Search

Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.

International audience

International audience; A new electromechanical press for fuel pellet manufacturing was built last year in partnership between CEA-Marcoule and Champalle$^{Alcen}$. This press was developed to shape pellets in a hot cell via remote handling. It has been qualified to show its robustness and to optimize the compaction cycle, thus obtaining a better sintered pellet profile and limiting damage. We will show you how 400 annular pellets have been products with good geometry's parameters, based on press settings management. This results are due to according good phenomenological pressing knowledge with Finite Element Modeling calculation. Therefore, during die pressing, a modification in the punch displacement sequence induces fluctuation in the axial distribution of frictional forces. The green pellet stress and density gradients are based on these frictional forces between powder and tool, and between grains in the powder, influencing the shape of the pellet after sintering. The pellet shape and diameter tolerances must be minimized to avoid the need for grinding operations. To find the best parameters for the press settings, which enable optimization, FEM calculations were used and different compaction models compared to give the best calculation/physical trial comparisons. These simulations were then used to predict the impact of different parameters when there is a change in the type of powder and the pellet size, or when the behavior of the press changes during the compaction time. In 2016, it is planned to set up the press in a glove box for UO$_2$ manufacturing qualification based on our simulation methodology, before actual hot cell trials in the future.

Background and Purpose: Selective nociceptor fibre block is achieved by introducing the cell membrane impermeant sodium channel blocker lidocaine N-ethyl bromide (QX-314) through transient receptor potential V1 (TRPV1) channels into nociceptors. We screened local anaesthetics for their capacity to activate TRP channels, and characterized the nerve block obtained by combination with QX-314. Experimental Approach: We investigated TRP channel activation in dorsal root ganglion (DRG) neurons by calcium imaging and patch-clamp recordings, and cellular QX-314 uptake by MS. To characterize nerve block, compound action potential (CAP) recordings from isolated nerves and behavioural responses were analysed. Key Results: Of the 12 compounds tested, bupivacaine was the most potent activator of ruthenium red-sensitive calcium entry in DRG neurons and activated heterologously expressed TRPA1 channels. QX-314 permeated through TRPA1 channels and accumulated intracellularly after activation of these channels. Upon sciatic injections, QX-314 markedly prolonged bupivacaine's nociceptive block and also extended (to a lesser degree) its motor block. Bupivacaine's blockade of C-, but not A-fibre, CAPs in sciatic nerves was extended by co-application of QX-314. Surprisingly, however, this action was the same in wild-type, TRPA1-knockout and TRPV1/TRPA1-double knockout mice, suggesting a TRP-channel independent entry pathway. Consistent with this, high doses of bupivacaine promoted a non-selective, cellular uptake of QX-314. Conclusions and Implications Bupivacaine, combined with QX-314, produced a long-lasting sensory nerve block. This did not require QX-314 permeation through TRPA1, although bupivacaine activated these channels. Regardless of entry pathway, the greatly extended duration of block produced by QX-314 and bupivacaine may be clinically useful.

The Edmonton Regional Palliative Care Program was established in July 1995 to measure the access of patients with terminal cancer to palliative care services, decrease the number of cancer-related deaths in acute care facilities and increase the participation of family physicians in the care of terminally ill patients. In this retrospective study the authors compared the pattern of care and site of deaths before establishment of the program (1992/93) and during its second year of operation (1996/97). Significantly more cancer-related deaths occurred in acute care facilities in 1992/93 than in 1996/97 (86% [1119/1304] v. 49% [633/1279]) (p < or = 0.001). The number of inpatient days decreased, from 24,566 in 1992/93 to 6960 in 1996/97. More cancer patients saw a palliative care consult team in 1996/97 than in 1992/93 (82% v. 22%). The shift from deaths in acute care facilities to palliative hospices suggests that the establishment of an integrated palliative care program has increased access of patients with terminal cancer to palliative care.

Increasingly, patients with cancer are dying at home and in continuing care facilities. The purpose of bus rounds is to provide continuing education to physicians and nurse palliative care consultants, to familiarize family physicians with the delivery of care in these settings and to educate family medicine and specialty residents as well as medical students. A total of 18 4-hour bus rounds took place during 1996. A mean of 13 (range 9 to 17) participants attended, to discuss a mean of 3.5 (range 2 to 4) patients and 4.5 (range 3 to 8) journal articles. A questionnaire was filled out anonymously by 18 first-time medical and 24 first-time nursing participants. On a scale from 1 (worst) to 5 (best), they gave the rounds an overall rating of 5 (range 4 to 5). The mean cost per round was $245.40. The authors conclude that bus rounds provide an opportunity for intensive exposure to community-based learning for physicians, nurses and students and are highly satisfactory from the participants' perspective.