Recent progress in biological clock research has facilitated genetic analysis of circadian rhythm sleep disorders, such as delayed sleep phase syndrome (DSPS) and non-24-h sleep-wake syndrome (N-24). We analyzed the human period3 (hPer3) gene, one of the human homologs of the Drosophila clock-gene period (Per), as a possible candidate for rhythm disorder susceptibility. All of the coding exons in the hPer3 gene were screened for polymorphisms by a PCR-based strategy using genomic DNA samples from sleep disorder patients and control subjects. We identified six sequence variations with amino acid changes, of which five were common and predicted four haplotypes of the hPer3 gene. One of the haplotypes was significantly associated with DSPS (Bonferroni's corrected P = 0.037; odds ratio = 7.79; 95% CI 1.59-38.3) in our study population. Our results suggest that structural polymorphisms in the hPer3 gene may be implicated in the pathogenesis of DSPS.

A convenient way to estimate internal body time (BT) is essential for chronotherapy and time-restricted feeding, both of which use body-time information to maximize potency and minimize toxicity during drug administration and feeding, respectively. Previously, we proposed a molecular timetable based on circadian-oscillating substances in multiple mouse organs or blood to estimate internal body time from samples taken at only a few time points. Here we applied this molecular-timetable concept to estimate and evaluate internal body time in humans. We constructed a 1.5-d reference timetable of oscillating metabolites in human blood samples with 2-h sampling frequency while simultaneously controlling for the confounding effects of activity level, light, temperature, sleep, and food intake. By using this metabolite timetable as a reference, we accurately determined internal body time within 3 h from just two anti-phase blood samples. Our minimally invasive, moleculartimetable method with human blood enables highly optimized and personalized medicine.metabolomics | circadian rhythm | liquid chromatography mass spectrometry | diagnostic tool M any organisms possess a molecular time-keeping mechanism, a circadian clock, which has endogenous, self-sustained oscillations with a period of about 24 h. Circadian regulation of cell activity occurs in diverse biological processes such as electrical activity, gene/protein expression, and concentration of ions and substances (1, 2). In mammals, for example, several clock genes regulate circadian gene expression in central and peripheral clock tissues (3-9), as well as metabolites in the blood (10-15). Reflecting circadian regulation of such processes, the potency and toxicity of administered drugs depends on an individual's body time (BT) (16)(17)(18)(19)(20)(21)(22). Drug delivery according to body time improves the outcome of pharmacotherapy by maximizing potency and minimizing toxicity (23), and administrating drugs at an inappropriate body time can result in severe side effects (22). For example, rhythm disturbances were induced by administration of IFN-α during the early active phase in mice, although unaffected during the early rest phase (22); and the time of administration of two anticancer drugs, adriamycin (6:00 AM) and cisplatin (6:00 PM), made a lower toxicity effect than its antiphasic administration (24). However, several reports showed that internal body time varies by 5-6 h in healthy humans (25, 26) and as much as 10-12 h in shift workers without forced entrainments (27,28). Therefore, for efficient application of body-time drug delivery or "chronotherapy" (16-20) in a clinical setting, a simple and robust method for estimating an individual's internal body time is needed.Additionally, the timing of food intake may contribute to weight gain (29) and metabolic disease (30) because energy regulation and circadian rhythms are molecularly and physiologically intertwined (31-41). For example, mice fed a high-fat diet during a 12-h light phase gain significantly more ...

Fourteen inpatients with dementia showing sleep and behavior disorders (average age = 75 years), and 10 control elderly people (average age = 75 years) were carefully observed for 2 months. Four weeks of morning light therapy markedly improved sleep and behavior disorders in the dementia group. The measurement of sleep time and the serum melatonin values suggests that sleep and behavior disorders in the dementia group are related to decreases in the amplitude of the sleep-wake rhythm and decreases in the levels of melatonin secretions. Morning light therapy significantly increased total and nocturnal sleep time and significantly decreased daytime sleep time. These results indicate that morning bright light is a powerful synchronizer that can normalize disturbed sleep and substantially reduce the frequency of behavior disorders in elderly people with dementia.

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