Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms

Non-image related responses to light, such as the synchronization of circadian rhythms to the day/night cycle, are mediated by classical rod/cone photoreceptors and by a small subset of retinal ganglion cells that are intrinsically photosensitive, expressing the photopigment, melanopsin. This raises the possibility that the melanopsin cells may be serving as a conduit for photic information detected by the rods and/or cones. To test this idea, we developed a specific immunotoxin consisting of an anti-melanopsin antibody conjugated to the ribosome-inactivating protein, saporin. Intravitreal injection of this immunotoxin results in targeted destruction of melanopsin cells. We find that the specific loss of these cells in the adult mouse retina alters the effects of light on circadian rhythms. In particular, the photosensitivity of the circadian system is significantly attenuated. A subset of animals becomes non-responsive to the light/dark cycle, a characteristic previously observed in mice lacking rods, cones, and functional melanopsin cells. Mice lacking melanopsin cells are also unable to show light induced negative masking, a phenomenon known to be mediated by such cells, but both visual cliff and light/dark preference responses are normal. These data suggest that cells containing melanopsin do indeed function as a conduit for rod and/or cone information for certain non-image forming visual responses. Furthermore, we have developed a technique to specifically ablate melanopsin cells in the fully developed adult retina. This approach can be applied to any species subject to the existence of appropriate anti-melanopsin antibodies

Contribution of limbic norepinephrine to cannabinoid-induced aversion

RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007)

A Comparison of the Caprini Score With an Institutional Risk Assessment Tool for Prediction of Venous Thromboembolism After Total Joint Arthroplasty at an Urban Tertiary Care Health Safety Net Hospital

Background: Patients undergoing total joint arthroplasty (TJA) are at increased risk for venous thromboembolism (VTE). Prediction tools such as the Caprini Risk Assessment Model (RAM) have been developed to identify patients at higher risk. However, studies have reported heterogeneous results when assessing its efficacy for TJA. Patients treated in an urban health safety net hospital have increased medical complexity, advanced degenerative joint disease, and severe disability prior to TJA increasing the risk of VTE. We hypothesize that use of a tool designed to account for these conditions—the Boston Medical Center (BMC) VTE score—will more accurately predict VTE in this patient population. Methods: A retrospective case-control study was performed including subjects 18 years of age and older who underwent primary or revision TJA in an urban academic health safety net hospital. Patients with hemiarthroplasties, simultaneous bilateral TJA, and TJA after acute trauma were excluded. A total of 80 subjects were included: 40 who developed VTE after TJA (VTE+) and 40 who did not develop VTE (controls). Subjects were matched by age, gender, and surgical procedure. Results: There was a statistically significant difference between the mean BMC VTE score for VTE+ and controls (4.40 and 3.13, respectively, P = .036). Conversely, there was no statistical difference between the mean Caprini scores for VTE+ and controls (9.50 and 9.35, respectively, P = .797). Conclusions: In a health safety-net patient population, an institutional RAM—the BMC VTE score—was found to be more predictive of VTE than the modified Caprini RAM following TJA. The BMC-VTE score should be externally validated to confirm its reliability in VTE prediction in similar patient populations