| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
Chronobiology Laboratory, School of Biological Sciences, University of Surrey (S.W.L., D.J.S., J.A.), Guildford; and the Institute of Ophthalmology, Moorfields Eye Hospital (H.T., A.C.B.), London, United Kingdom; and Institut de Recherches Internationales Servier (R.D.), Courbevoie, France
Address all correspondence and requests for reprints to: Dr. Steven W. Lockley, Chronobiology Laboratory, School of Biological Sciences, University of Surrey, Guildford, Surrey, United Kingdom GU2 5XH. E-mail: s.lockley{at}surrey.ac.uk
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The circadian rhythm of melatonin is generated in the suprachiasmatic nuclei (SCN) of the hypothalamus, the site of the major circadian pacemaker, and it is entrained to the 24-h day primarily by the light-dark (LD) cycle (4). In the absence of a LD cycle (i.e. under constant conditions or temporal isolation), the melatonin rhythm reverts to its endogenous timing, usually to a "day" longer than 24 h (4, 20). This light-dark control is mediated by the eyes and transduced to the SCN via the retinohypothalamic tract (RHT) (21). The periodicity and timing of circadian rhythms can thus be an indirect assessment of the integrity of the retina-RHT-SCN pathway.
Blind individuals may have abnormal retinal processing and/or a defective RHT and, therefore, may not be capable of photic entrainment. In this case, their circadian rhythms, including the rhythm of melatonin production, would be expected to exhibit a non-24-h pattern. The occurrence and incidence of free running rhythms in the blind have been documented for the rhythms of melatonin, temperature, cortisol, and, to a lesser extent, sleep (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). Studies have concluded that blind individuals can be classified into four categories: 1) normally entrained to 24 h, 2) abnormally entrained to 24 h, 3) free running with a period either greater or less than 24 h, and 4) unstable, with no discernible pattern (25, 31).
In previous studies, the majority of blind individuals have had no conscious light perception. As the effects of light are intensity dependent with regard to both light-induced melatonin suppression (7, 35, 36, 37) and light-induced phase shifts in sighted humans (38, 39), the severity of visual loss may determine whether photic entrainment can occur. There has been no previous attempt to assess the relationship between endogenous circadian rhythms and visual loss or type of disease. Additionally, there have been few longitudinal field studies of blind individuals living in normal conditions measuring the effect of a conventional 24-h lifestyle on endogenous rhythms.
This report describes the aMT6s rhythms of 49 registered blind individuals, many of whom had sleep disorders, and relates the pattern of melatonin production to the severity of their visual loss and eye disease.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Forty-nine registered blind subjects were recruited from a
database compiled to assess the incidence of sleep disorders in the
blind (40). Ethical permission for the study was granted by the
University of Surrey advisory committee on ethics and the Moorfields
Eye Hospital ethics committee. Informed consent was obtained from all
subjects and included consent for the assessment of urine for excluded
medications. Ophthalmological examination and a structured interview
revealed that they suffered from a range of diseases and that the
duration and rapidity of onset of blindness varied (Table 1
). Of these 49
individuals, 19 had conscious light perception or better (LP subjects),
and 30 had no conscious perception of light (NPL subjects). LP subjects
were classified according to the severity of their visual loss as
having visual acuity of at least 3/60 vision (n = 7), being able
to count fingers (CF; n = 5), being able to see hand movements
only (HMO; n = 4), or being able to perceive light only (PL;
n = 3) and are referred to as LP subjects throughout this report
(Table 1a). NPL subjects were classified into 3 groups according to the
number of eyes present on the basis that there may be a quantitative
difference in the number of photoreceptors present in each group [2
eyes present (2E; n = 12), 1 eye present (1E; n = 7), or no
eyes present (0E; n = 11); Table 1b].
|
|
5) (41). All of
the subjects were in good health and were excluded if they were taking
any medication known to affect sleep and/or melatonin production
(tricyclic antidepressants, monoamine oxidase inhibitors, serotonin
reuptake inhibitors, benzodiazepines, neuroleptics, ß-blockers, or
sleeping medication). During the study, 8 of 19 LP subjects and 21 of
30 NPL subjects were employed, with conventional working hours. Study schedule
All subjects were studied for at least 3 consecutive weeks. No attempt was made to alter the lifestyles of the individuals during the study. For 48 h each week, the subjects collected sequential approximately four- hourly urine samples (eight-hourly overnight) for measurement of aMT6s. After each collection period, the subjects measured and recorded the volume or weight of the sample and the time of the urine collection period. A 5-mL urine aliquot was frozen (-20 C) until assay of aMT6s.
