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14 - "#$&’-$" Daniel F Kripke M.D 8950 Villa...

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Unformatted text preview: !!!"#$%&’()*+,-$.%/)"%*/, Daniel F. Kripke, M.D. 8950 Villa La Jolla Dr Suite A203 [email protected] 012345 64%$789%8*;,<)7-<8$=’>?%,<,&> [email protected];8*87(%A%(> 64%$789%8*;)9%78<%;=<%78(%,*? 6.%&’(8*9=’8?)$)?=,*?)? 6B)<8>)9?<))==’8?)?>*9$,;) [email protected];8*=’,(,=)$%,9%?; 6.%&’(($)8(;)*(,/9)=$)??%,* 012345 64%$789%8*;,<)7-<8$=’>?%,<,&> Adapted from Okamura, Yamaguchi, and Yagita, 2002 CYTOPLASM NUCLEUS NUCLEUS E box Per1, per2, per3, Cry DNA mRNA Clock|BMAL1 + CRY1 & CRY2 PER1 PER2 PER3 PER1 PER2 PER3 CRY Form heterodymers. protein enters nucleus mRNA translate proteins CELL CYTOPLASM NUCLEUS E box Per1, per2, per3, Cry DNA mRNA Clock|BMAL1 + CRY1 & CRY2 PER1 PER2 PER3 PER1 PER2 PER3 CRY Form heterodymers. protein enters nucleus mRNA translate proteins CELL CYTOPLASM NUCLEUS PER1 PER2 PER3 CRY Form heterodymers. protein enters nucleus CELL CYTOPLASM nuclear import-export CSNK1E CSNK1D GSK3B-P-P TIMELESS METABOLIZE Protein binding miRNA loops histones-P LIVER and HEART from Storch et al. Nature 2002;417:78-83 LIVER and HEART from Storch et al. Nature 2002;417:78-83 Double plots of RNA expression, ordered by progressive phases. Light: above mean. Dark: below mean. Number of RNA’s peaking at different times. 012345 @-;8*87(%A%(> CD#E.C01F+D1G301F3GH [email protected] .%&’(?)*?,$%?8*,=(%,* [email protected] [email protected] NOON 6PM MN 6AM NOON DI.C01G3G 0ID2IFC0EFI KKK5.II2+KKK 2$)/)$$)95<))= 012345 64%$789%8*;)9%78<%;=<%78(%,*? [email protected][email protected] 3GL.EIG4IM 6ILLI4051LBFEH5 6FI521G5I5013GNEF+ O)"&"P01Q3430+1LBFEH5 O)"&"PF35R51L5EFHIF+ [email protected] S#IGIL305TF35R5FC0315 CANCER CHEMOTHERAPY CANCER CHEMOTHERAPY • Always benefits and risks related to dose • Optimal time for benefits/risks ratio • Optimal times have not been studied for almost any treatment. LEUKEMIA CHEMOTHERAPY Black line is percent maintaining remission with standard treatment. Dotted line is percent maintaining remission with chronotherapy. Double-plotted study Subject in isolation shows Free-running component And longer sleep-wake Of ~ 36 hours. Synchronized NOON 6PM MN 6AM NOON DI.C01G3G 0ID2IFC0EFI KKK5.II2+KKK 2$)/)$$)95<))= SHIFTWORKERS (Especially graveyard night shift) • May be working during circadian low point • Result: sleeping on the job • Result: errors, e.g., Chernobyl, Exon Valdez, Three-Mile Island, Bhopal • Rhythms including low point may shift in time, but rarely enough for high on-job performance or good sleep off-job JET LAG • Trying to stay awake when the circadian system is ready for sleep. • Trying to sleep when the circadian system is ready for wake—leading to sleep loss---leading to more daytime sleepiness. • Adjustment may require 2 weeks. 012345 6.%&’(8*9=’8?)$)?=,*?)? PRC to 3000 lux LIGHT (exposure for 3 days for 3 hr/day) DELAY ADVANCE REGION: MORNING LIGHT SHIFTS SLEEPINESS EARLIER DELAY REGION: EVENING LIGHT SHIFTS SLEEPINESS LATER [email protected] DELAY ADVANCE SLEEPINESS ADVANCE LUX FOOT-CANDLE FULL MOON...
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14 - "#$&’-$" Daniel F Kripke M.D 8950 Villa...

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