue. METHODS: A sample of outpatients with breast, gastrointestinal, gynecological, and lung cancer (N=586) completed demographic and symptom questionnaires a total of six times over two cycles of CTX. Fatigue severity was evaluated using the Lee Fatigue Scale. Hierarchical linear modeling (HLM) was used to answer the study objectives. RESULTS: A large amount of interindividual variability was found in the morning fatigue trajectories. A piecewise model fit the data best. Patients with higher body mass index (BMI), who did not exercise regularly, with a lower functional status, and who had higher levels of state anxiety, sleep disturbance and depressive symptoms, reported higher levels of morning fatigue at enrollment. Variations in the trajectories of morning fatigue were predicted by the patients' ethnicity and younger age. CONCLUSION: The modifiable risk factors that were associated with only morning fatigue were BMI, exercise, and state anxiety. Modifiable risk factors that were associated with both morning and evening fatigue included functional status, depressive symptoms, and sleep disturbance. Using this information, clinicians can identify patients at higher risk for more severe morning fatigue and evening fatigue, provide individualized patient education, and tailor interventions to address the modifiable risk factors.

Purpose: The Penumbra RubyTM Coil system (Ruby) is a new generation of larger (.020) platinum detachable coils designed for peripheral arterial and venous embolization. Recent literature has shown the importance of packing density on occlusion stability and recanalization rates.1 Reported herein are preliminary results from the multicenter Aneurysm Coiling Efficiency (ACE) registry on the packing density and resulting long term outcomes of patients with peripheral embolizations by Ruby. Materials and Methods: Between Mar 2012 and Sep 2014, data from 62 Ruby cases at 12 centers were collected: 11 splenic artery aneurysms, 9 renal artery aneurysms, 1 hepatic artery aneurysm, 2 mesenteric artery aneurysms, 7 AVMs, 6 fistulae, 3 varices, and 23 vessel sacrifices. Results: Mean Ruby placed per aneurysm was 9 with a mean packing density of 26% in the aneurysms/malformations cases (N=39). Aneurysm volumes at the splenic and renal arteries were 110 to 21,500 mm³ and neck width was from 4 to 16 mm. Mean fluoroscopy time was 29 min. Among the 21 aneurysm cases with post-treatment occlusion data, 100% achieved Raymond Scale Class I occlusion. Of the 10 patients with 6-month follow up data, 100% displayed complete Class I occlusion with 0% recanalization. The remaining 11 patients are expected to complete their 6-month follow up at time of presentation.Of the 23 peripheral vessel sacrifices, 100% had successful coil embolization. Mean number of Ruby placed was 4 with a mean fluoroscopy time of 22 min. Out of the 11 patients with 6-month follow up data, 100% displayed stable occlusion. No procedural SAEs were recorded in any of the 62 cases. Conclusion: Using Ruby in the peripheral vasculature resulted in a high packing density and complete occlusion which remained stable for 6 months. Consistent with the published literature that 24% packing density is optimal to prevent recanalization, these results confirmed an association between high packing density and low recurrence of recanalization.1 Upon further validation, the use of packing density as an index for stable long-term outcome in the treatment of peripheral malformations should be considered, perhaps even emphasized

Differential thermal nociception across inbred mouse strains has genetic determinants. Thermal nociception is largely attributed to the heat/capsaicin receptor TRPV1; however, the contribution of this channel to the genetics of thermal nociception has not been revealed. In this study we compared TRPV1 expression levels and electrophysiological properties in primary sensory neurons and thermal nociceptive behaviors between two (C57BL/6 and BALB/c) inbred mouse strains. Using immunofluorescence and patch-clamp physiology methods, we demonstrated that TRPV1 expression was significantly higher in isolectin B4 (IB4) -positive trigeminal sensory neurons of C57BL/6 relative to BALB/c; the expression in IB4-negative neurons was similar between the strains. Furthermore, using electrophysiological cell classification (current signature method), we showed differences between the two strains in capsaicin sensitivity in IB4-positive neuronal cell types 2 and 13, that were previously reported as skin nociceptors. Otherwise electrophysiological membrane properties of the classified cell types were similar in the two mouse strains. In publicly available nocifensive behavior data and our own behavior data from the using the two mouse strains, C57BL/6 exhibited higher sensitivity to heat stimulation than BALB/c, independent of sex and anatomical location of thermal testing (the tail, hind paw and whisker pad). The TRPV1 selective antagonist JNJ-17203212 inhibited thermal nociception in both strains; however, removing IB4-positive trigeminal sensory neurons with IB4-conjugated saporin inhibited thermal nociception on the whisker pad in C57BL/6, but not in BALB/c. These results suggest that TRPV1 expression levels in IB4-positive type 2 and 13 neurons contributed to differential thermal nociception in skin of C57BL/6 compared to BALB/c.

