45 results on '"Varvel S"'
Search Results
2. Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice
- Author
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Varvel, S. A., Anum, E. A., and Lichtman, A. H.
- Published
- 2005
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3. Δ9-THC-induced cognitive deficits in mice are reversed by the GABAA antagonist bicuculline
- Author
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Varvel, S. A., Anum, E., Niyuhire, F., Wise, L. E., and Lichtman, A. H.
- Published
- 2005
- Full Text
- View/download PDF
4. Effects of antipsychotic drugs on operant responding after acute and repeated administration
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Varvel, S., Vann, R., Wise, L., Philibin, S., and Porter, J.
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- 2002
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5. Differential effects of Δ9-THC on spatial reference and working memory in mice
- Author
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Varvel, S., Hamm, R., Martin, B., and Lichtman, A.
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- 2001
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6. Clozapine discrimination with a low training dose distinguishes atypical from typical antipsychotic drugs in rats
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Porter, J. H., Varvel, S. A., Vann, R. E., Philibin, S. D., and Wise, L. E.
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- 2000
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7. The discriminative stimulus properties of the atypical antipsychotic olanzapine in rats
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Porter, J. H., McCallum, S. E., Varvel, S. A., and Vann, R. E.
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- 2000
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8. The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo
- Author
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Pertwee, R G, Thomas, A, Stevenson, L A, Ross, R A, Varvel, S A, Lichtman, A H, Martin, B R, and Razdan, R K
- Published
- 2007
- Full Text
- View/download PDF
9. Mianserin as a discriminative stimulus in rats: asymmetrical cross-generalization with scopolamine
- Author
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Kelley, B. M., Porter, J. H., and Varvel, S. A.
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- 1995
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10. First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes
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Cousminer, DL, Ahlqvist, E, Mishra, R, Andersen, MK, Chesi, A, Hawa, MI, Davis, A, Hodge, KM, Bradfield, JP, Zhou, K, Guy, VC, Akerlund, M, Wod, M, Fritsche, LG, Vestergaard, H, Snyder, J, Hojlund, K, Linneberg, A, Karajamaki, A, Brandslund, I, Kim, CE, Witte, D, Sorgjerd, EP, Brillon, DJ, Pedersen, O, Beck-Nielsen, H, Grarup, N, Pratley, RE, Rickels, MR, Vella, A, Ovalle, F, Melander, O, Harris, RI, Varvel, S, Grill, VER, Hakonarson, H, Froguel, P, Lonsdale, JT, Mauricio, D, Schloot, NC, Khunti, K, Greenbaum, CJ, Asvold, BO, Yderstraede, KB, Pearson, ER, Schwartz, S, Voight, BF, Hansen, T, Tuomi, T, Boehm, BO, Groop, L, Leslie, RD, Grant, SFA, Cousminer, DL, Ahlqvist, E, Mishra, R, Andersen, MK, Chesi, A, Hawa, MI, Davis, A, Hodge, KM, Bradfield, JP, Zhou, K, Guy, VC, Akerlund, M, Wod, M, Fritsche, LG, Vestergaard, H, Snyder, J, Hojlund, K, Linneberg, A, Karajamaki, A, Brandslund, I, Kim, CE, Witte, D, Sorgjerd, EP, Brillon, DJ, Pedersen, O, Beck-Nielsen, H, Grarup, N, Pratley, RE, Rickels, MR, Vella, A, Ovalle, F, Melander, O, Harris, RI, Varvel, S, Grill, VER, Hakonarson, H, Froguel, P, Lonsdale, JT, Mauricio, D, Schloot, NC, Khunti, K, Greenbaum, CJ, Asvold, BO, Yderstraede, KB, Pearson, ER, Schwartz, S, Voight, BF, Hansen, T, Tuomi, T, Boehm, BO, Groop, L, Leslie, RD, and Grant, SFA
- Abstract
OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
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- 2018
11. 39 The cost of a night nursing service at rennie grove hospice care, and the total community cost of care at home compared to an admission to hospital
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Varvel, S, primary, Spiro, SG, additional, Graham, A, additional, Sixsmith, J, additional, and Ward, A, additional
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- 2018
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12. 40 How satisfied are carers/families with a night team service as part of 24/7 hospice at home care?
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Varvel, S, primary, Ward, A, additional, Sixsmith, J, additional, Graham, A, additional, and Spiro, SG, additional
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- 2018
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13. Developing National Standards for Hospice-at-home Services
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Bell, G., primary, Greene, K., additional, Hunt, J., additional, and Varvel, S., additional
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- 2013
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14. PCA3: A urine-based genetic assay for detection of prostate cancer in men with elevated PSA
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Drewnowska, K., primary, Crawford, E. D., additional, Qian, J., additional, Varvel, S., additional, Wilk, M., additional, Mason, L., additional, Kaminetsky, J., additional, Huisman, T. K., additional, Bilowus, M., additional, Freedman, S. J., additional, and Bostwick, D. G., additional
- Published
- 2009
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15. SR 141716 (Rimonabant) precipitates withdrawal in marijuana-dependent mice
- Author
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WILSON, D, primary, VARVEL, S, additional, HARLOE, J, additional, MARTIN, B, additional, and LICHTMAN, A, additional
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- 2006
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16. Δ9-Tetrahydrocannbinol Accounts for the Antinociceptive, Hypothermic, and Cataleptic Effects of Marijuana in Mice
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Varvel, S. A., primary, Bridgen, D. T., additional, Tao, Q., additional, Thomas, B. F., additional, Martin, B. R., additional, and Lichtman, A. H., additional
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- 2005
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17. Differential behavioral responses to nicotine in Lewis and Fischer-344 rats
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PHILIBIN, S, primary, VANN, R, additional, VARVEL, S, additional, COVINGTONIII, H, additional, ROSECRANS, J, additional, JAMES, J, additional, and ROBINSON, S, additional
- Published
- 2005
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18. Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice
- Author
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Varvel, S. A., primary, Anum, E. A., additional, and Lichtman, A. H., additional
- Published
- 2004
- Full Text
- View/download PDF
19. ?9-THC-induced cognitive deficits in mice are reversed by the GABAA antagonist bicuculline
- Author
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Varvel, S. A., primary, Anum, E., additional, Niyuhire, F., additional, Wise, L. E., additional, and Lichtman, A. H., additional
- Published
- 2004
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20. Evaluation of CB1 Receptor Knockout Mice in the Morris Water Maze
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Varvel, S. A., primary and Lichtman, A. H., additional
- Published
- 2002
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21. The psychoactive plant cannabinoid, Delta9-tetrahydrocannabinol, is antagonized by Delta8- and Delta9-tetrahydrocannabivarin in mice in vivo.
