Actigraphic estimates of sleep and the sleep-wake rhythm,and 6-sulfatoxymelatonin levels in healthy Dutch children

ABSTRACT

Sleep and the sleep-wake rhythm are essential for children’s health and well-being, yet reference values are lacking. This study therefore aimed to assess actigraphic estimates of sleep and the 24-h sleep-wake rhythm, as well as 6-sulfatoxymelatonin (aMT6s) levels in healthy children of different age groups. Additionally, relationships between the outcomes and sex, highest parental educational level (as an indication of socioeconomic status (SES)), and body-mass-index (BMI) were explored. In this cross-sectional study, healthy Dutch children (2–18 years) wore an actigraph (GT3x) for 7 consecutive days, collected first-morning void urine and completed a sleep log and sociodemographic questionnaire. Actigraphically estimated sleep variables were sleep onset latency (SOL), sleep efficiency (SE), total sleep time (TST), and wake after sleep onset (WASO). Non-parametric sleep-wake rhythm variables were intradaily variability (IV); interdaily stability (IS); the activity counts and timing of the least active 5-h period (L5counts and midpoint) and of the most active 10-h period (M10 counts and midpoint); and the relative amplitude (RA), i.e. the ratio of the difference and the sum of M10 and L5 counts. Finally, creatinine-corrected aMT6s levels were obtained by isotope dilution mass spectrometry. Effects of age group (preschool 2–5 years/school-aged 6–12 years/teenager 13–18 years), sex, highest parental educational level and BMI (Z-scores) were explored. Ninety-four children participated, equally divided across age groups (53% boys). Teenagers slept less, but more efficiently, than younger children, while their 24 h sleep-wake rhythm was the least stable and most fragmented (likely due to fragmentation of daytime activity). Additionally, aMT6s levels significantly declined over the age groups. Children from highly educated parents had lower sleep efficiency, but a more stable sleep-wake rhythm. Finally, sex or increase in BMI was not associated with any of the outcomes in this study. In conclusion, this study provides reference values of healthy children across different age groups and different sociodemographic factors. In the future, this information may help to better interpret outcomes in clinical populations.     

Small Molecular Inhibitors Block TRPM4 Currents in Prostate Cancer Cells,with Limited Impact on Cancer Hallmark Functions

Transient receptor potential melastatin 4 (TRPM4) is a broadly expressed Ca²⁺ activated monovalent cation channel that contributes to the pathophysiology of several diseases.For this study, we generated stable CRISPR/Cas9 TRPM4 knockout (K.O.) cells from the human prostate cancer cell line DU145 and analyzed the cells for changes in cancer hallmark functions. Both TRPM4-K.O. clones demonstrated lower proliferation and viability compared to the parental cells. Migration was also impaired in the TRPM4-K.O. cells. Additionally, analysis of 210 prostate cancer patient tissues demonstrates a positive association between TRPM4 protein expression and local/metastatic progression. Moreover, a decreased adhesion rate was detected in the two K.O. clones compared to DU145 cells.Next, we tested three novel TRPM4 inhibitors with whole-cell patch clamp technique for their potential to block TRPM4 currents. CBA, NBA and LBA partially inhibited TRPM4 currents in DU145 cells. However, none of these inhibitors demonstrated any TRPM4-specific effect in the cellular assays.To evaluate if the observed effect of TRPM4 K.O. on migration, viability, and cell cycle is linked to TRPM4 ion conductivity, we transfected TRPM4-K.O. cells with either TRPM4 wild-type or a dominant-negative mutant, non-permeable to Na⁺. Our data showed a partial rescue of the viability of cells expressing functional TRPM4, while the pore mutant was not able to rescue this phenotype. For cell cycle distribution, TRPM4 ion conductivity was not essential since TRPM4 wild-type and the pore mutant rescued the phenotype.In conclusion, TRPM4 contributes to viability, migration, cell cycle shift, and adhesion; however, blocking TRPM4 ion conductivity is insufficient to prevent its role in cancer hallmark functions in prostate cancer cells.     

CONSEQUENCES OF SHIFTWORKING ON SLEEP DURATION,SLEEPINESS, AND SLEEP ATTACKS

Rotating shift and permanent night work arrangements are known to compromise sleep. This study examined the effects of work schedule on sleep duration, excessive sleepiness, sleep attacks, driving, and domestic/professional accidents. A representative sample of the general population of the state of New York—3,345 individuals ≥18 yrs of age—was interviewed by telephone regarding their sleep and psychiatric and organic disorders. Multivariate models were applied to derive odds ratios (OR) after adjustment for age, sex, physical illness, mental disorders, obstructive sleep apnea, and sleep duration. On average (±SE), workers slept 6.7?±?1.5?h, but 40% slept <6.5?h/main sleep episode. Short-sleep duration (<6?h) was strongly associated with fixed night (OR: 1.7) and day-evening-night shiftwork arrangement (OR: 1.9). Some 20% of the workers manifested excessive sleepiness in situations requiring high attention, and it was associated with the fixed night (OR: 3.3) and day-evening-night work arrangements (OR: 1.5). Overall, 5% of the workers reported sleep attacks; however, they occurred three-times more frequently in the fixed night (15.3%) than other work arrangements (OR: 3.2). Driving accidents during the previous 12 months were reported by 3.6% of the workers and were associated with fixed night (OR: 3.9) and day-evening-night (OR: 2.1) work schedules. The findings of this study indicate that working outside the regular daytime hours was strongly associated with shorter sleep duration, sleepiness, and driving accident risk. Night work is the most disrupting, as it is associated with insufficient sleep during the designated rest span and excessive sleepiness and sleep attacks during the span of activity, with an associated consequence being increased driving accident risk. (Author correspondence: mohayon@stanford.edu)     

