Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep.

Advanced primary open-angle glaucoma (POAG) is characterized by progressive retinal ganglion cell complex (RGCC) damage that may cause subsequent disruption of the circadian rhythms. Therefore, we evaluated circadian body temperature (BT) rhythm and sleep characteristics of 115 individuals (38 men and 77 women) diagnosed with POAG. GLV (global loss volume; %), a measure of RGCC damage, was estimated by high-definition optical coherence tomography, and RGC functional ability was assessed by pattern electroretinogram amplitude (PERGA). Depending on dynamics of POAG progression criteria, two groups were formed that were distinctively different in GLV: Stable POAG group (S-POAG; GLV = 5.95 ± 1.84, n = 65) and Progressive POAG group (P-POAG; GLV = 24.27 ± 5.09, n = 50). S-POAG and P-POAG groups were not different in mean age (67.61 ± 7.56 versus 69.98 ± 8.15) or body mass index (24.66 ± 3.03 versus 24.77 ± 2.90). All subjects performed 21 around-the-clock BT self-measurements during a 72-h period and kept activity/sleep diaries. Results showed pronounced disruption of circadian physiology in POAG and its progression with increasing severity of the disease. The daily mean of BT was unusually low, compared to age-matched controls. Moreover, our results revealed distinctive features of BT circadian rhythm alterations in POAG development and POAG progression. S-POAG is associated with lowered BT circadian rhythm robustness and inter-daily phase stability compared to controls. In the P-POAG group, the mean phase of the circadian BT rhythm was delayed by about 5 h and phases were highly scattered among individual patients, which led to reduced group mean amplitude. Circadian amplitudes of individuals were not different between the groups. Altogether, these results suggest that the body clock still works in POAG patients, but its entrainment to the 24-h environment is compromised. Probably because of the internal desynchronization, bedtime is delayed, and sleep duration is accordingly shortened by about 55 min in P-POAG compared to S-POAG patients. In the entire POAG cohort (both groups), later sleep phase and shorter mean sleep duration correlate with the delayed BT phase (r = 0.215; p = 0.021 and r = 0.322; p = 0.0004, respectively). An RGCC GLV of 15% apparently constitutes a threshold above which a delay of the circadian BT rhythm and a shortening of sleep duration occur.

Cation exchange capacity of biochar: An urgent method modification.

Biochar, produced through pyrolysis of organic matter, is negatively charged, thus contributing to electrostatic adsorption of cations. However, due to its porous structure and contents of alkaline ashes, the determination of the cation exchange capacity (CEC) is challenging. Literature values for the CEC of biochar are surprisingly variable and are often poorly reproducible, suggesting methodological problems. Here, we modify and critically assess different steps in the existing ammonium acetate (NH4OAc) method (pH 7), where ammonium (NH4+) is displaced by potassium chloride (KCl), following removal of excess NH4OAc with isopropanol, in batch mode. We used pigeon pea biochar to develop the method and conducted a test on three additional biochars with different acid neutralizing capacity. A pretreatment step of biochar was introduced, using diluted hydrochloric acid, to decrease biochar pH to near neutral, so that 1 M NH4OAc effectively buffers the biochar suspension pH at 7. This allows the CEC of all biochars to be determined at pH 7, which is crucial for biochar comparison. The dissolution of ashes may cause relatively large weight losses (e.g. for cacao shell biochar), which need to be accounted for when computing the CEC of raw biochar. The sum of NH4OAC-extractable base cations provided a smaller and better estimate of the CEC than KCl-extractable NH4+. We hypothesize that the overestimation of the CEC based on KCl-extractable NH4+ is due to the ineffectiveness of the relatively large isopropanol molecules to remove excess NH4OAc in biochars rich in micro-pores, due to size exclusion. The amount of base cations removed in the pretreatment was about three (rice husk biochar) to ten times (pigeon pea biochar) greater than the amount of exchangeable cations. The CEC values of biochar increased from 10.8 cmol/Kg carbon to 119.6 cmol/Kg carbon. These values are smaller than reported CEC values of soil organic carbon.