- Author
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Pertwee, R G, Thomas, A, Stevenson, L A, Ross, R A, Varvel, S A, Lichtman, A H, Martin, B R, and Razdan, R K
- Abstract
Background and Purpose: To follow up in vitro evidence that Delta(9)-tetrahydrocannabivarin extracted from cannabis (eDelta(9)-THCV) is a CB(1) receptor antagonist by establishing whether synthetic Delta(9)-tetrahydrocannabivarin (O-4394) and Delta(8)-tetrahydrocannabivarin (O-4395) behave as CB(1) antagonists in vivo.Experimental Approach: O-4394 and O-4395 were compared with eDelta(9)-THCV as displacers of [(3)H]-CP55940 from specific CB(1) binding sites on mouse brain membranes and as antagonists of CP55940 in [(35)S]GTPgammaS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg(-1) (i.v.) Delta(9)-tetrahydrocannabinol in mice was then investigated.Key Results: O-4394 and O-4395 exhibited similar potencies to eDelta(9)-THCV as displacers of [(3)H]-CP55940 (K (i)=46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [(35)S]GTPgammaS binding assay (apparent K (B)=82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent K (B)=4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg(-1) O-4394 and O-4395 attenuated Delta(9)-tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Delta(9)-tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg(-1) (i.v.) and antinociception at doses above 10 mg kg(-1) (i.v.). O-4395 also induced hypothermia at 3 mg kg(-1) (i.v.) and above.Conclusions and Implications: O-4394 and O-4395 exhibit similar in vitro potencies to eDelta(9)-THCV as CB(1) receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Delta(9)-tetrahydrocannabinol in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2007
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22. The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo.
- Author
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Pertwee, R. G., Thomas, A., Stevenson, L. A., Ross, R. A., Varvel, S. A., Lichtman, A. H., Martin, B. R., and Razdan, R. K.
- Subjects
CANNABINOIDS ,CANNABIS (Genus) ,DRUG receptors ,IN vivo toxicity testing ,VAS deferens ,HYPOTHERMIA - Abstract
Background and purpose:To follow up in vitro evidence that Δ
9 -tetrahydrocannabivarin extracted from cannabis (eΔ9 -THCV) is a CB1 receptor antagonist by establishing whether synthetic Δ9 -tetrahydrocannabivarin (O-4394) and Δ8 -tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo.Experimental approach:O-4394 and O-4395 were compared with eΔ9 -THCV as displacers of [3 H]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [35 S]GTPγS binding assays performed with mouse brain membranes and of R-(+)-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg−1 (i.v.) Δ9 -tetrahydrocannabinol in mice was then investigated.Key results:O-4394 and O-4395 exhibited similar potencies to eΔ9 -THCV as displacers of [3 H]-CP55940 (Ki =46.6 and 64.4 nM, respectively) and as antagonists of CP55940 in the [35 S]GTPγS binding assay (apparent KB =82.1 and 125.9 nM, respectively) and R-(+)-WIN55212 in the vas deferens (apparent KB =4.8 and 3.9 nM respectively). At i.v. doses of 0.1, 0.3, 1.0 and/or 3 mg kg−1 O-4394 and O-4395 attenuated Δ9 -tetrahydrocannabinol-induced anti-nociception (tail-flick test) and hypothermia (rectal temperature). O-4395 but not O-4394 also antagonized Δ9 -tetrahydrocannabinol-induced ring immobility. By themselves, O-4395 and O-4394 induced ring immobility at 3 or 10 mg kg−1 (i.v.) and antinociception at doses above 10 mg kg−1 (i.v.). O-4395 also induced hypothermia at 3 mg kg−1 (i.v.) and above.Conclusions and implications:O-4394 and O-4395 exhibit similar in vitro potencies to eΔ9 -THCV as CB1 receptor ligands and as antagonists of cannabinoid receptor agonists and can antagonize Δ9 -tetrahydrocannabinol in vivo.British Journal of Pharmacology (2007) 150, 586–594. doi:10.1038/sj.bjp.0707124; published online 22 January 2007 [ABSTRACT FROM AUTHOR]- Published
- 2007
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23. Disruption of CB1 receptor signaling impairs extinction of spatial memory in mice.
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Varvel, S. A., Anum, E. A., and Lichtman, A. H.
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EXTINCTION (Psychology) , *CANNABINOIDS , *MEMORY , *MICE , *BEHAVIOR - Abstract
Presents a study that evaluated whether the endocannabinoid system also plays a role in extinguishing learned escape behavior and spatial memory of mice in a Morris water maze task.
- Published
- 2005
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24. ?9-THC-induced cognitive deficits in mice are reversed by the GABAA antagonist bicuculline.
- Author
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Varvel, S. A., Anum, E., Niyuhire, F., Wise, L. E., and Lichtman, A. H.
- Subjects
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GABA , *MARIJUANA , *CANNABINOIDS , *TETRAHYDROCANNABINOL , *SHORT-term memory , *LABORATORY mice - Abstract
Presents information on a study which investigated the effect of the γ-aminobutyric acid antagonist bicuculline on the Δ9-tetrahydrocannabinol-induced cognitive deficits in mice. Assessment of the disruptive effects of marijuana consumption on learning and memory; Details of statistical analysis; Results.
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- 2005
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25. Differential effects of Δ[sup 9] -THC on spatial reference and working memory in mice.
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Varvel, S. A., Hamm, R. J., Martin, B. R., and Lichtman, A. H.
