Bioclox lecture17

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Human chronobiology: Jet lag, shift work : 

Human chronobiology: Jet lag, shift work PSYCH 623 Fall 2007 LECTURE 17


“This dead of midnight is the noon of thought, And Wisdom mounts her zenith with the stars.” --Anna Letitia (Aikin) Barbauld (1743-1825) A Summer's Evening Meditation

Goals for Lecture : 

Goals for Lecture Describe human applied chronobiology Describe shift work Describe jet lag Describe other effects of rhythms on human performance

Jet Lag: 

Jet Lag

Jet Lag: 

Jet Lag

Post-lunch Dip Effect : 

Post-lunch Dip Effect The "post-lunch dip" is a period of decreased alertness that strikes between 1 p.m. and 4 p.m. Between 1 p.m. and 4 p.m.: Work performance suffers People in dimly lit meeting rooms are apt to nod off The likelihood of getting into a car accident increases. Daily body temperature, hormone levels and other physiological cycles place us at a low ebb in the early afternoon, in contrast to periods of peak alertness we experience in the morning and early evening.

Post-lunch Dip Effect: 

Post-lunch Dip Effect The post-lunch dip occurs whether you eat lunch or not, but, a large, heavy lunch can exacerbate the effect. Strategies for coping with the post-lunch dip: a brief power nap (no longer than 10-15 minutes) a brisk walk outside drinking tea, coffee or ice-cold juice doing work that requires moderate physical exertion. If possible, the most mentally demanding work should be done in the morning or evening, depending on a person's rhythm.

Time-of-day and Errors : 

Time-of-day and Errors Human error catastrophes, such as Three Mile Island, Bhopal and Chernobyl, occurred in the middle of the night. The majority of single-vehicle driving accidents occur in the hours near dawn. We have relatively poor senses of night vision, hearing and smell compared with predatory animals, consequently our circadian rhythms put us to sleep at night for protection, and wake us up and get us going again the next day.

Time-of-day and Errors : 

Time-of-day and Errors The biological imperative to sleep creates problems for shift work, and for the military. Time-of-day (TOD) effects are highly variable between people

TOD and Visual Search : 

TOD and Visual Search Several studies show that visual search speed performance is better in the morning than the evening (Monk, 1979)

TOD and Thinking : 

TOD and Thinking Performance on thinking tests is better around lunchtime than in the morning or evening (Folkard, 1975)

TOD and Immediate Memory : 

TOD and Immediate Memory TOD effects on immediate memory for prose (Folkard and Monk, 1980)

TOD and Working Memory : 

TOD and Working Memory TOD effects on working memory depend on the memory load of the task (Folkard and Monk, 1979)

Cancer Treatment: 

Cancer Treatment Dr. Francis Lévi and colleagues reported a distinct advantage in those cancer patients who received variable drug infusion that corresponded to circadian rhythms as opposed to those who received constant drug infusion. They also observed that chronotherapy reduced the rate of severe adverse effects of drugs on the lining of the gastrointestinal tract by 5-fold, and halved the rate of functional impairment from peripheral nerve damage.

Cancer Treatment: 

Cancer Treatment They, concluded therefore that chronotherapy resulted in significantly less toxic and more effective results than constant drug administration. A very narrow margin exists between maximum therapeutic and unacceptable toxic effects for cytotoxic and cytostatic drugs used in chemotherapy of malignant tumors. Cytotoxic agents as well as being toxic to the tumor cells are also toxic to the healthy host cells.

Cancer Treatment: 

Cancer Treatment Requires a method to reduce the damage to the non-cancerous host cells when applying chemotherapy. Studies on rats and mice have shown that the effectiveness of anti-cancer agents are highly dependent on the time of the day when most cells are moving in to the DNA synthesis phase (S phase) of the cell cycle. If the cell cycle phase of the tumor cells can be changed from that of the host cells, treatment can be given at the time of the day when damage by the cytotoxic agents to the healthy cells is at a minimum and susceptibility of the tumor cells to cytotoxic agents is at a maximum.


Vinorelbine toxicity / efficacy in PO3-bearing B6D2F1 mice VRL 20 mg/kg Lethal toxicity Tumour relapse on day 60 13 13 8 11 P < 0.005 7 or 11 19 or 23 7 or 11 19 or 23 Injection time (HALO) Injection time (HALO)

Cure rate of weekly vinorelbine in B6D2F1 mice with P388 leukemia depending on dosing time: 

Cure rate of weekly vinorelbine in B6D2F1 mice with P388 leukemia depending on dosing time Cure rate Dosing time (HALO) % Dose mg/kg

Diurnal cortisol rhythm as a predictor of breast cancer survival (Sephton et al 2000: 92, 994): 