Maternal exercise, season and sex modify the daily fetal heart rate rhythm.

AIM: The knowledge on biological rhythms is rapidly expanding. We aimed to define the longitudinal development of the daily (24-hour) fetal heart rate rhythm in an unrestricted, out-of-hospital setting and to examine the effects of maternal physical activity, season and fetal sex. METHODS: We recruited 48 women with low-risk singleton pregnancies. Using a portable monitor for continuous fetal electrocardiography, fetal heart rate recordings were obtained around gestational weeks 24, 28, 32 and 36. Daily rhythms in fetal heart rate and fetal heart rate variation were detected by cosinor analysis; developmental trends were calculated by population-mean cosinor and multilevel analysis. RESULTS: For the fetal heart rate and fetal heart rate variation, a significant daily rhythm was present in 122/123 (99.2%) and 116/121 (95.9%) of the individual recordings respectively. The rhythms were best described by combining cosine waves with periods of 24 and 8 hours. With increasing gestational age, the magnitude of the fetal heart rate rhythm increased, and the peak of the fetal heart rate variation rhythm shifted from a mean of 14:25 (24 weeks) to 20:52 (36 weeks). With advancing gestation, the rhythm-adjusted mean value of the fetal heart rate decreased linearly in females (P < .001) and nonlinearly in males (quadratic function, P = .001). At 32 and 36 weeks, interindividual rhythm diversity was found in male fetuses during higher maternal physical activity and during the summer season. CONCLUSION: The dynamic development of the daily fetal heart rate rhythm during the second half of pregnancy is modified by fetal sex, maternal physical activity and season.

Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus.

We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40-69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.

Registered Replication Report: Rand, Greene, and Nowak (2012).

In an anonymous 4-person economic game, participants contributed more money to a common project (i.e., cooperated) when required to decide quickly than when forced to delay their decision (Rand, Greene & Nowak, 2012), a pattern consistent with the social heuristics hypothesis proposed by Rand and colleagues. The results of studies using time pressure have been mixed, with some replication attempts observing similar patterns (e.g., Rand et al., 2014) and others observing null effects (e.g., Tinghög et al., 2013; Verkoeijen & Bouwmeester, 2014). This Registered Replication Report (RRR) assessed the size and variability of the effect of time pressure on cooperative decisions by combining 21 separate, preregistered replications of the critical conditions from Study 7 of the original article (Rand et al., 2012). The primary planned analysis used data from all participants who were randomly assigned to conditions and who met the protocol inclusion criteria (an intent-to-treat approach that included the 65.9% of participants in the time-pressure condition and 7.5% in the forced-delay condition who did not adhere to the time constraints), and we observed a difference in contributions of -0.37 percentage points compared with an 8.6 percentage point difference calculated from the original data. Analyzing the data as the original article did, including data only for participants who complied with the time constraints, the RRR observed a 10.37 percentage point difference in contributions compared with a 15.31 percentage point difference in the original study. In combination, the results of the intent-to-treat analysis and the compliant-only analysis are consistent with the presence of selection biases and the absence of a causal effect of time pressure on cooperation.

Season's appreciations.

To follow the tradition set by the late Franz Halberg, highlights of research performed over the last year from his Minnesota Center are summarized. They illustrate the broad international cooperation enjoyed by his center and the diversity of applications of the discipline he founded. The results briefly summarized herein in the form of an annotated bibliography are a testimony that his legacy continues to live on and constitutes a tribute to his memory.

Coastal sediments in the Gulf of Bothnia as a source of dissolved PCDD/Fs and PCBs to water and fish.