Assay
Urinary aMT6s concentrations were measured by RIA using the method of Arendt et al. (5) adapted by Aldhous and Arendt (42). Antiserum was supplied by Stockgrand Ltd., University of Surrey (Guildford, UK; batch G/S/1118–23884). All samples from an individual were measured in a single assay. The intraassay coefficients of variation (CVs) were 10.8% and 10.5% at 3.7 ng/mL (n = 10) and 26.4 ng/mL (n = 10), respectively, and the interassay coefficients of variation (CV) were 17.7%, 21.8%, 12.8%, and 10.0% at 3.4 ng/mL (n = 59), 23.5 ng/mL (n = 59), 39.6 ng/mL (n = 32), and 43.9 ng/mL (n = 19), respectively.
24-h aMT6s production
The mean 24-h aMT6s output was calculated for each week
(micrograms per 24 h) for each subject with the associated CV. The
data were grouped according to sex, age (19–29, 30–39, 40–49,
50–59, and 60 yr), severity of visual loss (LP subjects, 3/60
vision, CF, HMO, PL; NPL subjects, two, one, or no eyes present), light
perception (LP or NPL), and circadian rhythmicity (normally entrained,
abnormally entrained, free running, and unclassified) and were assessed
by one-way ANOVA.
Assessment of circadian rhythmicity
aMT6s output for each sequential collection period (nanograms
per mL) was converted to nanograms per h and subjected to cosinor
analysis (software provided by Dr. D. S. Minors, University of
Manchester, Manchester, UK) to provide the acrophase time (
),
amplitude, and mesor of the aMT6s rhythm. Only results that showed a
significant fit to a cosine curve (P < 0.05) were used
in further analyses. To assess any change in the timing of aMT6s
production and to determine the periodicity of the rhythm for each
subject, regression lines were fitted through the significant
acrophases (
= 24 h + slope). A rhythm was considered to be
significantly free running when the 95% confidence limits of the line
did not cross 0 (i.e. 24.00 h). Subjects were considered to
be entrained if the regression analysis was not significantly different
from 24 h. Subjects were classified as abnormally entrained if the
mean acrophase time fell outside the normal range for sighted
individuals (range; mean ± 2 SD, 4.2 ± 2.9
h; n = 80) (English J. and Arendt J., unpublished results) and as
normally entrained if the mean acrophase fell inside the normal range.
For free running subjects, any correlations of with age and PSQI
score were determined. Amplitudes derived from cosinor analysis were
analyzed by one-way ANOVA to investigate any difference between
subjects, and a CV for amplitude was calculated to measure within
subject variability. The data were grouped according to sex, age,
severity of visual loss, light perception, and circadian rhythmicity as
described for 24-h aMT6s production and were assessed by one-way
ANOVA.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The mean age and PSQI scores (±SD) for the whole
population (n = 49) were 46.1 ± 12.3 yr (range, 19–72 yr)
and 8.4 ± 3.5 (range, 3–16), respectively. There were no
significant differences with respect to age or PSQI score within the LP
subgroups, within NPL subgroups, or between all LP and NPL subgroups
(by one-way ANOVA, P > 0.05; Fig. 1, A and B). Overall, however, NPL
subjects were significantly older than LP subjects (mean ages ±
SD for LP and NPL subjects were 41.7 ± 11.7 and
48.9 ± 12.0 yr, respectively; P < 0.05),
although there was no significant difference in the PSQI scores
(P > 0.05; Fig. 1, A and B).
|
All subjects produced measurable amounts of urinary aMT6s. There
was a high degree of consistency in the 24-h aMT6s output within an
individual. The mean CVs (±SD) for 24-h aMT6s output for
LP and NPL subjects were 21.3 ± 10.9% and 17.1 ± 12.3%,
respectively. There was no significant difference in the mean 24-h
output within LP or NPL subgroups, between all LP and NPL subgroups, or
overall between LP and NPL subjects (P > 0.05; Fig. 1C
). The mean (±SD) 24-h aMT6s outputs were 12.7 ±
7.5 µg/24 h (range, 1.9–28.6 µg/24 h) and 9.4 ± 6.4 µg/24
h (range, 1.7–30.1 µg/24 h) for LP and NPL subjects, respectively.