- Subjects
TETRAHYDROCANNABINOL ,EFFECT of drugs on memory ,SPACE perception ,PHYSIOLOGY - Abstract
Rationale: Marijuana remains the most widely used illicit drug in the U.S., and recent attention has been given to putative therapeutic uses of marijuana and cannabinoid derivatives. Thus, developing a better understanding of Δ[sup 9] -THC (tetrahydrocannabinol)-induced mnemonic deficits is of critical importance. Objectives: These experiments were conducted to determine whether Δ[sup 9] -THC has differential effects on spatial reference and working memory tasks, to investigate its receptor mechanism of action, and to compare these effects with those produced by two other compounds – scopolamine and phencyclidine – known to produce mnemonic deficits. In addition, the potency of Δ[sup 9] -THC in these memory tasks was compared with its potency in other pharmacological effects traditionally associated with cannabinoid activity. Methods: Two different versions of the Morris water maze were employed: a working memory task and a reference memory task. Other effects of Δ[sup 9] -THC were assessed using standard tests of hypomotility, antinociception, catalepsy, and hypothermia. Results: Δ[sup 9] -THC disrupted performance of the working memory task (3.0 mg/kg) at doses lower than those required to disrupt performance of the reference memory task (100 mg/kg), or elicit hypomotility, antinociception, catalepsy, and hypothermia. These performance deficits were reversed by SR 141716A. The effects of Δ[sup 9] -THC resembled those of scopolamine, which also selectively disrupted the working maze task. Conversely, phencyclidine disrupted both tasks only at a dose that also produced motor deficits. Conclusions: These data indicate that Δ[sup 9] -THC selectively impairs performance of a working memory task through a CB[sub 1] receptor mechanism of action and that these memory disruptions are more sensitive than other pharmacological effects of Δ[sup 9] -THC. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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26. Delta9-tetrahydrocannbinol accounts for the antinociceptive, hypothermic, and cataleptic effects of marijuana in mice.
- Author
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Varvel, S A, Bridgen, D T, Tao, Q, Thomas, B F, Martin, B R, and Lichtman, A H
- Abstract
Although it is widely accepted that delta9-tetrahydrocannabinol (delta9-THC) is the primary psychoactive constituent of marijuana, questions persist as to whether other components contribute to marijuana's pharmacological activity. The present experiments assessed the cannabinoid activity of marijuana smoke exposure in mice and tested the hypothesis that delta9-THC mediates these effects through a CB1 receptor mechanism of action. First, the effects of delta9-THC on analgesia, hypothermia, and catalepsy were compared with those of a marijuana extract with equated delta9-THC content after either i.v. administration or inhalation exposure. Second, mice were exposed to smoke of an ethanol-extracted placebo plant material or low-grade marijuana (with minimal delta9-THC but similar levels of other cannabinoids) that were impregnated with varying quantities of delta9-THC. To assess doses, delta9-THC levels in the blood and brains of drug-exposed mice were determined following both i.v. and inhalation routes of administration. Both marijuana and delta9-THC produced comparable levels of antinociception, hypothermia, and catalepsy regardless of the route of administration, and these effects were blocked by pretreatment with the CB1 antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl]. Importantly, the blood and brain levels of delta9-THC were similar in mice exhibiting similar pharmacological effects, regardless of the presence of non-delta9-THC marijuana constituents. The present experiments provide evidence that the acute cannabinoid effects of marijuana smoke exposure on analgesia, hypothermia, and catalepsy in mice result from delta9-THC content acting at CB1 receptors and that the non-delta9-THC constituents of marijuana (at concentrations relevant to those typically consumed) influence these effects only minimally, if at all.
- Published
- 2005
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27. Evaluation of CB1 receptor knockout mice in the Morris water maze.
- Author
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A, Varvel S and H, Lichtman Aron
- Abstract
The endocannabinoid system has been proposed to modulate a variety of physiological processes, including those that underlie cognition. The present study tested whether this system is tonically active in learning and memory by comparing CB(1) receptor knockout mice (CB(1)(-/-)) to wild-type mice (CB(1)(+/+)) in several Morris water maze tasks. Also, the effects of three cannabinoid agonists, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), R-(+)-[2,3-dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1, 4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2), and methanandamide, were evaluated in a working memory procedure. Both genotypes exhibited identical acquisition rates in a fixed platform procedure; however, the CB(1)(-/-) mice demonstrated significant deficits in a reversal task in which the location of the hidden platform was moved to the opposite side of the tank. This phenotype difference was most likely due to an increased perseverance of the CB(1)(-/-) mice in that they continued to return to the original platform location, despite being repeatedly shown the new platform location. In addition, Delta(9)-THC (ED(50) = 1.3 mg/kg), WIN 55,212-2 (ED(50) = 0.35 mg/kg), and methanandamide (ED(50) = 3.2 mg/kg) disrupted the performance of CB(1)(+/+) mice in the working memory task at doses that did not elicit motivational or sensorimotor impairment as assessed in a cued version of the task. Furthermore, doses of each drug that were maximally disruptive in CB(1)(+/+) mice were ineffective in either N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A)-treated CB(1)(+/+) or CB(1)(-/-) mice. These results provide strong evidence that cannabinoids disrupt working memory through a CB(1) receptor mechanism of action, and suggest that the endocannabinoid system may have a role in facilitating extinction and/or forgetting processes.
- Published
- 2002
28. 39 The cost of a night nursing service at rennie grove hospice care, and the total community cost of care at home compared to an admission to hospital
- Author
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Varvel, S, Spiro, SG, Graham, A, Sixsmith, J, and Ward, A
- Abstract
BackgroundRennie Grove (RG) runs a 24/7 Hospice at Home service. An independent study calculated the cost of a visit and the total community cost of home care, including all health care professional (HCP), carer, and family member visits.MethodsOver a period of 145 days, 550 calls and 335 visits made to/by the night team were recorded, averaging 3.79 per night. The salary cost per hour for each nurse, plus organisational add on costs, were calculated. To derive a total community cost, 35 families, able to consent, kept a diary for up to two-weeks, recording all HCP, carer and family support visits and duration of each visit. 17 diaries were returned. Descriptive analysis was used with the Statistical Package for the Social Sciences (SPSS v22). Costs were taken for HCPs and social care services from the PSSRU data 2015/2016.ResultsAverage length of the diaries was 10.4 days. For 3.79 visits per night the cost per visit was £195 (RG nurses travel in pairs). 17 patient diaries covered 177 days and showed a range of visits and complexity of care. RG staff provided 19% of the care at a cost of £3,295; district nurses 13%, cost £2,005; formal carers 55% at a cost of £1344. 23 GPs visits comprised 4% of visits but 15% of total costs. MacMillan/Marie Curie nurses accounted for just 2% of visits but 19% of cost as they stayed overnight. The cost of 177 days of care for 17 patients was £11,814; i.e. £66.7 per day as care was not needed every day of each diary period.ConclusionsThe cost of home care seems acceptable, compared to the national average cost of a day in an inpatient specialist palliative care bed at £397-£400 (Data.Gov.UK, 2015).
