Biological Time‐Dependent Difference in Effect of Peroxynitrite Demonstrated by the Mouse Hot Plate Pain Model

We previously demonstrated the rhythmic pattern of L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO‐mediated toxicity. In the present study, we evaluated the biological time‐dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite‐induced changes in the analgesic effect of morphine using the mouse hot‐plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light‐dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot‐plate testing, respectively. The analgesic effect of morphine exhibited significant biological time‐dependent differences in the thermally‐induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine‐induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.     

Age-Related Differences of Blood Pressure Profile in Essential Hypertension

The purpose was to assess age-related circadian changes of blood pressure profile (BPP) employing a truncated Fourier series with four harmonics (tFs) in patients with essential hypertension. The study was performed on 32 patients with essential hypertension divided in two groups: (A) 15 patients younger than 55 years and (B) 17 patients older than 60 years. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were monitored every 20 minutes for 24h with a noninvasive portable device (SpaceLabs 90202). To evaluate the existence of SBP and DBP circadian rhythms a one-sample runs-test was performed and the mesor, amplitude, and acrophase from the overall curve of each patient were obtained by tFs. In both groups, SBP and DBP profiles showed a first peak in the late morning and a second peak in the early evening around the same hours. The two peaks in the SBP profile were higher and the two peaks in the DBP profile were lower in older patients than in younger ones (p. 01, p <. 05, p>. 3, p>. 05). The truncated Fourier series with four harmonics evidences different age-related BP profiles characterized by two peaks with higher SBP and lower DBP in elderly patients. These changes of BPP are in accordance with the reported higher risk of cardiovascular events observed around the same hours. (Chronobiology International, 14(4), 397–407, 1997)     

Circadian Rhythm of Blood Pressure and Heart Rate in Healthy Persons and Kidney Transplant Patients: Correlations with Activity

Fourteen diurnally active (07: 00–22: 39 h) normotensive healthy control subjects and 14 kidney transplant patients were studied by ambulatory blood pressure monitoring and wrist actigraphy simultaneously during one 24-h period. In the control group, circadian rhythms in systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressure, heart rate (HR), and wrist activity were documented by cosinor analysis with comparable afternoon peak times. In contrast, circadian rhythms with afternoon acrophases were detected only in HR and wrist activity in the patient group. The correlation of wrist activity with HR in controls and patients was comparable. Wrist activity and blood pressure were associated (r = 0.65 DBP and 0.54 SBP; p < 0.05) in controls, while in patients the relationship was weak or absent (r ranging from 0.02 SBP to 0.22 DBP). In 6 of 14 patients, BP and wrist activity were negatively correlated, reflecting the existence of nocturnal hypertension. In eight others, the correlation was small but positive. The 24-h pattern in BP and wrist activity in controls was comparably phased; however, this was not the case for the transplant patients, indicating the day-night pattern in blood pressure in this group is strongly dependent on pathologic phenomena rather than activity level and pattern.     

Physical activity,and not fat mass is a primary predictor of circadian parameters in young men

Circadian rhythms are ≈24?h oscillations in physiology and behavior, and disruptions have been shown to have negative effects on health. Wrist skin temperature has been used by several groups as a valid method of assessing circadian rhythms in humans. We tested the hypothesis that circadian temperature amplitude (TempAmp) and stability (TempStab) would significantly differ among groups of healthy young men of varying adiposities, and that we could identify physiological and behavioral measures that were significantly associated with these temperature parameters. Wrist skin temperatures taken at 10?min intervals for 7 consecutive days were determined in 18 optimal (OGroup), 20 fair (FGroup) and 21 poor (PGroup) %Fat grouped young men and subsequently analyzed using available validated software. Body composition, cardiorespiratory fitness, actigraphy, daily nutritional and sleep data, and fasting lipid, insulin and glucose concentration measures were also determined. Significant changes in TempAmp and TempStab parameters in subjects with a single metabolic syndrome (MetS) risk factor compared to those with no MetS factors was observed. In addition, stepwise multivariate regression analyses showed that 50% of the variance in TempAmp was explained by actigraphy (mean steps taken per day; MSTPD), cardiorespiratory fitness, and late night eating per week (#LNE); and 57% in TempStab by MSTPD, time spent in moderate-to-vigorous activity per day, fat mass, and #LNE. Overwhelmingly, physical activity was the most important measure associated with the differences in circadian rhythm parameters. Further research is warranted to determine the effects of increasing the amount and timing of physical activity on the status of the circadian system in a variety of populations.     

