Cosinor Regression Research Articles

Circadian characteristics of term and preterm labors

The labor is a physiological event considered to have its own circadian (diurnal) rhythm, but some of the data remain conflicting, especially for preterm births. In this retrospective study, we analyzed the circadian trends of labor onset times in the Slovenian birth cohort from 1990 to 2018 with over 550,000 cases of singleton births. The number of term and preterm labor onsets was calculated for each hour in a day and circadian trends were evaluated for each of the study groups by modeling with a generalized Poisson distribution linked with the cosinor regression model using logarithmic link function. The induced labors were taken as the control group since the timing of labor depends mostly on the working schedule of personnel and not on the intrinsic rhythmic characteristics. For induced labors, the main peak in the number of labor cases was observed in the late morning hours (around 10 AM) for all gestational ages. The prominence of this peak becomes smaller in spontaneous premature labors with gradually disrupting rhythmicity in very preterm and extremely preterm cases. Labors starting with spontaneous contractions peak between 6 and 7 AM and lose the rhythmicity at 35 weeks of gestation while labors starting with a spontaneous rupture of membranes peak at 1 AM and lose the rhythmicity at 31 weeks of gestation, suggesting differences in underlying mechanisms. According to our knowledge, this is the first study that shows differences of circadian trends between different types of spontaneous labors, i.e., labors initiated with contraction and labors initiated with a spontaneous rupture of membranes. Moreover, the obtained results represent evidence of gradual disruption of rhythmicity from mild to extreme prematurity.

Age-related changes in circadian regulation of the human plasma lipidome

Aging alters the amplitude and phase of centrally regulated circadian rhythms. Here we evaluate whether peripheral circadian rhythmicity in the plasma lipidome is altered by aging through retrospective lipidomics analysis on plasma samples collected in 24 healthy individuals (9 females; mean ± SD age: 40.9 ± 18.2 years) including 12 younger (4 females, 23.5 ± 3.9 years) and 12 middle-aged older, (5 females, 58.3 ± 4.2 years) individuals every 3 h throughout a 27-h constant routine (CR) protocol, which allows separating evoked changes from endogenously generated oscillations in physiology. Cosinor regression shows circadian rhythmicity in 25% of lipids in both groups. On average, the older group has a ~14% lower amplitude and a ~2.1 h earlier acrophase of the lipid circadian rhythms (both, p ≤ 0.001). Additionally, more rhythmic circadian lipids have a significant linear component in addition to the sinusoidal across the 27-h CR in the older group (44/56) compared to the younger group (18/58, p < 0.0001). Results from individual-level data are consistent with group-average results. Results indicate that prevalence of endogenous circadian rhythms of the human plasma lipidome is preserved with healthy aging into middle-age, but significant changes in rhythmicity include a reduction in amplitude, earlier acrophase, and an altered temporal relationship between central and lipid rhythms.

Plasma corticosterone rhythmicity loss dysregulates the renal artery circadian transcriptome and abolishes daily vasodilation variation