There was no significant effect of age on aMT6s output
(P > 0.05), but there was a trend for output to
decrease with increasing age (r = -0.19). There was also no
significant difference between the 24-h aMT6s output with respect to
sex (P > 0.05).
Assessment of circadian rhythmicity
Subjects with light perception.
Overall, 18 of the 19 LP
subjects showed a significant rhythm in aMT6s production, as assessed
by cosinor analysis. Table 2A shows the
mean acrophase times and the period of the aMT6s rhythm. With respect
to the severity of visual loss, Table 3
shows that the majority of subjects in the LP subgroups were normally
entrained (range, 57–100%), and a minority of subjects were
abnormally entrained (range, 20–33%). One subject (S8) did not show
any significant rhythm and was defined as unclassified. Overall, of the
19 LP subjects, 14 individuals had normally entrained aMT6s rhythms
(74%), 4 subjects appeared to be abnormally entrained (21%), and 1
was unclassified (5%; Table 3). Figure 2A shows a representative example of a
subject with a normally entrained aMT6s rhythm.
|
|
|
Subjects with no perception of light.
Overall, 29 of 30 NPL
subjects showed a significant rhythm in aMT6s production (Table 2B).
With respect to the number of eyes present in NPL subjects, Table 3 and
Fig. 3 show that the distribution of the
circadian rhythm types varied among the 3 NPL subgroups. The incidence
of rhythm abnormalities was greater in unilaterally and bilaterally
enucleated individuals (2 eyes present, 42% abnormally entrained, 17%
free-running; 1 eye present, 71% free-running; no eyes present, 91%
free-running; Table 3). One subject (S35) did not show any
significant rhythm and was defined as unclassified. Three NPL subjects
(S28, S43, and S46) had visibly free-running rhythms, but the 95%
confidence limits of the line crossed 24.00 h. An additional
subject (S45) was classified as free running, although due to technical
problems, there were fewer samples, and the cosinor fits were
nonsignificant. Observation of the raw data plots revealed a
free-running rhythm with a of approximately 24.9 h.
|
). Figure 2, B and C, shows representative plots of individuals with
abnormally entrained and free running aMT6s rhythms, respectively.
In free-running NPL subjects, there was no significant correlation
between and the age or PSQI score of the subjects (r = -0.05
and -0.14, respectively). There was no significant difference in age,
PSQI, or 24-h aMT6s output within all subjects (n = 49) when
classified according to the four circadian types (P >
0.05). There was also no effect of rapidity or duration of blindness on
circadian type.
There was a significant difference (P < 0.05) in the mean amplitude between individuals, although this was not associated with any particular variable. The mean (±SD) amplitudes were 0.6 ± 0.4 µg/h (range, 0.1–1.4 µg/h) and 0.5 ± 0.3 µg/h (range, 0.1–1.4 µg/h) for LP and NPL subjects, respectively. However, aMT6s rhythm amplitudes were consistent within an individual; the mean CVs (±SD) for amplitude for LP and NPL subjects were 23.6 ± 9.7% and 27.9 ± 22.9%, respectively. There was no significant difference in the mean amplitude within and between LP and NPL subgroups (P > 0.05). Similarly, there was no significant difference in the mean amplitude between the different circadian rhythm types (P > 0.05). There was a nonsignificant trend for a decrease in amplitude with increasing age in all subjects (r = -0.28).
Disease
Several diseases were prevalent in the study population. Only individuals with eyes were included in this assessment, as the loss of eyes clearly prevents analysis of light perception in relation to disease.