High levels of PCDD/Fs and PCBs in Baltic Sea biota have been a matter of great concern during the last decades. We measured the freely dissolved concentrations of PCDD/Fs and PCBs in sediment pore water and bottom water in eight areas along the Swedish coast of the Gulf of Bothnia, by using state-of-the-art passive samplers. Chemical activity ratios (calculated from freely dissolved concentrations in pore water and bottom water based on chemical activity ratios) for PCDD/Fs were higher than 1 at all stations (PCDD/Fs average 27; stdev 22). High activity ratios suggest that the sediments have a potential to act as a source of dissolved PCDD/Fs to the water column. Activity ratios for PCBs varied between 0.3 and 17 (average 2; stdev 4). The concentrations of PCDD/Fs and PCBs in bottom water were significantly correlated with concentrations in sediment pore water (p<0.00001 to p=0.03) as well as with concentrations in juvenile perch caught in the same areas (p<0.00001 to p=0.02). To our knowledge, this is the first study demonstrating a correlation between in-situ measured freely dissolved PCDD/F concentrations and lipid-normalized contents in stationary fish. Our results confirm that freely dissolved concentrations should be used as chemical predictors of bioaccumulation. The results from this study imply that continued efforts to reduce levels of PCDD/Fs and PCBs in coastal sediments will have positive effects on concentrations of these contaminants in lower trophic levels of Baltic Sea ecosystems.

27-day cycles in human mortality: Traute and Bernhard Düll.

This tribute to her parents by one co-author (NDP) is the fruit of a more than a decade-long search by the senior author (FH) for the details of the lives of Bernhard and Gertraud ("Traute") Düll. These pioneers studied how space/terrestrial weather may differentially influence human mortality from various causes, the 27-day mortality pattern being different whether death was from cardiac or respiratory disease, or from suicide. FH is the translator of personal information about her parents provided by NDP in German. Figuratively, he also attempts to "translate" the Dülls' contribution in the context of the literature that had appeared before their work and after their deaths. Although the Dülls published in a then leading journal, among others (and FH had re-analyzed some of their work in a medical journal), they were unknown to academies or libraries (where FH had inquired about them). The Dülls thoroughly assembled death certificates to offer the most powerful evidence for an effect of solar activity reflected in human mortality, as did others before them. They went several steps further than their predecessors, however. They were the first to show possibly differential effects of space and/or Earth weather with respect to suicide and other deaths associated with the nervous and sensory systems vs. death from cardiac or respiratory disease as well as overall death by differences in the phase of a common 27-day cycle characterizing these mortality patterns. Furthermore, Bernhard Düll developed tests of human visual and auditory reaction time to study effects of weather and solar activity, publishing a book (his professorial dissertation) on the topic. His unpublished finding of an increased incidence of airplane crashes in association with higher solar activity was validated after his death, among others, by Tatiana Zenchenko and A. M. Merzlyi.

The sorption and desorption of phosphate-P, ammonium-N and nitrate-N in cacao shell and corn cob biochars.

The sorption of PO4-P, NH4-N and NO3-N to cacao shell and corn cob biochars produced at 300-350°C was quantified. The biochars were used; (i) as received (unwashed), (ii) after rinsing with Millipore water and (iii) following leaching with Millipore water. In addition to sorption, desorption of PO4-P from the unwashed biochars was quantified. There was no sorption of PO4-P to either washed or rinsed biochars, but following leaching, both biochars adsorbed PO4-P and distribution coefficients (Kd L kg(-1)) were very similar for both materials (10(1.1±0.5) for cacao shell biochar and 10(1.0±0.2) for corn cob biochar). The BET surface area and micropore volume increased 80% and 60% for the cacao shell and corn cob biochars following leaching. After 60 d, 1483±45 mg kg(-1) and 172±1 mg kg(-1) PO4-P was released from the cacao shell and corn cob biochars. NH4-N was sorbed by both unwashed biochars, albeit weakly with Kd values around 10(2) L kg(-1). We speculate that NH4-N could bind via an electrostatic exchange with other cationic species on the surface of the biochar. There was no significant release or sorption of NO3-N from or to either of the biochars.