- Published
- 2018
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29. 40 How satisfied are carers/families with a night team service as part of 24/7 hospice at home care?
- Author
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Varvel, S, Ward, A, Sixsmith, J, Graham, A, and Spiro, SG
- Abstract
BackgroundRennie Grove (RG) runs a 24/7 service with a dedicated responsive night team. Through an independent study, carers’ levels of service satisfaction with the night team were investigated.MethodsA questionnaire was sent to carers (n=268) who had a relative die under the care of RG within the last 6 weeks to one year, 84 completed questionnaires were returned. Follow-up face-to-face semi-structured interviews were carried out with carers (n=18). Quantitative data was analysed using SPSS v 22, while qualitative data was thematically analysed.ResultsThe carer questionnaire reported that 71% thought the speed of the response by the night team was fast. Overall satisfaction with telephone call response was high with 82% very satisfied. Carers also agreed strongly that the telephone calls provided good quality of care (90%), good follow-up care (88%), that they were given sufficient time (88%), and received useful advice (83%). For a visit, 93% of carers were highly satisfied and 7% satisfied. Carers strongly agreed that they were given sufficient time (90%), and were confident in the care provided (90%), care was useful (87%) and follow-up was good (84%), worries were reduced (81%) and they had a say in decisions made (81%). During the interviews, carers described the night service as: supportive, amazing, caring, reassuring, professional, kind and compassionate, excellent, loving, calm. Carers perceived the service to be holistic and rated the service highly for supporting them to ensure family members could be cared for at home, as preferred. For comparison, of those dying in hospital, only 46% were highly satisfied. Carer wellbeing scores were lower than the national average, but reported similar levels of anxiety.ConclusionsA night team service can provide excellent, reassuring and holistic care that meets the care needs and wishes of the patient and family.
- Published
- 2018
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30. An omicron-specific neutralizing antibody test predicts neutralizing activity against XBB 1.5.
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Varvel S, Galdzicka M, Nystrom S, Liu H, Chen G, Ragan I, and Shabahang S
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- Humans, Flow Cytometry, SARS-CoV-2, Antibodies, Neutralizing, Biological Assay, Spike Glycoprotein, Coronavirus
- Abstract
Introduction: Understanding the immune status of an individual using neutralizing antibody testing is complicated by the continued evolution of the SARS-CoV-2 virus. Previous work showed that assays developed against the wildtype strain of SARS-CoV-2 were insufficient predictors of neutralization of omicron variants, thus we developed an omicron-specific flow cytometry-based neutralizing antibody test and performed experiments to assess how well it compared to an omicron-specific PRNT assay (gold standard) and whether it could predict neutralizing activity to more recent omicron subvariants such as XBB.1.5., Methods: Accuracy of a novel flow cytometry-based neutralizing antibody (FC-NAb) assay was determined by comparison with an omicron-specific PRNT assay. A series of samples were evaluated in both the omicron FC-NAb assay and a second test was designed to assess neutralization of XBB.1.5., Results: Good concordance between the omicron FC-NAb test and the omicron PRNT was demonstrated (AUC = 0.97, p <0.001; sensitivity = 94%, specificity = 100%, PPV = 100%, and NPV = 97%). A strong linear relationship between the omicron FC-NAb and neutralization of XBB1.5 was observed (r = 0.83, p<0.001). Additionally, the omicron FC-NAb test was a very strong predictor of positive XBB1.5 NAb activity (AUC = 0.96, p<0.001; sensitivity = 94%, specificity = 90%, positive predictive value = 90%, and negative predictive values = 94%)., Discussion: Our data suggest that despite continued evolution of the SARS-CoV-2 spike protein, the omicron FC-NAb assay described here is a good predictor of XBB1.5 neutralizing activity, as evidenced by a strong correlation and good predictive performance characteristics., Competing Interests: SV, MG, SN, HL, GC, and SS are all employees and or shareholders of Pearsanta Inc. or its parent company Aditxt Inc. Pearsanta provides clinical laboratory services, including SARS-CoV-2 neutralizing antibody tests. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Varvel, Galdzicka, Nystrom, Liu, Chen, Ragan and Shabahang.)
- Published
- 2024
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31. Simultaneous measurement of multiple variant-specific SARS-CoV-2 neutralizing antibodies with a multiplexed flow cytometric assay.
- Author
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Liu H, Varvel S, Chen G, McConnell J, Caffrey R, Galdzicka M, and Shabahang S
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- Humans, SARS-CoV-2, Flow Cytometry, Breakthrough Infections, Antibodies, Neutralizing, COVID-19
- Abstract
Introduction: Neutralizing antibodies (NAbs) have been recognized as surrogates of protection against SARS-CoV-2; however, the emergence of variants/subvariants escaping neutralization suggests that laboratory assessments of NAbs against the ancestral/wild type (WT) antigens likely overestimate the degree of protection., Methods: A novel flow cytometry-based multiplex test system was developed for the simultaneous detection of NAbs of multiple SARS-CoV-2 variants. SARS-CoV-2 antibodies (Abs) including IgG, IgM, IgA isotypes were measured in the same system. Samples from negative, convalesced, vaccinated, boosted, and breakthrough infection (BTI) populations were tested for both NAbs and Abs., Results: NAbs induced by WT showed neutralization activity that correlated strongly to all variants (R
2 > 0.85) except omicron BA.1/BA.2 (R2 <0.50). Two doses of vaccine elicited very little protective immunity against BA.1/BA.2, though a booster dose significantly improved NAbs for all variants. NAbs/Abs increased more following BTI than after a booster, suggesting that hybrid immunity (vaccination + natural immunity) was more robust to all variants including BA.1/BA.2. BTIs occurring in the omicron era led to stronger NAb responses against BA.1/BA.2 than did older BTIs. In all comparisons, the RBD antigens demonstrated greater differences between WT and BA.1/BA.2 than the spike antigens., Discussion: Taken together, we demonstrated that both Ab and NAb against multiple SARS-CoV-2 variants/subvariants can be reliably detected on the same multiplex platform. Distinguishing NAbs to the appropriate antigenic target of prevalent variants offers the best correlate of protection and aids individual decisions about the appropriateness and cadence of vaccine boosters and other exposure mitigation strategies., Competing Interests: All authors are employees or stockholders of Aditxt, Inc., which performs the tests described., (Copyright © 2022 Liu, Varvel, Chen, McConnell, Caffrey, Galdzicka and Shabahang.)- Published
- 2022
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32. Carer and staff perceptions of end-of-life care provision: case of a hospice-at-home service.