In Sync with the Family: Children and Partners Influence the Sleep‐Wake Circadian Rhythm and Social Habits of Women

Different factors have been proposed to influence morningness‐eveningness, biological rhythms, and sleep‐wake cycles, but few studies focused on the influence of social habits. Here, we focus on the influence of children and partners on the social habits of women at different stages of their lives and on synchronization within the family. One hundred and seventy‐nine women participated in the study and were allocated into four groups: women without children, pregnant women without children, pregnant women with children, and non‐pregnant mothers. Morningness was predicted by the presence of children, and earlier chronotype was predicted by the presence of children, pregnancy, and age. Average sleep duration was longest in pregnant women. The presence of children was responsible for a difference in rise times of approximately 1.5 h on the weekend. Subjective sleep‐onset latencies were shortest in women with children. The synchrony between partners (husband/wife) was 0.46 in women without children, 0.79 in pregnant women, 0.40 in women with children, and 0.56 between mother and child. Partners’ chronotypes were highly correlated, as were those of mother and child. This study suggests children have a strong influence on their mother's lifestyle and sleep‐wake rhythm, far beyond the first months of life, and that children are a more important social factor than the male partner.     

Validation of an innovative method,based on tilt sensing,for the assessment of activity and body position

Since there is less movement during sleep than during wake, the recording of body movements by actigraphy has been used to indirectly evaluate the sleep–wake cycle. In general, most actigraphic devices are placed on the wrist and their measures are based on acceleration detection. Here, we propose an alternative way of measuring actigraphy at the level of the arm for joint evaluation of activity and body position. This method analyzes the tilt of three axes, scoring activity as the cumulative change of degrees per minute with respect to the previous sampling, and measuring arm tilt for the body position inference. In this study, subjects (N?=?13) went about their daily routine for 7 days, kept daily sleep logs, wore three ambulatory monitoring devices and collected sequential saliva samples during evenings for the measurement of dim light melatonin onset (DLMO). These devices measured motor activity (arm activity, AA) and body position (P) using the tilt sensing of the arm, with acceleration (wrist acceleration, WA) and skin temperature at wrist level (WT). Cosinor, Fourier and non-parametric rhythmic analyses were performed for the different variables, and the results were compared by the ANOVA test. Linear correlations were also performed between actimetry methods (AA and WA) and WT. The AA and WA suitability for circadian phase prediction and for evaluating the sleep–wake cycle was assessed by comparison with the DLMO and sleep logs, respectively. All correlations between rhythmic parameters obtained from AA and WA were highly significant. Only parameters related to activity levels, such as mesor, RA (relative amplitude), VL5 and VM10 (value for the 5 and 10 consecutive hours of minimum and maximum activity, respectively) showed significant differences between AA and WA records. However, when a correlation analysis was performed on the phase markers acrophase, mid-time for the 10 consecutive hours of highest (M10) and mid-time for the five consecutive hours of lowest activity (L5) with DLMO, all of them showed a significant correlation for AA (R?=?0.607, p?=?0.028; R?=?0.582, p?=?0.037; R?=?0.620, p?=?0.031, respectively), while for WA, only acrophase did (R?=?0.621, p?=?0.031). Regarding sleep detection, WA showed higher specificity than AA (0.95?±?0.01 versus 0.86?±?0.02), while the agreement rate and sensitivity were higher for AA (0.76?±?0.02 versus 0.66?±?0.02 and 0.71?±?0.03 versus 0.53?±?0.03, respectively). Cohen’s kappa coefficient also presented the highest values for AA (0.49?±?0.04) and AP (0.64?±?0.04), followed by WT (0.45?±?0.06) and WA (0.37?±?0.04). The findings demonstrate that this alternative actigraphy method (AA), based on tilt sensing of the arm, can be used to reliably evaluate the activity and sleep–wake rhythm, since it presents a higher agreement rate and sensitivity for detecting sleep, at the same time allows the detection of body position and improves circadian phase assessment compared to the classical actigraphic method based on wrist acceleration.     

Epigenetic Maternal Effects on Endogenous Rhythms in Precocial Birds

Development involves interactions between genetic and environmental influences. Vertebrate mothers are generally the first individuals to encounter and interact with young animals. Thus, their role is primordial during ontogeny. The present study evaluated non‐genomic effects of mothers on the development of rhythms of precocial Japanese quail (Coturnix c. japonica). First, we investigated the influence of mothering on the ontogeny of endogenous rhythms of young. We compared circadian and ultradian rhythms of feeding activity of quail reared with or without adoptive mothers. More brooded than non‐brooded quail presented a circadian and/or an ultradian rhythm. Thus, the presence of the mother during the normal brooding period favors, in the long term, expression of rhythms in the young. Second, we investigated the influence of rhythmic phenotype of the mother on the development of endogenous rhythms of young by comparing quail brooded by circadian‐rhythmic adoptive mothers (R) to quail brooded by circadian‐arrhythmic adoptive mothers (A). More R‐brooded than A‐brooded quail expressed circadian rhythmicity, and circadian rhythm clarities were greater in R‐brooded than A‐brooded quail. Ultradian rhythmicity did not differ between R‐ and A‐brooded quail, nor between R and A adoptive mothers. Thus, the rhythmic phenotypes of quail mothers influence the rhythmic phenotypes of their young. Our results demonstrate that mothers of precocial birds influence epigenetically the ontogeny of endogenous rhythms of the young they raise.     