Geographically selective assortment of cycles in pandemics: meta-analysis of data collected by Chizhevsky.

In the incidence patterns of cholera, diphtheria and croup during the past when they were of epidemic proportions, we document a set of cycles (periods), one of which was reported and discussed by A. L. Chizhevsky in the same data with emphasis on the mirroring in human disease of the ~11-year sunspot cycle. The data in this study are based on Chizhevsky's book The Terrestrial Echo of Solar Storms and on records from the World Health Organization. For meta-analysis, we used the extended linear and nonlinear cosinor. We found a geographically selective assortment of various cycles characterizing the epidemiology of infections, which is the documented novel topic of this paper, complementing the earlier finding in the 21st century or shortly before, of a geographically selective assortment of cycles characterizing human sudden cardiac death. Solar effects, if any, interact with geophysical processes in contributing to this assortment.

Egeson's (George's) transtridecadal weather cycling and sunspots.

In the late 19th century, Charles Egeson, a map compiler at the Sydney Observatory, carried out some of the earliest research on climatic cycles, linking them to about 33-year cycles in solar activity, and predicted that a devastating drought would strike Australia at the turn of the 20th century. Eduard Brückner and William J. S. Lockyer, who, like Egeson, found similar cycles, with notable exceptions, are also, like the map compiler, mostly forgotten. But the transtridecadal cycles are important in human physiology, economics and other affairs and are particularly pertinent to ongoing discusions of climate change. Egeson's publication of daily weather reports preceded those officially recorded. Their publication led to clashes with his superiors and his personal life was marked by run-ins with the law and, possibly, an implied, but not proven, confinement in an insane asylum and premature death. We here track what little is known of Egeson's life and of his bucking of the conventional scientific wisdom of his time with tragic results.

BLOOD PRESSURE, HEART RATE AND MELATONIN CYCLES SYNCHRONIZATION WITH THE SEASON, EARTH MAGNETISM AND SOLAR FLARES.

Three spectral components with periods of about (~) 0.41, ~0.5 and ~1.0 year had been found with serially independent sampling in human circulating melatonin. The time series consisted of around-the-clock samples collected for 24 hours at 4-hour intervals from different patients over several years. Some of these components had been found to be circadian stage-dependent, the daytime measurements following mostly a circannual variation, whereas a half-year characterized the nighttime samples. The latter were incorporated into a circasemiannual map. The relative brevity of the series prevented a check for the coexistence of all three spectral components, even if each component seemed to have a raison d'être. In time series of transdisciplinary data, a 1.00-year synchronized component is interpreted as representing the seasons. The half-year may qualify the circannual waveform, but it is also a signature of geomagnetics. An ~0.41-year (~5-month) component is the signature of solar flares. It has been called a cis-half-year (cis = on this side of a half-year) and may be detected only intermittently. Charles L. Wolff predicted the existence, among others, of ~0.42- and ~0.56-year components as beat periods of rotations at different solar latitudes.The multiple components characterizing circulating melatonin could also be found in a (to our knowledge unique) data set of a clinically healthy scientist (RBS). Herein, we focus on vascular data self-measured by RBS as he aged from ~20 to ~60 years. A multi-component model consisting of cosine curves with periods of 0.41, 0.50 and 1.00 year was fitted to weekly means of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) collected ~5 times a day over 39 years by RBS. All three components can coexist for a while, although all of them are nonstationary in their characteristics and come and go by the criterion of statistical significance.Intermittently, BP and HR are synchronized selectively with one or the other aspect of RBS' physical environment, namely the seasons (at ~1.0 year), earth magnetism (at ~0.5 year) and/or solar flares (at ~0.42 year). Cosmic-biotic transfer of information, albeit hardly of energy (the biospheric amplitudes are very small) may be mediated in this set of frequency windows. As found earlier, RBS' circulation is also frequency-trapped environmentally in multidecadal windows, HR being locked into the transtridecadal Brückner, or rather Brückner-Egeson-Lockyer, BEL sunspot and terrestrial weather cycle, while his BP follows Hale's didecadal cycle in the changing polarity of sunspots.The ~0.41-year HR cycle may be associated with changes in solar flares, the cis-half-year amplitude of HR showing a cross-correlation coefficient of 0.79 with the total solar flare index (from both solar hemispheres) at a lag of ~3.2 years. The superposed time courses of these two variables indicate the presence of a shared Horrebow-Arago-Schwabe sunspot cycle of ~11 years, the cis-half-year in HR being more prominent after the total solar flare index reaches its ~11-year peak. Differences in the time-varying behavior of BP vs. HR are also described.

