Twenty-four-hour and Ultradian Rhythmicities in Healthy Full-Term Neonates: Exogenous and Endogenous Influences

Eleven healthy, full-term babies were studied on the second day after birth and again 4 weeks later. The babies lived on a 24-h light/dark cycle (light from 0700D1900) and were bottle-fed every 4 h. Systolic blood pressure, heart rate, skin (abdomen) and rectal temperatures were measured at 10-min intervals for 24 h on each occasion of study. The behavioural state of the baby was measured at the same time, and this information was used to purify the raw data (i.e., to separate it into the endogenous, clock-driven and exogenous, lifestyle-driven components). Raw and purified data were assessed for 24-h and ultradian (12-, 8-, 6-, 4-, 3-, 2-h) periodicities by cosinor analysis. We confirm the development of 24-h rhythmicity in skin and rectal temperatures between day 2 and week 4; at the same time, ultradian rhythms (4-h) developed in all variables. For heart rate and systolic blood pressure the development of a 4-h ultradian rhythm was in phase with the behavioural changes produced by feeding; by contrast, for the temperatures, these weak exogenous components were accompanied by a stronger 4-h component, that was out of phase with feeding. Masking effects due to sleep and activity changed in size between day 2 and week 4. Also, those positive masks produced by waking activities were more marked in the light, whereas the negative masks produced by sleep were more marked in the dark. Some implications of these results for the development of rhythmicity in infants, particularly whether due to lifestyle or the development of internal processes, are discussed.     

Relationship between sleep stages and short‐term changes in rectal temperature in humans

Abstract

Sixteen volunteers have been studied during 3–4 control nights and eight of these subjects again during four successive sleeps on 30‐h “days”;. The experiments took place in a comfortable environment provided by an isolation chamber. Rectal temperature and the sleep EEG were measured throughout. The relationship between sleep stages, particularly SWS and REM sleep, and short‐term changes in rectal temperature has been investigated during both protocols. Care was taken to correct for or remove those temperature changes that could be attributed to circadian rhythmicity or the effects of loss of masking due to being awake. Results showed that there was a small but significant effect of sleep stages, with SWS producing a fall and REM sleep a rise in rectal temperature after a delay of about 30–48 minutes. It is concluded that such spontaneous changes in sleeping subjects accord with the results of other studies which indicate that thermoregulatory reflexes to hot or cold stimuli alter in different sleep stages.     

Sensitivity of Heart Rate and Blood Pressure to Spontaneous Activity in Transgenic Rats

Spontaneous changes in heart rate (HR), activity and systolic (SBP) and diastolic (DBP) blood pressure have been measured in 3 groups of 7 transgenic [TGR(mRen-2)27] rats for 4 weeks, starting at 12 weeks of age, and living on a 12:12 L:D schedule (light on at 07:00 h). Group TG-ENA was given enalapril, an angiotensin-converting enzyme inhibitor, in its drinking water; group TG-AMLO was given the calcium-channel blocker, amlodipine, by the same route; and group TG-VEH had no addition to its drinking water and so acted as a control. The sensitivity of the cardiovascular variables (CV's) to spontaneous activity was assessed throughout the study period by measuring the gradient of [CV / activity]. For the control (TG-VEH) group, mean HR was highest during the dark phase, at which time the sensitivity to spontaneous activity was least. By contrast, the circadian rhythms of SBP and DBP were inverted, peaking in the light (resting) phase, and there was no reliable difference between the light and dark phases with regard to the sensitivity of SBP or DBP to the effects of spontaneous activity. Enalapril reduced SBP and DBP, but did not alter their phase inversion with respect to HR. However, in SBP and DBP, as well as HR, sensitivities to spontaneous activity were now greater in the light phase. Amlodipine also reduced SBP and DBP and, in addition, greatly reduced the amplitude of their circadian rhythms. With this treatment also, sensitivity to spontaneous activity was greatest in the light phase for HR, SBP and DBP. A simple explanation of these results is that, in the absence of treatment, transgenic rats of this age have DBP and, particularly, SBP values that are too high in the light (resting) phase to permit much further rise due to spontaneous activity, and that this "ceiling effect" no longer holds if SBP and DBP have been reduced pharmacologically.     

Sleep wakefulness cycle

Abstract

48 right‐handed subjects performed verbal and spatial hemifield tachistoscopic tasks, half of them in spring and the other half in autumn. Significant differences were detected showing increased right visual field (left hemisphere) advantage in spring and increased left visual field (right hemisphere) advantage in autumn. Results may help to explain the reported seasonal propensity towards elevated mood in spring and towards depressed mood in autumn as related to the relative role of both hemispheres.     

Synthesis and evaluation of non-dimeric HCV NS5A inhibitors

Based on the symmetrical bidentate structure of the NS5A inhibitor BMS-790052, a series of new monodentate molecules were designed. The synthesis of 36 new non-dimeric NS5A inhibitors is reported along with their ability to block HCV replication in an HCV 1b replicon system. Among them compound 5a showed picomolar range activity along with an excellent selectivity index (SI > 90,000).     

Design,synthesis, and structure–activity relationships of dihydrofuran-2-one and dihydropyrrol-2-one derivatives as novel benzoxazin-3-one-based mineralocorticoid receptor antagonists

Dihydrofuran-2-one and dihydropyrrol-2-one derivatives were identified as novel, potent and selective mineralocorticoid receptor (MR) antagonists by the structure-based drug design approach utilizing the crystal structure of MR/compound complex. Introduction of lipophilic substituents directed toward the unfilled spaces of the MR and identification of a new scaffold, dihydropyrrol-2-one ring, led to potent in vitro activity. Among the synthesized compounds, dihydropyrrol-2-one 11i showed an excellent in vitro activity (MR binding IC₅₀ = 43 nM) and high selectivity over closely related steroid receptors such as the androgen receptor (AR), progesterone receptor (PR) and glucocorticoid receptor (GR) (>200-fold for AR and PR, 100-fold for GR).