- Author
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Ward A, Sixsmith J, Spiro S, Graham A, Ballard H, Varvel S, and Youell J
- Subjects
- Caregivers, Humans, Palliative Care, Perception, Home Care Services, Hospices, Terminal Care
- Abstract
People requiring palliative care should have their needs met by services acting in accordance with their wishes. A hospice in the south of England provides such care via a 24/7 hospice at home service. This study aimed to establish how a nurse-led night service supported patients and family carers to remain at home and avoid hospital admissions. Semi-structured interviews were carried out with family carers (n=38) and hospice-at-home staff (n=9). Through night-time phone calls and visits, family carers felt supported by specialist hospice staff whereby only appropriate hospital admission was facilitated. Staff provided mediation between family carer and other services enabling more integrated care and support to remain at home. A hospice-at-home night service can prevent unnecessary hospital admissions and meet patient wishes through specialist care at home.
- Published
- 2021
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33. The Cost of Visit-based Home Care for up to Two Weeks in the Last Three Months of Life: APilot Study of Community Care Based at a Hospice-at-home Service in South East of England.
- Author
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Spiro S, Ward A, Sixsmith J, Graham A, and Varvel S
- Subjects
- Cost-Benefit Analysis, England, Home Care Services statistics & numerical data, Humans, Pilot Projects, Terminal Care methods, Terminal Care statistics & numerical data, Home Care Services economics, Terminal Care economics, Time Factors
- Abstract
The cost of visit-based community care based around a 24/7 hospice-at-home (HatH) service in the last 3 months of life was assessed. Thirty families completed a health and social carediary of at-home visits over two-weeks following contact with the HatH night service. Diaries captured 333 days of care provision, averaging 11 diary days per family, 708 health care professional and carer visits, lasting 604 hours at a cost of £20,192 ($24,946). Hat H care, integrated with community support, seems an economic proposition but highlights the complexities of assessing cost of end of life care.
- Published
- 2020
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- View/download PDF
34. Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.
- Author
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Mishra R, Åkerlund M, Cousminer DL, Ahlqvist E, Bradfield JP, Chesi A, Hodge KM, Guy VC, Brillon DJ, Pratley RE, Rickels MR, Vella A, Ovalle F, Harris RI, Melander O, Varvel S, Hakonarson H, Froguel P, Lonsdale JT, Mauricio D, Schloot NC, Khunti K, Greenbaum CJ, Yderstræde KB, Tuomi T, Voight BF, Schwartz S, Boehm BO, Groop L, Leslie RD, and Grant SFA
- Subjects
- Adolescent, Adult, Age of Onset, Alleles, Case-Control Studies, Child, Child, Preschool, Chromosomes, Human, Pair 6 genetics, Cohort Studies, Diabetes Mellitus, Type 1 classification, Diabetes Mellitus, Type 1 diagnosis, Diabetes Mellitus, Type 1 epidemiology, Diagnosis, Differential, Female, Genetic Association Studies, Humans, Latent Autoimmune Diabetes in Adults classification, Latent Autoimmune Diabetes in Adults diagnosis, Male, Polymorphism, Single Nucleotide, Young Adult, Diabetes Mellitus, Type 1 genetics, Genes, MHC Class I genetics, Genes, MHC Class II genetics, Genetic Testing methods, Latent Autoimmune Diabetes in Adults genetics
- Abstract
Objective: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region., Research Design and Methods: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects ( n = 1,985) and control subjects ( n = 2,219). The same approach was applied to a LADA cohort ( n = 1,428) using population-based control subjects ( n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects)., Results: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA., Conclusions: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes., (© 2019 by the American Diabetes Association.)
- Published
- 2020
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35. First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.
- Author
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Cousminer DL, Ahlqvist E, Mishra R, Andersen MK, Chesi A, Hawa MI, Davis A, Hodge KM, Bradfield JP, Zhou K, Guy VC, Åkerlund M, Wod M, Fritsche LG, Vestergaard H, Snyder J, Højlund K, Linneberg A, Käräjämäki A, Brandslund I, Kim CE, Witte D, Sørgjerd EP, Brillon DJ, Pedersen O, Beck-Nielsen H, Grarup N, Pratley RE, Rickels MR, Vella A, Ovalle F, Melander O, Harris RI, Varvel S, Grill VER, Hakonarson H, Froguel P, Lonsdale JT, Mauricio D, Schloot NC, Khunti K, Greenbaum CJ, Åsvold BO, Yderstræde KB, Pearson ER, Schwartz S, Voight BF, Hansen T, Tuomi T, Boehm BO, Groop L, Leslie RD, and Grant SFA
- Subjects
- Adult, Aged, Case-Control Studies, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 metabolism, Diabetes Mellitus, Type 2 immunology, Diabetes Mellitus, Type 2 metabolism, Female, Glucose Intolerance genetics, Glucose Intolerance immunology, Glucose Intolerance metabolism, Haplotypes, Humans, Insulin metabolism, Latent Autoimmune Diabetes in Adults immunology, Latent Autoimmune Diabetes in Adults metabolism, Male, Middle Aged, Young Adult, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 2 genetics, Genome-Wide Association Study, Immune System Phenomena genetics, Latent Autoimmune Diabetes in Adults genetics
- Abstract
Objective: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype., Research Design and Methods: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects ( n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes ( n = 2,454 vs. 968) and type 2 diabetes ( n = 2,779 vs. 10,396)., Results: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3 , encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes., Conclusions: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies., (© 2018 by the American Diabetes Association.)