COSMIC INHERITANCE RULES: IMPLICATIONS FOR HEALTH CARE AND SCIENCE.

Countering the trend in specialization, we advocate the trans-disciplinary monitoring of blood pressure and heart rate for signatures of environmental cyclic and other variabilities in space as well as terrestrial weather on the one hand, and for surveillance of personal and societal health on the other hand. New rules (if confirmed novel laws) emerge as we recognize our inheritance from the cosmos of cycles that constitute and characterize life and align them with inheritance from parents. In so doing, we happen to follow the endeavors of Gregor Mendel, who recognized the segregation and independent assortment of what became known as genes. Circadians, rhythms with periods, τ, between 20 and 28 hours, and cycles with frequencies that are higher (ultradian) or lower (infradian) than circadian, are genetically anchored. An accumulating long list of very important but aeolian (nonstationary) infradian cycles, characterizing the incidence patterns of sudden cardiac death, suicide and terrorism, with drastically different τs, constitutes the nonphotic (corpuscular emission from the sun, heliogeomagnetics, ultraviolet flux, gravitation) Cornélissen-series.

Circadian blood pressure and heart rate characteristics in haemorrhagic vs ischaemic stroke in Chinese people.

To compare the circadian variation of blood pressure (BP) between patients with intra-cerebral haemorrhage (ICH) and with cerebral infarction (CI), around-the-clock BP measurements were obtained from 89 hypertensive patients with ICH, from 63 patients with CI and from 16 normotensive volunteers. The single and population-mean cosinor yielded individual and group estimates of the MESOR (Midline Estimating Statistic Of Rhythm, a rhythm-adjusted mean value), circadian double amplitude and acrophase (measures of extent and timing of predictable daily change). Comparison shows that without any difference in BP MESOR, the circadian amplitude of systolic (S) BP was larger in ICH than CI patients (P<0.001), and both groups differed from the healthy volunteers in BP MESOR and pulse pressure (P<0.001) and in the circadian amplitude of SBP (P<0.005). The smaller population circadian amplitude of diastolic (D) BP of the ICH group (P=0.042) is likely related to a larger scatter of individual circadian acrophases in this group as compared with that in the other two groups, an inference supported by a smaller day-night ratio of DBP for ICH vs CI patients (P=0.007). Heart rate (HR) variability, gauged by the standard deviation (SD), was decreased in both patient groups as compared with that in healthy controls, more so among ICH than CI patients (P=0.025). Thus, patients with ICH had a higher incidence of abnormal circadian characteristics of BP than patients with CI, the major differences relating to a larger circadian amplitude of SBP, a smaller HR-SD, and a larger incidence of odd circadian acrophases of DBP.

In remembrance of Eugene Ladislas Kanabrocki (18 April 1922 * 23 April 2009): a 'General' in the battle of penetrating the normal range and in revealing its relation to the cosmos.