Ten of the 19 LP subjects and 4 of the 19 NPL subjects with eyes suffered from a form of retinitis pigmentosa (RP). Eleven of the RP subjects had normally entrained aMT6s rhythms (8 LP and 3 NPL), and 3 appeared to have abnormally entrained rhythms (2 LP and 1 NPL). Retinal detachment was present in 1 LP subject and 6 of the 19 NPL subjects with intact eyes. Of these, 2 were normally entrained (1 LP and 1 NPL), 4 were abnormally entrained (4 NPL), and 1 subject had a free running aMT6s rhythm (1 NPL). No other diseases were common to more than 3 subjects.
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
As the phase-shifting effects of light are intensity dependent (38, 39), it is possible that the rhythm abnormalities found were due to insufficient light intensities in the subjects’ normal environment. The light intensities to which these individuals were exposed were not measured in this study, but they were all living in a normal environment and were exposed to light intensities comparable to those experienced by sighted individuals who are known to exhibit normally entrained rhythms in these lighting conditions. Therefore, it is unlikely that the abnormal aMT6s rhythms observed are due to insufficient light exposure.
Blind subjects with normally entrained rhythms are likely to have an intact and functional RHT, whereas in subjects with free running rhythms, the RHT is likely to be dysfunctional. The type and anatomical position of the disease and/or the number of eyes present may quantitatively alter the number of "circadian" photoreceptors of the retina. Of the NPL subjects, those with one or two eyes present have the highest proportion of individuals who are normally entrained, and this may be due to light entraining the SCN via an intact retina-RHT-SCN pathway (31, 32). The finding that some individuals with one eye present have normally entrained rhythms supports the idea that bilateral photic innervation is not required for subconscious circadian entrainment.
Subjects with no eyes by definition do not have an intact retina-RHT-SCN pathway and, therefore, would not be expected to have photically entrained rhythms. This hypothesis is upheld in the present results. Only one subject (S34) did not appear to have a free running rhythm. Although this subject has been diagnosed as anophthalmic (i.e. the eyes are not present), there is the possibility that this subject may have vestigial eyes remaining (cryptophthalmos), and that subconscious light perception is entraining the rhythm. There are two other possible hypotheses to explain this finding. A likely explanation is that our 4-week study was not long enough to detect individuals with a slow, free running rhythm, and that we studied S34 during a normal phase of a very slow, free running cycle. Alternatively, nonphotic zeitgebers may be entraining the rhythm: the existence of such individuals has been previously reported (32).
In those NPL subjects with entrained aMT6s rhythms, this study cannot determine whether the entrainment is via subconscious light perception or by nonphotic zeitgebers. An evaluation of melatonin suppression by light (32, 35) would indirectly test the integrity of retina-RHT-SCN function in NPL subjects. The identification and role of nonphotic time cues in human circadian rhythms still requires thorough investigation. Most of the free running blind subjects (14 of 17) were fully employed with conventional working hours. As their aMT6s rhythms were not entrained by the very strong temporal and social signals associated with keeping working hours, our results imply that the influence of nonphotic zeitgebers on aMT6s rhythms in blind individuals is likely to be highly individual.
This study used urinary aMT6s as a marker of circadian rhythmicity. There is extensive evidence that urinary aMT6s faithfully reflects the timing of both the plasma aMT6s and melatonin rhythm in entrained and phase-shifted conditions (5, 6, 7, 8, 9, 10, 11). Although the resolution of such rhythm assessments could be improved by sampling plasma at frequent intervals, this method, however, is impractical for long term field studies. The amount of melatonin produced over 24 h does not appear to differ in blind subjects compared to sighted individuals (18). Our results confirm the well documented decreases in overall melatonin production and amplitude associated with increasing age (17, 18, 19). No other variables were associated with changes in total aMT6s production.
There are both LP and NPL subjects who appear to be abnormally entrained to a 24-h day, a result also described in previous studies (25, 31). These results may be artifactual due to the restricted length of the study period. A rhythm appearing abnormally entrained may be free running, but with a period very close to 24 h, and would, therefore, take many weeks to exhibit a clear free running rhythm. Similarly, repeated measurements at regular intervals may coincidentally measure the rhythm at the same circadian period. To control for this, longitudinal studies are required that measure rhythms at irregular intervals over at least several months, and these are currently being completed.
