Faculty Bibliography

INTRODUCTION/BACKGROUND:Pulpitis is an inflammation of dental pulp caused by bacterial proliferation near or within pulpal tissues. In advanced stages, when the inflammation is associated with pulp necrosis, pulp preservation is dependent on dental pulp stem cells (DPSCs) that can differentiate into odontoblastlike cells and produce reparative dentin. In this study, we evaluated the influence of sensory neurons through calcitonin gene-related peptide (CGRP) on DPSC viability and proliferation and the ability of DPSCs to differentiate into mineralizing cells. METHODS:Commercially available DPSCs were treated with varying doses of CGRP, and metabolic activity, viability, proliferation, and cell death were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, trypan blue staining, 5-bromo-2'-deoxyuridine cell proliferation assay, and caspase-3 staining, respectively. DPSC differentiation was assessed with alizarin red staining and by quantifying messenger RNA expression of odontoblast makers. RESULTS:CGRP induced a dose-dependent decrease of DPSC metabolic activity that was prevented by the CGRP receptor antagonist CGRP 8-37. The decrease in the proportion of live cells induced by CGRP is associated with a decrease of cell proliferation but not with caspase-3-dependent apoptosis. Interestingly, dexamethasone-induced DPSC differentiation into mineralizing cells was neither inhibited nor enhanced by CGRP treatment. CONCLUSIONS:The neuropeptide CGRP has an inhibitory effect on DPSC proliferation but does not enhance or inhibit the differentiation of DPSCs into mineralizing cells. This suggests that CGRP might negatively influence the ability of DPSCs to contribute to regenerative or tissue repair processes.

Injury of the tooth pulp is excruciatingly painful and yet the receptors and neural circuit mechanisms that transmit this form of pain remain poorly defined in both the clinic and preclinical rodent models. Easily quantifiable behavioral assessment in the mouse orofacial area remains a major bottleneck in uncovering molecular mechanisms that govern inflammatory pain in the tooth. In this study we sought to address this problem using the Mouse Grimace Scale and a novel approach to the application of mechanical Von Frey hair stimuli. We use a dental pulp injury model that exposes the pulp to the outside environment, a procedure we have previously shown produces inflammation. Using RNAscope technology, we demonstrate an upregulation of genes that contribute to the pain state in the trigeminal ganglia of injured mice. We found that mice with dental pulp injury have greater Mouse Grimace Scores than sham within 24 hours of injury, suggestive of spontaneous pain. We developed a scoring system of mouse refusal to determine thresholds for mechanical stimulation of the face with Von Frey filaments. This method revealed that mice with a unilateral dental injury develop bilateral mechanical allodynia that is delayed relative to the onset of spontaneous pain. This work demonstrates that tooth pain can be quantified in freely behaving mice using approaches common for other types of pain assessment. Harnessing these assays in the orofacial area during gene manipulation should assist in uncovering mechanisms for tooth pulp inflammatory pain and other forms of trigeminal pain.

BACKGROUND:Pain descriptors capture the multidimensional nature of pain and can elucidate underlying pathophysiological mechanisms. This study determined whether the pain descriptors chosen by subjects experiencing acute dental pain associate with the outcomes of two commonly performed dental sensory tests. The goal of the study is to clarify whether pain descriptors are useful in discriminating the underlying biological processes contributing to dental pain. METHODS:Participants (n= 228) presenting with acute toothache underwent standardized clinical dental sensory testing and described their pain in reference to 22 pain quality descriptors. Univariate and 2-way ANOVA determined the relationship between groups defined by cold detection (positive or negative) and percussion hypersensitivity (painful or not) on the affected tooth, and pain descriptor reporting. RESULTS:Subjects experiencing painful toothache most frequently reported evoked pain to temperature and chewing, and pain descriptors such as "throbbing" and "aching". They also reported neuropathic pain descriptors such as "tingling" and "electric shock". Subjects who detected a cold stimulus (thermal) on the affected tooth, frequently reported high intensity paroxysmal shooting pain compared to those that did not detect cold. By contrast, patients with percussion (mechanical) hypersensitivity on the affected tooth, reported higher levels of global pain intensity at rest and in function, and reported significantly higher intensity "radiating" and "throbbing" pain, than subjects with non-painful percussion. CONCLUSIONS:The reporting of neuropathic pain descriptors by subjects experiencing acute toothache was more frequent than expected, suggesting that neuropathic mechanisms could contribute to typical toothache pain. Subjects experiencing toothache with mechanical hypersensitivity experience more intense pain overall. This article is protected by copyright. All rights reserved.