Col. Eugene L. (Gene) Kanabrocki, PhD, commanding officer of the 361st Medical Laboratory of the U.S. Army Reserve, together with Col. Lawrence E. (Larry) Scheving, Professor at the University of Arkansas, initiated in May 1969 a linked cross-sectional (hybrid) study at Fort Sam Houston, TX, to examine the oscillatory (circadian) nature of many physiological variables in a group of 13 army men, 22-28 years of age, anticipating that such data would serve, as indeed they did, as time-specified reference values in future investigations of health and aging. In the initial study, 36 variables were examined around the clock in observations at 3-hour intervals. In subsequent 24-hour profiles, mapped in May of 1971 (mostly on new, young subjects, and not officially part of the Aging Project), 1979, 1988, 1993, 1998 and 2003, additional subjects and variables were included. The follow-up studies were conducted at the Hines VA Medical Center in Hines, Illinois. Of the original 13 subjects, four were measured in all 6 studies and another four in 5 of the 6 studies. Three of the eight became diabetic (Type II) and three had vascular circulatory problems. Presently, a bank of circadian data for 187 medically relevant variables of blood (plasma or serum), saliva, urine, vital signs and other variables on the same subjects covers a span of 34 years. Dr. Robert B. Sothern (RBS), of the University of Minnesota, USA, the major analyst of Gene's investigations, in addition to being an add-on subject as he was in three studies, set up the half-hourly monitoring of blood pressure (BP) and heart rate (HR) in the 2003 study that yielded the data suggesting that the standard deviations (SD) of systolic (S) and diastolic (D) BP and HR are infl uenced by a magnetic storm. Since the standard deviation rather than the amplitude of a vascular spectral component was affected, we may be dealing with a stochastic rather than frequency window-dependent resonance with a magnetic storm. Gene and RBS also found (p< 0.08) an about-decadal signature of solar activity in long-acting natriuretic peptide (LANP), vessel dilator (VSDL), insulin, LH, prolactin, T3 uptake and, most importantly, in melatonin (p=0.004), noted solely to constitute a stimulus for follow-up studies, even when resonance occurs in an anticipated Horrebow-Schwabe circadecadal window gauged by relative sunspot (Wolf) numbers and involves many endocrine variables, as anticipated on the basis of independent evidence in melatonin and cortisol. The wealth of circadian information collected in these studies by Gene constitutes a treasure trove of unique advances in the battle of the normal range, with solid contributions also by Prof. Germaine Cornélissen of the University of Minnesota, USA, and by Prof. Ramon C. Hermida of the University of Vigo, Spain.

Cugini's syndrome in statu nascendi. Oratio contra morem prevalentem et pro chronobiologica ratione ad pressione sanguinis curandam. A plea against the prevailing custom and in favor of a chronobiological approach to treating blood pressure.

An increase in the circadian amplitude (A) of blood pressure (BP) had been reported to precede a rise in the circadian BP average (MESOR, M), as pre-hypertension in the stroke-prone Okamoto rat. In humans, children with a positive family history of high BP and/or related cardiovascular disease had, on average, a larger BP-A than children with a negative family history, and an elevated BP-A was associated with intermediate values of the left ventricular mass index (LVMI), whereas an elevation in BP-M was only observed for larger LVMI values. Against this background, with 24-hour ambulatory monitoring (ABPM) interpreted chronobiologically, Pietro Cugini (University La Sapienza of Rome, Italy) has reported an elevation of both the circadian BP-M and BP-A as occurring with a minimal change (hypertensive) retinopathy. He determined by cosinor the extent of predictable BP change within a day as BP-2A, estimated by the least squares fit of a 24-hour cosine curve to the data. As compared to controls without retinopathy, he found a retinal end-organ involvement associated with average systolic (S) / diastolic (D) BP-Ms of 124/76 vs. 112/72 mmHg, with corresponding SBP/DBP-As of 12/10 vs. 8/7 mmHg. We refer to "Cugini's syndrome", suggesting the need for clarification, preferably in longitudinal studies, of any generalizable sequence in end-organ involvement, that may occur in the course of the development of some human Vascular Variability Disorders (VVDs) of unknown etiology, that include an elevation of the circadian BP-A and/or BP-M, concomitantly or separately in a sequence with the BP-A increase preceding that in BP-M, as in models of high BP in the rat or vice versa. Seven-day half-hourly or hourly around-the-clock monitoring of BP and HR variability interpreted chronobiologically, C-ABPM, as a minimum, is recommended for routine medical care to detect VVDs consisting of 1. MESOR-hypertension, MH; 2. Circadian Hyper-Amplitude-Tension, CHAT (BP overswing); 3. odd timing of the circadian rhythm of BP but not that of HR; 4. above-threshold pulse pressure; and/or 5. below-threshold HR variability. All conditions are best determined by 24-hour/7-day or, when abnormality is detected, longer C-ABPM. Eventually, all conditions will need to be assessed in the light of reference values from gender- and age-matched peers, as is now the case for the fi rst three VVDs listed above. When C-ABPM is not practicable, a 7-day series of 3-hourly manual self-measurements during waking (and one measurement about mid-sleep) (C-MBPM) is recommended. When continuous monitoring becomes possible, as it is within the state of the science, detecting Cugini's syndrome will also become possible with the clarification as to whether any change in BP-M and/or BP-A occurs concomitantly or sequentially, with changes in BP-A anticipated to precede changes in BP-M.