The abnormal timing of strongly endogenous circadian rhythms (e.g. melatonin, core body temperature, and cortisol) is known to be associated with some sleep disorders (28, 29, 30, 31, 32, 33, 34). In the present study, the PSQI was used to select patients with disordered sleep and therefore possibly disordered circadian rhythms. Our results show that individuals with free running rhythms had a higher PSQI score than normally entrained individuals. This difference did not reach statistical significance because there was a small proportion of individuals (n = 3) with free running rhythms who did not report a subjective sleep disorder according to the PSQI (PSQI score, <5).
The effects of specific visual diseases on light processing for circadian function in humans is unknown. Studies have attempted to isolate the retinal photoreceptors required for circadian entrainment (43, 44), but it is still unclear whether rods, cones, a novel photoreceptor, or a combination or subset of photoreceptor types are involved. Although the association between human ocular disease type and circadian rhythms has not been investigated fully, preliminary studies of color-blind individuals suggest that deficient cone function has no effect on the ability of melatonin to be suppressed by light (45). Due to the large diversity of visual disorders in the study population, this report can only draw preliminary conclusions about the relationship between disease type and circadian rhythms in the blind. Several diseases were relatively common and could be associated with circadian rhythm status. Fourteen subjects were diagnosed as having RP, a group of disorders, some of which affect rods primarily and others of which affect midperipheral rods and cones. The majority of these (n = 11; 79%) had normally entrained rhythms, suggesting that RP does not significantly interfere with photic information processing for circadian entrainment. The possibility exists, however, that a mutation different from those in the subjects tested might affect circadian entrainment. Of the seven individuals with retinal detachments, two were normally entrained, four appeared to have abnormally entrained aMT6s rhythms, and one was free running. Interestingly, of only five NPL individuals in total with abnormally entrained rhythms, four of these (80%) had retinal detachments. These preliminary observations should prompt a closer inspection of visual disease in addition to levels of light perception of individuals when investigating circadian rhythms in blind subjects.
In conclusion, this study has shown that blind individuals with no perception of light (NPL) have a higher incidence of circadian rhythm disorders than subjects with light perception, as measured by aMT6s production.
|
Footnotes |
|---|
Received April 22, 1997.
Revised July 16, 1997.
Accepted July 25, 1997.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  S. Thompson, R. F. Mullins, A. R. Philp, E. M. Stone, and N. Mrosovsky Divergent Phenotypes of Vision and Accessory Visual Function in Mice with Visual Cycle Dysfunction (Rpe65rd12) or Retinal Degeneration (rd/rd) Invest. Ophthalmol. Vis. Sci., June 1, 2008; 49(6): 2737 - 2742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Czeisler and J. J. Gooley Sleep and Circadian Rhythms in Humans Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 579 - 597. [Abstract] [PDF]
|
|
|
|
|
|
A. J. Lewy Melatonin and Human Chronobiology Cold Spring Harb Symp Quant Biol, January 1, 2007; 72(0): 623 - 636. [Abstract] [PDF]
|
|
|
|
 |
|
 S. A. Jasser, J. P. Hanifin, M. D. Rollag, and G. C. Brainard Dim light adaptation attenuates acute melatonin suppression in humans. J Biol Rhythms, October 1, 2006; 21(5): 394 - 404. [Abstract] [PDF]
|
|
|
|
 |
|