OBJECTIVE:To compare the clinicopathologic features and survival outcomes of neuroendocrine tumor of the uterine corpus (NET-U) to endometrioid type endometrial carcinoma (EC). METHODS:From 1993 to 2012, the Surveillance, Epidemiology and End Results cancer registry was queried for women diagnosed with EC or NET-U. Data regarding stage, grade, presence of extra-uterine disease, lymph node metastasis, receipt of adjuvant radiation, surgical intervention and overall survival (OS) was extracted. Chi-square tests, t-tests and Kaplan Meir curves were used for statistical analysis. RESULTS:A total of 98,363 patients were identified: 98,245 with EC and 118 with NET-U. The mean age at diagnosis for EC was 61.7 years and 64.8 years for NET-U (p=0.01). NET-U cases were more likely to be poorly differentiated (97.0% vs. 15.6%; p≤0.01) and have nodal metastasis (56.4% vs. 11.1%; p≤0.01) when compared to EC. Presence of extrapelvic disease at the time of diagnosis was observed more frequently in NET-U compared to EC, 49.1% vs. 4.8%, respectively (odds ratio=18; 95% confidence interval=13.1-27.2; p≤0.01). Significant improvement in OS was observed in NET-U patient who received radiation (OS: 7.7 vs. 3.3 years; p≤0.01) or underwent surgical management (5.6 vs. 0.9 years; p≤0.01). The OS for EC was 14.4 vs. 4.6 years for NET-U (p≤0.01). CONCLUSION/CONCLUSIONS:NET-U represents an aggressive form of uterine malignancy. When compared to EC, patients with NET-U present at more advanced stage, have more frequent extra-uterine disease and lower OS.

BACKGROUND:Primary gynecologic neuroendocrine tumors are uncommon malignant neoplasms associated with poor prognosis. Clinically, these tumors present a significant challenge because of the lack of standardized management guidelines. OBJECTIVE:The objective of this study is to evaluate the clinicopathologic features, incidence, and survival trends in gynecologic neuroendocrine tumors. MATERIALS AND METHODS:Tests, Pearson correlation, and Kaplan-Meier curves were used for statistical analysis. RESULTS:In all, 559 cases of gynecologic neuroendocrine tumors were identified during the study period: 242 cervical, 160 ovarian, 118 uterine, and 39 vulvar/vaginal. The majority of patients in all subsets of gynecologic neuroendocrine tumors presented with poorly differentiated tumors, extrauterine disease spread, and advanced-stage disease. Poorly differentiated tumors represented 65.0% of cervical tumors, 45.3% of ovarian tumors, and 57.4% of uterine tumors. Extrauterine disease at the time of diagnosis was present in the case of 66.9% of cervical tumors, 83.5% of ovarian tumors, and 83.6% of uterine tumors. The overall incidence of gynecologic neuroendocrine tumors increased 4-fold during the study period, from 0.3 in 1987 to 1.30 per million in 2012. The study period was divided into two 13-year periods (1987-1999 and 2000-2012) for time trend mean survival analysis. We observed no significant change in overall survival across all gynecologic neuroendocrine tumor subtypes. The mean survival time of cervical neuroendocrine tumors was 74.3 vs 45.4 months (P = .31), ovarian neuroendocrine tumors 47.8 vs 41.2 months (P = .56), and uterine neuroendocrine tumors 42.9 vs 47.7 months (P = .44) for each time period, respectively. CONCLUSION:Neuroendocrine tumors of the gynecologic tract are uncommon aggressive malignancies. These poorly differentiated tumors present at advanced stage, with a high incidence of extrauterine disease. Despite 25 years of advances in cancer therapy, we observed no improvement in overall survival.

Sensory neurons innervating the dental pulp have unique morphological and functional characteristics compared to neurons innervating other tissues. Stimulation of dental pulp afferents whatever the modality or intensity of the stimulus, even light mechanical stimulation that would not activate nociceptors in other tissues, produces an intense pain. These specific sensory characteristics could involve receptors of the Transient Receptor Potential channels (TRP) family. In this study, we compared the expression of the cold sensitive receptors TRPM8 and TRPA1 in trigeminal ganglion neurons innervating the dental pulp, the skin of the cheek or the buccal mucosa and we evaluated the involvement of these receptors in dental pulp sensitivity to cold. We showed a similar expression of TRPM8, TRPA1 and CGRP in sensory neurons innervating the dental pulp, the skin or the mucosa. Moreover, we demonstrated that noxious cold stimulation of the tooth induced an overexpression of cFos in the trigeminal nucleus that was not prevented by the genetic deletion of TRPM8 or the administration of the TRPA1 antagonist HC030031. These data suggest that the unique sensory characteristics of the dental pulp are independent to TRPM8 and TRPA1 receptors expression and functionality.