- Published
- 2018
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- View/download PDF
36. Prevalence of Elevated Lp(a) Mass Levels and Patient Thresholds in 532 359 Patients in the United States.
- Author
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Varvel S, McConnell JP, and Tsimikas S
- Subjects
- Aged, Biomarkers blood, Blood Glucose analysis, C-Reactive Protein analysis, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cholesterol, LDL blood, Databases, Factual, Female, Glycated Hemoglobin analysis, Humans, Insulin blood, Male, Middle Aged, Nephelometry and Turbidimetry, Predictive Value of Tests, Prevalence, Reference Values, Risk Factors, Sex Factors, Tertiary Care Centers, United States epidemiology, Up-Regulation, Cardiovascular Diseases blood, Lipoprotein(a) blood
- Abstract
Objective: Elevated lipoprotein(a) [Lp(a)] is a causal, independent risk factor for cardiovascular disease and aortic stenosis. We aimed to define the prevalence and patient thresholds of elevated Lp(a) levels in the United States., Approach and Results: We analyzed Lp(a) levels in 532 359 subjects from 2 data sets: (1) in 531 144 subjects from a referral laboratory and (2) in 915 patients from a tertiary referral center. Lp(a) mass levels were measured by immunoturbidometric assays in both centers and expressed as mg/dL. At the referral laboratory, the median age (interquartile range) of the subjects was 57.0 (46-67) years, and 51.9% were female. Lp(a) levels were skewed rightward as expected. The mean±SD levels were 34.0±40.0 mg/dL, and median (interquartile range) levels were 17 (7-47) mg/dL, with range 0 to 907 mg/dL. Lp(a) levels at 75%, 80%, 90%, 95%, 99%, and 99.9% percentiles were >47, >60, >90, >116, >180, and >245 mg/dL, respectively. At the referral laboratory, Lp(a) levels >30 and >50 mg/dL were present in 35.0% and 24.0% of subjects, respectively, and at the tertiary referral center, 39.5% and 29.2%, respectively. Females had higher mean (SD) (37.0 [42.7] versus 30.7 [36.7]; P<0.0001) and median (interquartile range) (19 [8-53] versus 15 [7-42]; P<0.0001) Lp(a) than males., Conclusions: This is the largest database to assess the distribution of Lp(a) and is derived from patients as opposed to general populations. Lp(a) levels >30 and >50 mg/dL were fairly common, particularly in a tertiary care setting. These data may inform consensus documents, guidelines, and therapeutic cutoffs for Lp(a)-mediated cardiovascular risk., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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37. From Value Assessment to Value Cocreation: Informing Clinical Decision-Making with Medical Claims Data.
- Author
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Thompson S, Varvel S, Sasinowski M, and Burke JP
- Subjects
- Adult, Aged, Case-Control Studies, Cohort Studies, Female, Humans, Male, Medicare, Middle Aged, Retrospective Studies, United States, Clinical Decision-Making, Insurance Claim Review
- Abstract
Big data and advances in analytical processes represent an opportunity for the healthcare industry to make better evidence-based decisions on the value generated by various tests, procedures, and interventions. Value-based reimbursement is the process of identifying and compensating healthcare providers based on whether their services improve quality of care without increasing cost of care or maintain quality of care while decreasing costs. In this article, we motivate and illustrate the potential opportunities for payers and providers to collaborate and evaluate the clinical and economic efficacy of different healthcare services. We conduct a case study of a firm that offers advanced biomarker and disease state management services for cardiovascular and cardiometabolic conditions. A value-based analysis that comprised a retrospective case/control cohort design was conducted, and claims data for over 7000 subjects who received these services were compared to a matched control cohort. Study subjects were commercial and Medicare Advantage enrollees with evidence of CHD, diabetes, or a related condition. Analysis of medical claims data showed a lower proportion of patients who received biomarker testing and disease state management services experienced a MI (p < 0.01) or diabetic complications (p < 0.001). No significant increase in cost of care was found between the two cohorts. Our results illustrate the opportunity healthcare payers such as Medicare and commercial insurance companies have in terms of identifying value-creating healthcare interventions. However, payers and providers also need to pursue system integration efforts to further automate the identification and dissemination of clinically and economically efficacious treatment plans to ensure at-risk patients receive the treatments and interventions that will benefit them the most.
- Published
- 2016
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38. Does APOE genotype modify the relations between serum lipid and erythrocyte omega-3 fatty acid levels?
- Author
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Harris WS, Pottala JV, Thiselton DL, A Varvel S, Baedke AM, Dayspring TD, Warnick GR, and McConnell JP
- Subjects
- Adult, Aged, Apolipoprotein B-100 blood, Biomarkers blood, Cholesterol, HDL blood, Cross-Sectional Studies, Female, Genotype, Humans, Male, Middle Aged, Phenotype, Triglycerides blood, Apolipoproteins E genetics, Cholesterol, LDL blood, Erythrocytes metabolism, Fatty Acids, Omega-3 blood
- Abstract
Earlier reports indicated that patients with the apolipoprotein APOE ε4 allele responded to fish oil supplementation with a rise in serum low-density lipoprotein cholesterol (LDL-C) compared to ε3 homozygotes. In this study, we used clinical laboratory data to test the hypothesis that the cross-sectional relation between RBC omega-3 fatty acid status (the Omega-3 Index) and LDL-C was modified by APOE genotype. Data from 136,701 patients were available to compare lipid biomarker levels across Omega-3 Index categories associated with heart disease risk in all APOE genotypes. We found no adverse interactions between APOE genotype and the Omega-3 Index for LDL-C, LDL particle number, apoB, HDL-C, or triglycerides. However, we did find evidence that ε2 homozygotes lack an association between omega-3 status and LDL-C, apoB, and LDL particle number. In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype.
- Published
- 2014
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39. The changing role of ancillary health care service providers: an evaluation of Health Diagnostic Laboratory, Inc.