Time microscopy of circadian expression of cardiac clock gene mRNA transcription: chronodiagnostic and chrono-therapeutic implications.

BACKGROUND AND PURPOSE: Molecular clocks present in organs and individual cells throughout the body are central for the temporal coordination of internal biological processes among themselves and with external environmental cycles. Relationships between circadian clocks and normal vs. abnormal organ physiology can have significant impact relevant to not only cardiovascular health, but also to the general treatment and prognosis of human disease. Chronobiological statistical procedures were applied to previously published circadian clock gene (CG) mRNA expression data which were described macroscopically, in order to establish rhythm probability and point and interval estimates for amplitudes and acrophases for 14 clock and clock-controlled genes in mouse heart. CGs in general and their importance to cardiovascular health, as well as to diagnosis and treatment of human disease, are reviewed. MATERIALS AND METHODS: Organs from male Balb/c mice were harvested every 4 h for 24-h on the 3rd day in constant darkness and analyzed by quantitative real-time reverse transcription-polymerase chain reaction for 14 CGs: mPer1, mPer2, mPer3, mCry1, mCry2, mBmal1, mCK1delta, mCK1epsilon, mClock, mDbp, mNpas2, mRev-erbalpha, mRev-erbbeta, and mTim. Relative mRNA levels normalized to corresponding G3-PDH RNA levels were re-expressed as percent of the highest value for each CG and analyzed for circadian time effect by one-way ANOVA and for circadian rhythm characteristics by single cosinor. RESULTS: 12 CGs showed a significant time-effect at p < or = 0.031 by ANOVA and 13 CGs displayed a significant 24-h rhythm at p < or = 0.011 by cosinor analysis. Five CGs (mRev-erbalpha, mDbp, mPer1, mRev-erbbeta, mPer3) reached their maxima late in the presumed resting span, 5 CGs (mPer2, mCry2, mCK1delta, mCK1epsilon, mCry1) reached their peak early in the presumed activity span, while 3 genes (mBmal1, mClock, mNpas2) reached their peak late in the presumed activity span. CONCLUSIONS: Macroscopic inspection concluded a robust circadian rhythm in 8 CGs, while cosinor analysis detected significance in 13 of 14 CGs (the developmental gene mTim is usually not circadian rhythmic) and computed point and interval estimates for amplitudes and acrophases, useful in making future objective comparisons among organisms and conditions. Information on statistically-determined rhythm characteristics of the molecular clock presents new avenues for diagnosis and therapeutic intervention in conditions where disturbance of circadian CG expression is an important cause of morbidity in chronic illnesses and diseases with a strong circadian component, including coronary vascular disease.