Use of Shared Faculty in U.S. and Canadian Dental Schools

Dental schools are facing substantial financial challenges and a shortage of faculty members. One solution to address these issues has been to hire “shared” faculty members, i.e., faculty members whose primary appointment is at one institution who are hired by another institution to teach a course or part of a course. This is a controversial concept. A survey of academic deans at U.S. and Canadian dental schools was conducted for this study; thirty-nine (54 percent) of the seventy-two academic deans completed the online survey. This survey found that the use of shared faculty members is not rare amongst U.S. and Canadian dental schools and that the opinions of the academic deans about the use of shared faculty members ranged widely—from strong support to strong disapproval. Using shared faculty members has advantages and disadvantages for students, the shared faculty members, and both institutions. Many of the disadvantages could be potentially minimized by stakeholders’ working together to develop collaborative arrangements. Networks could be developed in which institutions coordinate hiring of shared faculty members based on what expertise is needed. Financial challenges and shortages of faculty members are unlikely to be resolved in the near future, but use of shared faculty members is one promising approach to begin to meet these challenges

Mechanism of Cancer Pain

Cancer pain is a formidable clinical problem, reflecting a complex series of cellular, tissue, and systemic changes that occur during proliferation, invasion, and metastasis. Primary afferent nociceptors are modulated by a number of mediators released by cancer cells, and immune cells that are drawn into the cancer further complicate pain perception. The peripheral neuropathic changes and the influence of tumors upon neurons in the elaboration of pain and central sensitization are beginning to be understood in some detail. The judicious design and exploitation of animal models continue to help researchers unravel the complexities of cancer-evoked pain

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors

Compound 52 attenuated CFA-induced sensitization of C-fiber nociceptors to heat stimuli.

<p>Graphs plot number of action potentials (Aps) in response to thermal stimulus of indicated temperature. Administration of vehicle did not alter heat response thresholds in sensitized C-fiber nociceptors (upper panel). By contrast, heat response thresholds of sensitized C-fiber nociceptors were decreased 30 minutes following intravenous injection of compound 52 (lower panel). The two panels represent separate experiments taken from different cohorts of animals. *p < 0.05.</p

<i>In vitro</i> and <i>in vivo</i> properties of aminotriazines used in this study.

<p>Shown for each compound are IC50 on non-inactivated human Nav1.7, IC50 on 20%-inactivated human Nav1.7, and IC50 on 20%-inactivated rat Nav1.7, all taken with patch-clamp electrophysiology; <i>in vitro</i> plasma protein binding; the ratio of brain to plasma concentrations <i>in vivo</i>; whether the compound produced analgesic efficacy in the rat formalin model of pain; and the plasma concentration corresponding to the lowest dose that produced efficacy. IC50s on hNav1.7 were measured with manual patch-clamp electrophysiology; IC50s on rNav1.7 were measured with the PatchXpress® automated electrophysiology platform. Brain to plasma ratios were calculated from concentrations experimentally measured following the formalin test. ND = no data. Analgesic efficacy was determined by a statistically significant (p < 0.05) decrease in formalin-induced flinching for which the same dose did not produce a reduction in movement in the open field assay that obviated the formalin result. Effective [plasma] is the mean (n = 8, except n = 7 for compound E) terminal plasma concentration produced by the lowest effective dose of each compound.</p><p><i>In vitro</i> and <i>in vivo</i> properties of aminotriazines used in this study.</p

Compound 52 reduced the ongoing spontaneous activity of C-fiber nociceptors but not Aδ-fiber nociceptors.

<p>Intravenous injection of compound 52 decreased ongoing spontaneous activity of C-fiber nociceptors sensitized by intraplantar administration of CFA (upper panel). The level of ongoing spontaneous activity of sensitized C-fiber nociceptors was significantly lower following administration of compound 52 than following administration of vehicle, from 12 minutes post-administration on. The attenuation of ongoing spontaneous activity by compound 52 continued until the end of the monitoring period (26 minutes after administration of drug). In contrast, administration of compound 52 did not decrease the level of ongoing spontaneous activity in Aδ-fiber nociceptors when compared to vehicle (lower panel). *p < 0.05; **p < 0.01.</p

Compound 52 attenuated CFA-induced sensitization of C-fiber nociceptors but not Aδ-fiber nociceptors to mechanical stimuli.

<p><b>A</b>, Mechanical response thresholds of sensitized C-fiber nociceptors increased at 30 minutes (p = 0.07) and 60 minutes (p < 0.001) following intravenous injection of compound 52. Administration of vehicle did not alter mechanical response thresholds in sensitized C-fiber nociceptors. <b>B</b>, Compound 52 did not attenuate CFA-induced sensitization of Aδ-fiber nociceptors, as mechanical response thresholds were not significantly different from pre-drug levels following administration of compound 52 (lower panel). ***p < 0.001.</p

Testing of representative aminotriazine compound A in the formalin model of pain.

<p><b>A</b>, Timecourse of flinching binned every minute for each of five cohorts: vehicle, positive control morphine (2 mg/kg), and 10 mg/kg, 30 mg/kg, and 60 mg/kg compound A. All cohorts were n = 8 animals, except morphine was n = 5. <b>B</b>, Total flinches in phase 2 (10 minutes to 40 minutes) (bars and left y-axis) and terminal plasma concentrations of compound A (symbols and right y-axis). Total reduction in phase 2 flinching as percent of vehicle: morphine 68%, 10 mg/kg compound A 32%, 30 mg/kg compound A 66%, 60 mg/kg compound A 85%. Terminal plasma and brain concentrations of compound A: for the 10 mg/kg dose plasma 3.02 uM ± 0.21 μM and brain 0.28 μM ± 0.029 μM; for the 30 mg/kg dose plasma 8.07 μM ± 0.65 μM and brain 0.88 μM ± 0.14 μM; for the 60 mg/kg dose plasma 13.5 μM ± 1.60 μM and brain 1.54 μM ± 0.10 μM (for each dose cohort mean ± SEM, plasma n = 8, brain n = 4). <b>C</b>, Effects of compound A on spontaneous locomotor behaviors. Graph shows basic movement counts (bars and left y-axis) and terminal plasma concentrations (symbols and right y-axis) following indicated doses of compound A. Total percent reduction and the corresponding terminal plasma concentrations: for the 10 mg/kg dose -4.2% and 2.75 μM ± 0.26 μM; for the 30 mg/kg dose 14% and 5.53 μM ± 0.57 μM; for the 60 mg/kg dose 46% and 13.0 μM ± 1.7 μM (brains were not analyzed) (for each dose cohort mean ± SEM, n = 8). **p < 0.01, ***p < 0.001.</p