- Author
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Thompson S, Varvel S, Voros S, Thiselton D, Grami S, Turner RM, and Barron J
- Subjects
- Accountable Care Organizations economics, Ancillary Services, Hospital organization & administration, Case-Control Studies, Clinical Laboratory Services organization & administration, Cohort Studies, Cost Savings, Cost-Benefit Analysis, Female, Health Care Reform organization & administration, Health Personnel organization & administration, Humans, Male, Retrospective Studies, Role, United States, Ancillary Services, Hospital economics, Clinical Laboratory Services economics, Health Care Costs, Health Services economics, Quality of Health Care
- Abstract
In an effort to reduce cost and improve quality, health care payers have enacted a number of incentives to motivate providers to focus their efforts on achieving better clinical outcomes and reducing the prevalence and progression of disease. In response to these incentives, providers are entering into new arrangements such as accountable care organizations and patient-centered medical homes to redesign delivery processes and achieve quality and cost objectives. This article reports the results of a study designed to evaluate the impact on cost and quality of care resulting from services provided by Health Diagnostic Laboratory, Inc., a clinical laboratory with a comprehensive care model. The results show that patients who utilized these laboratory services experienced lower total cost of care (23% reduction, P<0.01) and improved lipid profiles during the follow-up period. Total cost reductions were related to cost reductions found in both inpatient and ambulatory care. These findings suggest that accountable care organizations, patient-centered medical homes, and other groups entering shared savings initiatives should consider the potential role ancillary service providers with comprehensive care models can play in the delivery of integrated care.
- Published
- 2014
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- View/download PDF
40. Targeting insulin resistance: the ongoing paradigm shift in diabetes prevention.
- Author
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Dall T, Thiselton D, and Varvel S
- Subjects
- Cost-Benefit Analysis, Diabetes Mellitus diagnosis, Diabetes Mellitus drug therapy, Diabetes Mellitus economics, Diagnostic Techniques and Procedures, Humans, Managed Care Programs, Primary Prevention economics, Risk Assessment, United States, Diabetes Mellitus prevention & control, Insulin Resistance, Primary Prevention methods
- Published
- 2013
41. Prostate needle biopsy quality in reduction by dutasteride of prostate cancer events study: worldwide comparison of improvement with investigator training and centralized laboratory processing.
- Author
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Bostwick DG, Qian J, Drewnowska K, Varvel S, Bostwick KC, Marberger M, and Rittmaster RS
- Subjects
- Administration, Oral, Adult, Aged, Clinical Laboratory Techniques, Double-Blind Method, Drug Administration Schedule, Dutasteride, Early Detection of Cancer methods, Education, Medical, Continuing, Enzyme Inhibitors therapeutic use, Global Health, Humans, Immunohistochemistry, Male, Middle Aged, Neoplasm Staging, Prospective Studies, Prostatic Neoplasms mortality, Quality Control, Risk Assessment, Survival Analysis, Treatment Outcome, Azasteroids therapeutic use, Biopsy, Fine-Needle methods, Clinical Competence, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- Abstract
Objectives: To compare biopsy quality factors among study sites worldwide at entry and at year 2 in the reduction by dutasteride of prostate cancer events study. The accuracy of prostate cancer detection is influenced by the length and number of biopsy cores., Methods: Biopsy quality factors at entry and at year 2 were compared for subjects enrolled from 6 geographic regions: North America, South America, Western Europe, Central/Eastern Europe, Australia, and Africa. Investigator training was provided for prostate biopsy collection before year 2, emphasizing core length and number of cores obtained., Results: Data were collected prospectively from 4649 subjects at entry and 6267 subjects at year 2. At entry, the aggregate length, number of cores, and mean length of cores differed significantly among regions. Aggregate length was longest in biopsies from Australia, and number of cores was highest from South America. At year 2, each region collected the protocol-required 10 cores, and aggregate length and mean length of cores were greater than for entry biopsies; site variance was reduced for all factors., Conclusions: There were significant differences in aggregate length, number of cores, and mean length of cores among regions at study entry. After investigator training by the study sponsor and use of a central laboratory for standardized processing, year 2 biopsies showed an increase in all 3 quality factors when compared with entry biopsies. Variance in biopsy quality can be reduced by investigator training and standardization of collection and processing, thereby optimizing detection of cancer. Biopsy quality may be a useful comparative measure in urologic practice., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
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42. Delta(9)-THC-induced cognitive deficits in mice are reversed by the GABA(A) antagonist bicuculline.
- Author
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Varvel SA, Anum E, Niyuhire F, Wise LE, and Lichtman AH
- Subjects
- Animals, Baclofen pharmacology, Brain drug effects, GABA-A Receptor Agonists, GABA-B Receptor Agonists, GABA-B Receptor Antagonists, Male, Maze Learning drug effects, Memory, Short-Term drug effects, Mice, Mice, Inbred C57BL, Muscimol toxicity, Organophosphorus Compounds pharmacology, Phenotype, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 genetics, Bicuculline pharmacology, Dronabinol toxicity, GABA-A Receptor Antagonists, Marijuana Abuse psychology, Mental Recall drug effects
- Abstract
Rationale: The results of recent in vitro studies have underscored the important role that activation of CB(1) receptors has on GABAergic activity in brain areas associated with memory., Objectives: The primary purpose of this study was to test the hypothesis that the memory disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in vivo are mediated through GABAergic systems. Conversely, we also evaluated whether blocking CB(1) receptor signaling would alter memory deficits elicited by GABA agonists., Methods: The GABA(A) antagonist bicuculline and GABA(B) antagonist CGP 36742 were evaluated for their ability to ameliorate Delta(9)-THC-induced deficits in a mouse working memory Morris water maze task. Mice were also assessed in a T-maze task, as well as non-cognitive behavioral assays. Additionally, the effects of GABA(A) and GABA(B) agonists were assessed in either CB(1) (-/-) mice or wild type mice treated with the CB(1) antagonist SR 141716., Results: Memory deficits resulting from 10 mg/kg Delta(9)-THC in the Morris water maze were completely reversed by bicuculline, though unaffected by CGP 36742. Bicuculline also blocked the disruptive effects of Delta(9)-THC in the T-maze, but failed to alter non-mnemonic effects of Delta(9)-THC. Although CB(1) (-/-) mice exhibited supersensitivity to muscimol-induced water maze deficits compared with wild type control mice, muscimol elicited virtually identical effects in SR 141716-treated and vehicle-treated wild type mice., Conclusions: This is the first demonstration of which we are aware showing that GABA(A) receptors may play a necessary role in Delta(9)-THC-induced memory impairment in whole animals.