Infradian Rhythmicity in Sleep/Wake Ratio in Developing Infants

Although there are several reports on ultradian and circadian rhythms in newborns, we found only one report in which infradian periodicities are described for heart-rate measurements in the early stages of human development. Here, we report infradian rhythms in the monthly range in the sleep/wake cycle of four infants studied along 24 consecutive weeks. Our procedure was applied to sleep diary records from four healthy newborns. The data were arranged in binary time series representing sleep (?1) or wake (1) states. These time series were integrated in order to obtain the cumulative sleep/wake time. A measure of the sleep/wake ratio (SWR) was obtained by computing the average slope of the cumulative sleep/wake time. To extract periodicities we applied the Fourier periodogram to the temporal course of the SWR. We found a notorious difference in the SWR pattern among infants. In two infants the SWR showed a marked linear decay, spending more time asleep than awake, while in the two other infants oscillated near zero. We found robust oscillations in all children. In all cases the Fourier periodogram results present significant power in the infradian range. From these results, we suggest that sleep and wake durations are probably modulated by some internal stimuli.     

M(en)TORship lessons on life and death by the integrated stress response

Cells employ pro-survival and pro-adaptive pathways to cope with different forms of environmental stress. When stress is excessive, and the damage caused by it is unsustainable, cells engage pro-death pathways, which are in place to protect the host from the deleterious effects of harmed cells. Two important pathways that determine the balance between survival and death of stressed cells are the integrated stress response (ISR) and the mammalian target of rapamycin (mTOR), both of which converge at the level of mRNA translation. The two pathways have established avenues of communication to control their activity and determine the fate of stressed cells in a context-dependent manner. The functional interplay between the ISR and mTOR may have significant ramifications in the development and treatment of human diseases such as diabetes, neurodegeneration and cancer.     

Food and water deprivation effects on reproduction in female Blattella germanica

The effects of food and water deprivation on survival and reproduction of adult female German cockroaches were examined. Females, maintained under constant conditions, were deprived of food or water following adult maturation, mating, during the oothecal incubation period, and after first oothecal hatch. It was found that both food and water deprivations caused increased mortality, delays in the reproductive cycle and decreased oothecal hatch. The relative importance of food vs. water deprivation on reproduction is discussed along with possible reproductive strategies for this species.

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Résumé Les femelles, maintenues en conditions constantes, ont été privées d'aliments et d'eau après la maturité imaginale, l'accouplement, pendant la période d'incubation et après l'éclosion de la première oothèque. On a observé une mortalité accure, un retard dans le cycle de reproduction et une diminution des éclosions de l'oothèque. L'importance relative de l'alimentation par rapport au jeûne hydrique sur la reproduction est discutée en relation avec les stratégies reproductives possibles de cette espèce.

     

Modulation of plasma arginine vasopressin during rehydration in the Bedouin goat

When severely dehydrated Bedouin goats were allowed to drink to satiation their plasma arginine vasopressin concentration immediately dropped from a value of 19.9±9.4 pmol·l^-1 to 9.4±3.9 pmol·l^-1 (P<0.05). It continued to drop further until a concentration of 1.8±2.9 pmol·l^-1 was recorded, similar to that reported for goats allowed to drink freely. When the goats were shown the water but drinking was denied, plasma arginine vasopressin immediately dropped to 11.7±4.0 pmol·l^-1 (P<0.05) and further decreased to 10.0±4.8 pmol·l^-1 5 min following their sighting the water. This level, however, was not sustained and 2 h after the initial drop the high pre-trial concentration of plasma arginine vasopression was regained. Presumably, sighting of water by dehydrated goats induces an abrupt drop in their plasma arginine vasopressin level even before drinking commences. When rehydrated, by introducing water directly to the rumen, circumventing both the sensing of the water and the drinking proper, no immediate drop in the plasma arginine vasopression concentration of the newly rehydrated goats was observed. A delayed drop in the plasma arginine vasopressin levels took place slowly, concurrently with the drop in osmolality and concentration of Na⁺ in the plasma. It is suggested that sighting of water by dehydrated goats is involved in the modulation of plasma arginine vasopressin.     

Twelve-Hour Night Shifts of Healthcare Workers: A Risk to the Patients?

We assessed the impact of 12h fixed night shift (19:00–07:00h) work, followed by 36h of off-time, on the sleep–wake cycle, sleep duration, self-perceived sleep quality, and work-time alertness on a group composed of 5 registered and 15 practical nurses. Wrist actigraphy (Ambulatory Monitoring, Inc.), with data analysis by the Cole-Kripke algorithm, was applied to determine sleep/wake episodes and their duration. The sleep episodes were divided into six categories: sleep during the night shift (x¯=208.6; SD±90.6mins), sleep after the night shift (x¯=138.7; SD±79.6min), sleep during the first night after the night work (x¯=318.5; SD±134.6min), sleep before the night work (x¯=104.3; SD±44.1min), diurnal sleep during the rest day (x¯=70.5; SD±43.0min), and nocturnal sleep during the rest day (x¯=310.4; SD±188.9mins). A significant difference (p<.0001; T-test for dependent samples) was detected between the perceived quality of sleep of the three diurnal sleep categories compared to the three nocturnal sleep categories. Even thought the nurses slept (napped) during the night shift, their self-perceived alertness systematically decreased during it. Statistically significant differences were documented by one-way ANOVA (F=40.534 p<.0001) among the alertness measurements done during the night shift. In particular, there was significant difference in the level of perceived alertness (p<.0001) between the 7^th and 10^thh of the 12h night shift. These findings of decreased alertness during the terminal hours of the night shift are of concern, since they suggest risk of comprised patient care.