The Daily Melatonin Pattern in Djungarian Hamsters Depends on the Circadian Phenotype

Djungarian hamsters (Phodopus sungorus) bred at the Institute of Halle reveal three different circadian phenotypes. The wild type (WT) shows normal locomotor activity patterns, whereas in hamsters of the DAO (delayed activity onset) type, the activity onset is continuously delayed. Since the activity offset in those hamsters remains coupled to “light-on,” the activity time becomes compressed. Hamsters of the AR (arrhythmic) type are episodically active throughout the 24?h. Previous studies showed that a disturbed interaction of the circadian system with the light-dark (LD) cycle contributes to the phenomenon observed in DAO hamsters. To gain better insight into the underlying mechanisms, the authors investigated the daily melatonin rhythm, as it is a reliable marker of the circadian clock. Hamsters were kept individually under standardized laboratory conditions (LD 14:10, T?=?22°C?±?2°C, food and water ad libitum). WT, DAO (with exactly 5?h delay of activity onset), and AR hamsters were used for pineal melatonin and urinary 6-sulfatoxymelatonin (aMT6s) measurement. Pineal melatonin content was determined at 3 time points: 4?h after “light-off” [D?+?4], 1?h before “light-on” [L???1], and 1?h after “light-on” [L?+?1]). The 24-h profile of melatonin secretion was investigated by transferring the animals to metabolic cages for 27?h to collect urine at 3-h intervals for aMT6s analysis. WT hamsters showed high pineal melatonin content during the dark time (D?+?4, L???1), which significantly decreased at the beginning of the light period (L?+?1). In contrast, DAO hamsters displayed low melatonin levels during the part of the dark period when animals were still resting (D?+?4). At the end of the dark period (L???1), melatonin content increased significantly and declined again when light was switched on (L?+?1). AR hamsters showed low melatonin levels, comparable to daytime values, at all 3 time points. The results were confirmed by aMT6s data. WT hamsters showed a marked circadian pattern of aMT6s excretion. The concentration started to increase 3?h after “light-off” and reached daytime values 5?h after “light-on.” In DAO hamsters, in contrast, aMT6s excretion started about 6?h later and reached significantly lower levels compared to WT hamsters. In AR animals, aMT6s excretion was low at all times. The results clearly indicate the rhythm of melatonin secretion in DAO hamsters is delayed in accord with their delayed activity onset, whereas AR hamsters display no melatonin rhythm at all. Since the regulatory pathways for the rhythms of locomotor activity and melatonin synthesis (which are downstream from the suprachiasmatic nucleus [SCN]) are different but obviously convey the same signal, we conclude that the origin of the phenomenon observed in DAO hamsters must be located upstream of the SCN, or in the SCN itself. (Author correspondence: weinert@zoologie.uni-halle.de)     

Circannual Variation in the Incidence of Uterine Cervix Cancer

The impact of uterine cervix cancer (UCC) can be greatly reduced by regular vaginal examination and other preventive measures. With this aim, UCC screening programs had been developed and applied for several years in Mexico and elsewhere. One point still to be considered in such preventive programs is the possible circannual pattern in the morbidity or mortality of UCC. With the aim of identifying a possible circannual pattern of variation in the incidence of UCC, we analyzed the monthly totals of positive detected cases of UCC in the state of Nuevo León (Mexico) between 1978 and 1987. For eliminating bias due to the seasonal variation in the number of preventive check-ups, data were first expressed in percentage of tests done in the same month. The least-squares fit of a 1 -year cosine curve to the data reveals a statistically significant circannual pattern (p = 0.013), with a maximum of relative incidence detected in February. Results indicate UCC incidence higher than the yearly average during the winter, with secondary peaks in August and November. This pattern of variation is similar if one considers separately for analysis the relative incidence of type III, IV, or V UCC (relating to cases suggesting, highly suggesting, or concluding a malignant alteration, respectively). For evaluating the cost-effectiveness of the UCC screening campaign providing these data, the monthly totals of screening check-ups done over the same period were also analyzed. Results reveal a statistically significant circannual rhythm (p > 0.001), with a maximum detected in June. This timing seems to be related to the incidence of most common diseases in Mexico, such as giardiasis and salmonellosis, but not to the UCC morbidity rates. Health educational and screening campaigns for prevention of UCC and other major conditions should be timed during the year according to morbidity and mortality statistics, for which a circannual pattern of variation is documented herein.