- Published
- 2005
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43. Endocannabinoids in cognition and dependence.
- Author
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Lichtman AH, Varvel SA, and Martin BR
- Subjects
- Animals, Cannabinoid Receptor Modulators, Cannabinoids pharmacology, Cognition drug effects, Eicosanoids pharmacology, Endocannabinoids, Humans, Learning drug effects, Memory drug effects, Neuronal Plasticity drug effects, Opioid-Related Disorders, Receptors, Cannabinoid, Receptors, Drug agonists, Receptors, Drug metabolism, Substance-Related Disorders, Cannabinoids metabolism, Cognition physiology, Eicosanoids metabolism
- Abstract
Cannabis use is associated with a wide range of pharmacological effects, some of which have potential therapeutic benefit while others result in negative outcomes. Acute cannabinoid intoxication has been well documented to produce deficits in cognitive functioning with concomitant changes in glutamatergic, GABAergic, and cholinergic neurochemical systems in the hippocampus, each of which has been implicated in memory. Additionally, cannabis-dependent individuals abstaining from this drug can undergo a constellation of mild withdrawal effects. The use of the CB(1) cannabinoid receptor antagonist SR141716A and transgenic mice lacking the CB(1) receptor are critical tools for investigating the role of the endocannabinoid system in cognition, drug dependence, and other physiological processes. Converging evidence in which performance in a variety of memory tasks is enhanced following either SR141716A treatment or in CB(1) receptor knockout mice indicates that this system may play an important role in modulating cognition. There are also indications that this system may function to modulate opioid dependence. The purpose of this review is to describe recent advances that have furthered our understanding of the roles that the endocannabinoid system play on both cognition and drug dependence., (Copyright 2002 Published by Elsevier Science Ltd.)
- Published
- 2002
- Full Text
- View/download PDF
44. Discriminative stimulus (DS) properties of nicotine in the C57BL/6 mouse.
- Author
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Varvel SA, James JR, Bowen S, Rosecrans JA, and Karan LD
- Subjects
- Analysis of Variance, Animals, Cues, Dose-Response Relationship, Drug, Generalization, Stimulus, Genotype, Male, Mice, Mice, Inbred C57BL, Stimulation, Chemical, Conditioning, Operant drug effects, Discrimination Learning drug effects, Nicotine pharmacology, Nicotinic Agonists pharmacology
- Abstract
Previous research conducted in this and other laboratories has examined the role of genetic factors in determining sensitivity to (-)-nicotine in a variety of behavioral and physiological measures in the rat. More recent research further indicates that genetic factors can also influence the level of sensitivity to (-)-nicotine when serving as a discriminative stimulus (DS) in different rat strains. However, there has been little work examining the influence of genotype on the discriminative stimulus (DS) properties of (-)-nicotine in mice, a species that has played a major role in understanding the relationship between genetics and (-)-nicotine pharmacological effects. To further our understanding of the role of genetics and the ability of (-)-nicotine to exert DS control of behavior in the mouse, a group of C57BL/6 mice was trained to discriminate 0.4 mg/kg (-)-nicotine from saline using a two-lever operant procedure. (-)-Nicotine's discriminative stimulus in C57BL/6 mice appears to be similar to that generated in the rat. Results from behavioral tests with other drugs indicated that d-amphetamine exhibited a partial generalization, while (+)-nicotine fully generalized with nicotine. Tests of antagonism with mecamylamine and scopolamine further showed the cholinergic specificity of the (-)-nicotine DS in the mouse; mecamylamine but not scopolamine completely antagonized the (-)-nicotine DS. This work lays the groundwork for future comparisons of different mouse strain's sensitivities to (-)-nicotine's discriminative stimulus as well as using this behavioral model to search for new nicotinic receptor agonists and antagonists.
- Published
- 1999
- Full Text
- View/download PDF
45. Effects of modulation of NMDA neurotransmission on response rate and duration in a conflict procedure in rats.
- Author
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Wiley JL, Compton AD, Holcomb JD, McCallum SE, Varvel SA, Porter JH, and Balster RL
- Subjects
- 2-Amino-5-phosphonovalerate pharmacology, Acetamides pharmacology, Animals, Conditioning, Operant drug effects, Dose-Response Relationship, Drug, Electroshock, Male, Quinoxalines pharmacology, Rats, Rats, Sprague-Dawley, Reward, 2-Amino-5-phosphonovalerate analogs & derivatives, Anti-Anxiety Agents pharmacology, Chlordiazepoxide pharmacology, Conditioning, Operant physiology, Conflict, Psychological, Diazepam pharmacology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Synaptic Transmission physiology
- Abstract
N-Methyl-D-aspartate (NMDA) antagonists and gamma-aminobutyric acid agonists share a number of common pharmacological properties, including motor and anticonvulsant effects. In the present study, site-selective NMDA antagonists were evaluated for potential anxiolytic efficacy and motor impairment in a modified Geller-Seifter conflict procedure, an animal model widely used to screen drugs for anxiolytic effects. Male Sprague-Dawley rats were trained to respond for food reward under a multiple FI 30 s (food only), FR 10 (food + shock) operant schedule. Consistent with the results of previous studies, the benzodiazepines chlordiazepoxide and diazepam selectively increased punished responding and increased response durations at higher doses. The competitive NMDA antagonist CGP 37,849 increased punished responding at some doses, though not selectively, and also increased response duration in both schedule components. The glycine-site modulators milacemide, ACEA 1011 and ACEA 1021, the NR2B-selective polyamine site antagonist eliprodil and NMDA did not produce anticonflict effects at any dose and had inconsistent effects on response durations. These results suggest that the anticonflict effects of NMDA antagonists are not as reliable as those of the benzodiazepines. Further research is needed to clarify the experimental conditions under which the anxiolytic potential of NMDA antagonists is most evident.
- Published
- 1998
- Full Text
- View/download PDF
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