 Y. Zhu, T. Zheng, R. G. Stevens, Y. Zhang, and P. Boyle Does "Clock" Matter in Prostate Cancer? Cancer Epidemiol. Biomarkers Prev., January 1, 2006; 15(1): 3 - 5. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. E. Blask, G. C. Brainard, R. T. Dauchy, J. P. Hanifin, L. K. Davidson, J. A. Krause, L. A. Sauer, M. A. Rivera-Bermudez, M. L. Dubocovich, S. A. Jasser, et al. Melatonin-Depleted Blood from Premenopausal Women Exposed to Light at Night Stimulates Growth of Human Breast Cancer Xenografts in Nude Rats Cancer Res., December 1, 2005; 65(23): 11174 - 11184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Arendt Melatonin: Characteristics, Concerns, and Prospects J Biol Rhythms, August 1, 2005; 20(4): 291 - 303. [Abstract] [PDF]
|
|
|
|
|
|
G. C. Brainard and J. P. Hanifin Photons, Clocks, and Consciousness J Biol Rhythms, August 1, 2005; 20(4): 314 - 325. [Abstract] [PDF]
|
|
|
|
|
|
J. F. Duffy and K. P. Wright Jr. Entrainment of the Human Circadian System by Light J Biol Rhythms, August 1, 2005; 20(4): 326 - 338. [Abstract] [PDF]
|
|
|
|
|
|
R. E. Mistlberger and D. J. Skene Nonphotic Entrainment in Humans? J Biol Rhythms, August 1, 2005; 20(4): 339 - 352. [Abstract] [PDF]
|
|
|
|
|
|
J. S. Emens, A. J. Lewy, B. J. Lefler, and R. L. Sack Relative Coordination to Unknown "Weak Zeitgebers" in Free-Running Blind Individuals J Biol Rhythms, April 1, 2005; 20(2): 159 - 167. [Abstract] [PDF]
|
|
|
|
|
|
J. Hannibal, P. Hindersson, J. Ostergaard, B. Georg, S. Heegaard, P. J. Larsen, and J. Fahrenkrug Melanopsin Is Expressed in PACAP-Containing Retinal Ganglion Cells of the Human Retinohypothalamic Tract Invest. Ophthalmol. Vis. Sci., November 1, 2004; 45(11): 4202 - 4209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Lewy, J. S. Emens, R. A. Bernert, and B. J. Lefler Eventual Entrainment of the Human Circadian Pacemaker by Melatonin is Independent of the Circadian Phase of Treatment Initiation: Clinical Implications J Biol Rhythms, February 1, 2004; 19(1): 68 - 75. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Fischer, R. Smolnik, M. Herms, J. Born, and H. L. Fehm Melatonin Acutely Improves the Neuroendocrine Architecture of Sleep in Blind Individuals J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5315 - 5320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Hack, S. W. Lockley, J. Arendt, and D. J. Skene The Effects of Low-Dose 0.5-mg Melatonin on the Free-Running Circadian Rhythms of Blind Subjects J Biol Rhythms, October 1, 2003; 18(5): 420 - 429. [Abstract] [PDF]
|
|
|
|
|
|
K.-i. Honma, S. Hashimoto, M. Nakao, and S. Honma Period and Phase Adjustments of Human Circadian Rhythms in the Real World J Biol Rhythms, June 1, 2003; 18(3): 261 - 270. [Abstract] [PDF]
|
|
|
|
|
|
R. G. Foster Keeping an Eye on the Time : The Cogan Lecture Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1286 - 1298. [Full Text] [PDF]
|
|
|
|
 |
|
 D.-J. Dijk and S. W. Lockley Functional Genomics of Sleep and Circadian Rhythm: Invited Review: Integration of human sleep-wake regulation and circadian rhythmicity J Appl Physiol, February 1, 2002; 92(2): 852 - 862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Arendt Melatonin, Circadian Rhythms, and Sleep N. Engl. J. Med., October 12, 2000; 343(15): 1114 - 1116. [Full Text]
|
|
|
|
|
|
M. von Schantz, I. Provencio, and R. G. Foster Recent Developments in Circadian Photoreception: More Than Meets the Eye Invest. Ophthalmol. Vis. Sci., June 1, 2000; 41(7): 1605 - 1607. [Full Text]
|
|
|
|
 |
|
 C. A. Czeisler, J. F. Duffy, T. L. Shanahan, E. N. Brown, J. F. Mitchell, D. W. Rimmer, J. M. Ronda, E. J. Silva, J. S. Allan, J. S. Emens, et al. Stability, Precision, and Near-24-Hour Period of the Human Circadian Pacemaker Science, June 25, 1999; 284(5423): 2177 - 2181. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
