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The well-known Two-Process Model of Sleep Regulation describes the integration of the circadian rhythm of arousal and sleep - Process C, and the homeostatic pressure to sleep - Process S. Presently, the known biological markers for Process C are melatonin and core body temperature; whereas, for Process S, there is no biological marker except that of aspects of the electroencephalogram (EEG). Endozepines are a class of endogenous compounds that act like benzodiazepines (BZ), i.e., serving as ligands for the BZ binding sites on GABA A receptors. Not much is known about the role of endozepines, in particular non-peptide endozepines, in the sleep field except very few reports about high concentrations observed in endozepine stupor, a rare phenomenon of idiopathic recurring stupor. We focused on hypoxanthine and thromboxane A2, which are considered to have endozepine function. This study aimed to examine the effect of 24 h of acute sleep deprivation on blood levels of hypoxanthine and thromboxane A2 of healthy subjects without sleep problems or disorders. The results showed a significant decrease of both compounds in the morning after sleep deprivation in comparison to the unrestricted normal sleep condition, thereby suggesting that these endozepines are secreted regularly while asleep, and, thus, are necessary for the sleep process. This study is the first to suggest a connection between specific biological markers - endozepines and Process S - in the Two-Process Model of Sleep Regulation and, furthermore, it sheds light on the possible role of endozepines in sleepiness and fatigue.

Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline , calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.

The last several decades have been characterized by the widespread usage of digital devices, especially smartphones. At the same time, there have been reports of both decline in sleep duration and quality and male fertility decline. The aim of this study was to assess the relationship between evening exposure to the light-emitting screens of digital media devices and measures of both sleep and sperm quality. Semen samples were obtained from 116 men undergoing fertility evaluation for the following sperm variables: volume (mL), pH, sperm concentration (million/mL), motility percentage (progressive% + non-progressive motility%), and total sperm count. Exposure to the screens of electronic devices and sleep habits was obtained by means of a questionnaire. Smartphone and tablet usage in the evening and after bedtime was negatively correlated with sperm motility (-0.392; -0.369; p < .05), sperm progressive motility (-0.322; -0.299; p < .05), and sperm concentration (-0.169; p < .05), and positively correlated with the percentage of immotile sperm (0.382; 0.344; p < .05). In addition, sleep duration was positively correlated with sperm total and progressive motility (0.249; 0.233; p < .05) and negatively correlated with semen pH (-0.349; p < .05). A significant negative correlation was observed between subjective sleepiness and total and progressive motility (-0.264; p < .05) as well as total motile sperm number (-0.173; p < .05). The results of this study support a link between evening and post-bedtime exposure to light-emitting digital media screens and sperm quality. Further research is required to establish the proposed causative link and may lead to the future development of relevant therapeutic and lifestyle interventions.

Sleep deprivation (SD) is suggested to be associated with reduced thermo-regulatory functions. This study aimed to quantify the effect of partial (PSD) and total (TSD) 24 h SD using a standard heat tolerance test (HTT). Eleven participants underwent HTT after well-rested state, PSD and TSD. No significant physiological differences were found between the exposures but subjective discomfort was higher after TSD. Evening chronotypes' temperature during HTT was higher after TSD compared with PSD (p = 0.017). After TSD, evening chronotypes compared to intermediate chronotypes' temperature was higher during the first hour of the HTT (p < 0.05), suggesting that thermo-regulatory function during exercise in the heat is influenced by chronotype.

Cognitive performance at night exhibits a substantial drop, typically before dawn. One of the means of dealing with this phenomenon, as well as with the accompanying sleepiness during sustained wakefulness, is the administration of stimulants. The most widely used and well-documented stimulants are caffeine, amphetamines, and modafinil. Of these, amphetamines are the least recommended, as they may severely affect behavior. Caffeine and modafinil seem to produce relatively milder side effects and usually only at high doses. Previous comparison studies have revealed equal efficacy of both the stimulants in maintaining alertness and performance during sustained wakefulness. However, these studies used relatively high, and thus not completely safe, doses of these drugs (600 mg caffeine and 400 mg modafinil). Therefore, the aim of the present study was to assess the efficacy of a low and medically safe dose of caffeine (200 mg) and modafinil (200 mg) in maintaining cognitive performance during sustained wakefulness. A flight simulation task was chosen for the assessment of the stimulants in a counter-balanced, within-subject design under four different conditions: baseline (no drugs), placebo, caffeine (200 mg), and modafinil (200 mg). The equal effectiveness of both drugs in abolishing the nocturnal drop in cognitive performance, as well as of oral temperature and blood pressure, supported the use of low doses of caffeine and modafinil for the maintenance of alertness in healthy subjects during sustained wakefulness.

A patient who developed an irregular sleep-wake pattern following prolactin-secreting pituitary microadenoma is described. The patient reported difficulties in sleep onset and awakening at the desired time, which caused major dysfunction in his daily life activities. Despite these difficulties, the sleep-related complaints of the patient remained unrecognized for as long as three yrs. Statistical analyses of the patient's rest-activity patterns revealed that the disruption of the sleep-wake circadian rhythm originated from a disharmony between ultradian (semicircadian) and circadian components. The circadian component displayed shorter than 24 h periodicity most of the time, but the semicircadian component fluctuated between longer and shorter than 12 h periods. Additionally, desynchrony in terms of period length was found in the tentative analyses of the rest-activity pattern, salivary melatonin, and oral temperature. While the salivary melatonin time series data could be characterized by a best-fit cosine curve of 24 h, the time series data of oral temperature was more compatible with 28 h best-fit curve. The rest-activity cycle during the simultaneous measurements, however, was best approximated by a best-fit curve of 21 h. The dysregulation of circadian rhythms occurred concomitantly, but not beforehand, with the onset of pituitary disease, thus suggesting an association between the two phenomena. This association may have interesting implications to the modeling of the circadian time-keeping system. This case also highlights the need to raise the awareness to circadian rhythm sleep disorders and to consider disruptions of sleep-wake cycle in patients with pituitary adenoma.

A patient with Gilles de la Tourette syndrome treated with haloperidol, ingested once daily after awakening from sleep, exhibited an irregular sleep-wake pattern with a free-running component of approximately 48 h. Transfer to risperidone, ingested once daily after awakening from sleep, was beneficial resulting in a sleep-wake cycle more synchronized at the appropriate phase to the external zeitgebers, and fewer nocturnal disturbances. The circadian sleep-wake schedule was fully synchronized when the patient had been subsequently treated with melatonin at 21:00h, before intended nocturnal sleep, in addition to risperidone in the morning. Restoration of the sleep-wake circadian pattern was accompanied by the patient's subjective report of significant improvement in his quality of life, social interactions, and occupational status. This observation suggests that circadian rhythm sleep disorders can be related to the typical neuroleptic haloperidol and restored by the atypical neuroleptic risperidone. Similar findings reported in patients suffering from other disorders support the hypothesis that the described disruption of the sleep-wake schedule is medication rather than illness-related. Therefore, it is very important to realize that circadian rhythm sleep disorders may be a side effect of neuroleptics.