Cancer pain sends a message. It is frightening to the patient. It heralds progression or recurrence to the oncologist. It is a biological readout of the cancer-nerve interaction for the scientist. Nerves have been considered bystanders within the cancer microenvironment. However, emerging information suggests that nerves are recruited and participate in the carcinogenic process. These newly formed fibers respond to mediators secreted by constituents of the cancer microenvironment. In this manner, these nerves serve as bellwethers and sensors embedded within the cancer. When we rigorously assess patients' cancer pain, we gain insight into the action of cancer. An enhanced understanding of cancer pain offers biological questions that if answered might not only provide relief from cancer pain but might also improve survival.

OBJECTIVE: The aim of this study was to develop a multidimensional metric for assessing quality of life (QoL) in patients with neurofibromatosis type 2 (NF2). STUDY DESIGN: Electronically distributed questionnaire. SETTING: University tertiary care hospital, NF2 support groups. SUBJECTS AND METHODS: Structured interviews with NF2 providers and patients identified relevant domains. Items in each domain were extracted from validated QoL modules, then combined with items unique to NF2 and pretested on NF2 providers and patients. The final 61-item questionnaire was administered electronically to patients with NF2 (N = 118). The form assessed overall QoL and 11 additional domains, including hearing, balance, facial function, vision, oral intake, future uncertainty, psychosocial, cognition, sexual activity, pain, and vocal communication. Responses were compared with reference values for the general population, patients with head and neck cancer, and patients with brain cancer. RESULTS: Overall, QoL in patients with NF2 was lower than that of the general population (P < .01) and similar to that of patients with cancer. Patients with more facial weakness, hearing loss, and imbalance reported significantly lower QoL. However, domains most predictive of overall QoL were psychosocial, future uncertainty, and pain. Compared with patients with head and neck and brain cancer, patients with NF2 demonstrated significantly higher levels of psychosocial stressors, including disease-related anxiety, personal and financial stress, and lack of social support (P < .01). CONCLUSION: Psychosocial stress and pain significantly affect QoL in NF2, indicating that mental health, pain management, and financial counseling could have an important impact on QoL in this population.

OBJECTIVES/HYPOTHESIS: This study investigated the differences between the standard guidelines and the practice patterns of otolaryngologists in managing "penicillin-allergic" patients. A major goal was to identify factors influencing an otolaryngologist's choice of antibiotic. STUDY DESIGN: Cross-sectional survey. METHODS: Four hundred seventy members of the American Society of Pediatric Otolaryngologists (ASPO) and 150 general otolaryngologists from the Florida Society of Otolaryngology (FSO) were surveyed. RESULTS: Ninety-six ASPO members (20.4%) and 22 members of FSO (14.6%) responded. When asked about the management of a pediatric patient with acute otitis media and a history of a nonsevere immunoglobulin E (IgE)-mediated amoxicillin allergy, 54% of ASPO respondents indicated they would initiate guideline-recommended cefdinir, whereas only 27% of FSO respondents chose cefdinir (P = .02). Otolaryngologists who are fellowship trained in pediatrics or have pediatric-focused practices were significantly more likely to prescribe cefdinir. Overall, 57% of respondents indicated that they were familiar with the literature regarding the cross-reactivity of beta-lactams, but only 25% of respondents felt that they could easily differentiate a potentially life-threatening IgE-mediated allergy from a non-IgE-mediated drug intolerance. CONCLUSIONS: The data show differences between the current recommendations and the behavior of otolaryngologists. Pediatric otolaryngologists were more familiar with the guideline-recommended therapy, likely from their frequent exposure to patients requiring a beta-lactam. Nevertheless, most otolaryngologists could benefit from increased awareness of the current literature. Patients may be receiving less than optimal medication management due to a misidentification of those at risk of life- threatening allergic cross-reactions. LEVEL OF EVIDENCE: NA Laryngoscope, 2015.