Diurnal cortisol rhythm as a predictor of breast cancer survival (Sephton et al 2000: 92, 994) Prospective study: 104 patients with metastatic breast cancer to look at psychotherapy Salivary cortisol at 08,12,17, 21 x 3 days NK cell number and activity Lack of circadian rhythm in cortisol Independent predictor of survival Average survival 3.2 vs. 4.5 years (p = 0.0036) Cortisol rhythm predicted survival from 1 - 7 years Associated with low NK cell activity and numbers

Survival based on cortisol slope: 

Survival based on cortisol slope

Circadian Factors Predictive of Outcome: 

Circadian Factors Predictive of Outcome Cortisol diurnal rhythm (breast cancer) Rest-activity cycle (colon cancer) Damped Normal Rhythm 11 26 22 55 0 10 20 30 40 50 60 Colon p < 0.0001 Breast p < 0.004 Survival at 4 years (%) Mormont et al. Clin Cancer Res 2000 ; Sephton et al. JNCI 2000

Circadian dysfunction promotes tumor growth in mice (Filipski et al 2001 ): 

Circadian dysfunction promotes tumor growth in mice (Filipski et al 2001 ) SNC-lesioned and sham-operated inoculated with osteosarcoma or pancreas ca cells Monitored for rhythms in Activity, temperature, cortisol, lymphocyte count Post mortem SCN ablation was confirmed histol. In mice where rest activity rhythms were ablated Tumor growth was 2-3 times faster (p = 0.01) On day 21 tumor weight 1443 mg vs. 490 mg Survival was shorter (P=0.01) 22 (23-29) vs 26 (19-25) days


Dexamethasone Feeding Melatonin Light Nonphotic stimuli Circadian system Resetting the clock Can we enhance circadian rhythms in cancer patients?

Cancer Surgery : 

Cancer Surgery In pre-menopausal women surgical cure of breast cancer is more likely to be successful if performed in the middle of the woman's menstrual cycle i.e. in the week following ovulation. This improved outcome is hormone related. In the first half of the menstrual cycle, estrogen levels are high while progesterone is not produced. In the second half of the cycle, progesterone levels rise and estrogen levels fall. Perhaps progesterone may be inhibiting the production of some enzymes that that help spread the cancer.

Asthma : 

Asthma Many asthma patients know the trauma of often staying awake most of the night. Normal lung functions show circadian rhythms, where airway resistance reaches a high point and lung function reaches a low point (particularly pronounced in asthma patients) early in the morning.

Asthma : 

Asthma This is correlated with other variables known to affect airway resistance showing a circadian rhythm, Plasma cortisol and catecholamines All reach a minimum during the night and bronchial activity to allergens and histamines which reach a maximum during the night. Therefore, chronotherapy for asthma is aimed at getting maximal effect from bronchodilator medications during the early hours of the day.

Asthma : 

Asthma In contrast to the physicians typical administration of oral drugs in the morning, it is now believed by many researchers that giving these drugs around 3 p.m. brings better results without increasing side effects. E.g., the bronchodilator Uniphyl, a long-acting theophylline preparation (approved by the FDA in 1989) when taken once a day in the evening (around 6 to 7 p.m.) causes theophylline blood levels to reach their peak and improves lung function during early morning (3 to 5 a.m.).

Allograft rejection : 

Allograft rejection   Researches have observed that over 60% of allograft rejections occur between 20.00 hours and 08.00 hours. Therefore, it has been suggested that evening administration of steroids might be more useful to obtain the immuno-suppressive response when it is most required.

Delayed and advanced phase sleep syndrome: 

Delayed and advanced phase sleep syndrome Delayed phase sleep syndrome is due to the phase of the sleep-wake cycle showing a circadian rhythm which is delayed and results in an inability to fall asleep and arise at conventional clock times. Sleep is usually delayed until early morning with a consequent delay in rising. Although, this may clearly represent the life style of certain individuals (such as teenagers), in others it is a disorder, where the pacemaker is less sensitive to light.

Delayed and advanced phase sleep syndrome: 

Delayed and advanced phase sleep syndrome Delayed phase sleep syndrome has been cured using chronotherapy through successively delaying sleep 1 to 2 hours per day for several days by exposing the patients to bright light.

Delayed and advanced phase sleep syndrome: 

Delayed and advanced phase sleep syndrome Advanced phase sleep syndrome is exactly the opposite of delayed phase sleep syndrome, where sleep is advanced to the early hours of the night following an early rise. Delayed and advanced phase sleep disorders can both be overcome by exposure to bright light which will help the patients to initiate and maintain the phase shift.

Delayed and advanced phase sleep syndrome: 

Delayed and advanced phase sleep syndrome It has been observed in patients with manic depression that their circadian rhythms are abnormally phased (earlier than normal). These patients therefore tend to wake up early. It has been suggested that in manic depressives, the endogenous oscillator may be faster than normal, showing a time period < 24 hours.

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