Molecular clocks control a daily transcriptional schedule that maintains tissue homeostasis. Glucocorticoids synchronize peripheral clocks with the master clock in the suprachiasmatic nucleus in response to ambient light. In humans and mice, arrhythmic glucocorticoids induce non-dipping blood pressure and vascular dysfunction. The mechanisms of this are poorly understood. We hypothesize that arrhythmic activation of the glucocorticoid receptor desynchronizes the molecular clock mechanism in the renal artery, a major component of blood pressure control, dysregulating normal function. Our aim was to dissect renal artery circadian physiology transcriptionally and functionally and interrogate the effect of arrhythmic glucocorticoids. Male mice, kept on a 12:12 light:dark cycle, were anesthetised with 4% isolflurane and implanted with a hypodermal pellet containing either vehicle or corticosterone (≈3.7 mg/kg per day), to flatten the endogenous glucocorticoid rhythm. After 7 days, mice were culled by cervical dislocation at 2hr intervals for 48 hours and the renal arteries taken. The renal artery circadian transcriptome was profiled using Illumina Truseq Stranded RNA-sequencing. Cosinor regression (Limorhyde) was applied to the control group and identified 465 of 14425 (~3%) protein coding transcripts with rhythmic expression (p&lt;0.005 for fit to a cosinor waveform). Of these, 265 (62%) lost their rhythm in the corticosterone-treated group. These arrhythmic transcripts were interrogated by gene set enrichment analysis (Biological Process, FDR&lt;0.05) and enriched gene sets were related to “Circadian Rhythm,” “Transforming growth factor beta” and “Smooth muscle proliferation.” Paradoxically, 919 transcripts gained de novo rhythmicity in the corticosterone group and were related to mitochondrial respiration and ATP synthesis. In parallel, we used wire myography to determine the diurnal variation in endothelium-independent vasodilation via sodium nitroprusside dose response. Renal arteries were taken from corticosterone and vehicle treated mice as described above, either during the active phase (subjective night) or inactive phase (subjective day). Data are mean ± SD and analysed by 2-way ANOVA. Vasodilation was higher during the night compared to the day in the control group, (night logEC50 =8.5±0.4 versus day logEC50 =7.5±0.4 p=0.01, n=12). In the corticosterone treated group circadian variability in vasodilation was blunted (night logEC50 =7.7±0.9 versus day logEC50=7.7±0.4, p=0.9, n=12). We speculate that temporal misalignment of the vascular molecular circadian machinery and the subsequent temporal changes in gene expression may have a direct effect on dilatory capacity. This novel study extends our understanding of circadian vascular physiology, undelining the impact of glucocorticoids on temporal gene expression.This may be clinically relevant in the pathogenesis of vascular dysfunction linked to elevated glucocorticoids in metabolic syndrome. This study was funded by the British Heart Foundation (PhD studentship code: FS/18/57/34178) and the Kidney Research UK (Intermediate Grant Code: INT_001_20181115 and IN_002_2021 0729). Analyses were carried out by Edinburgh Genomics at the University of Edinburgh. Edinburgh Genomics is partly supported through core grants from NERC (R8/H10/56), MRC (MR/K001744/1) and BBSRC (BB/J004243/1). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Circular Pattern of Temperature Changes and Its Effect on Workers’ Attitude (A Case Study of the Federal Polytechnic Offa)

This study is to determine the effect of temperature on workplace attitude, which led to the investigation of a circular pattern of temperature changes. The idea of time series data being presented in circular form since time itself rotates around the circle of a clock was the moving force in studying the pattern and behaviour of air temperature to identify peak periods. The data on air temperature (0C) in Offa was collected monthly from 2016 to 2020 from a reliable online source tcktcktck.org which tally with an available short period of temperature recorded by the Metrological Garden of Science Laboratory Department, The Federal Polytechnic Offa. While the data on workers’ attitudes was from a questionnaire with an 8.5 reliability index. The study adopted a descriptive approach in the first instance, where responses from the questionnaire were in tabular form and the monthly means temperature in a circular plot before the application of cosinor regression to the original monthly temperature data for further examinations. The result of the circular plot indicated seasonality in the data because the monthly mean temperature differs, making the plot not perfectly circular. The presence of seasonality noticed in the cosinor plot was confirmed in the cosinor regression analysis as being significant at a 5% level of significance. The temperature amplitude from 2016 to 2020 had its peaks in February when 50.9% to 56% of workers are likely to experience fatigue (exhausted). The analysis for 2016 indicates temperature amplitude in Offa at 2.30C which peaks in early February. While in 2020, the temperature amplitude of 3.80C peaks at the beginning of February. The increase between 2016 and 2020 is due to climate change. The government and other stakeholders should provide facilities to reduce workers’ fatigue and do more about climate change.

Circadian rhythms are not captured equal: Exploring Circadian metrics extracted by differentcomputational methods from smartphone accelerometer and GPS sensors in daily life tracking.

ObjectiveTo identify the differences between circadian rhythm (CR) metrics characterized by different mobile sensors and computational methods.MethodsWe used smartphone tracking and daily survey data from 225 college student participants, applied four methods (survey construct automation, cosinor regression, non-parametric method, Fourier analysis) on two types of smartphone sensor data (GPS, accelerometer) to characterize CR. We explored the inter-relations among the extracted circadian metrics as well as between the circadian metrics and participants’ self-reported mood and sleep outcomes.ResultsCompared to GPS signals, smartphone accelerometer activity follows an intradaily distribution that starts earlier in the day, winds down later, reaches half cumulative activity about the same time, conforms less to a sinusoidal wave, and exhibits more intradaily fragmentation but higher CR strength and lower interdaily disruption. We found a notable negative correlation between intradaily variability and CR strength especially pronounced in GPS activity. Self-reported sleep and mood outcomes showed significant correlations with particular CR metrics.ConclusionsWe revealed significant inter-relations and discrepancies in the circadian metrics discovered from two smartphone sensors and four CR algorithms and their bearings on wellbeing indicators such as sleep quality and loneliness.

CosinorPy: a python package for cosinor-based rhythmometry

BackgroundEven though several computational methods for rhythmicity detection and analysis of biological data have been proposed in recent years, classical trigonometric regression based on cosinor still has several advantages over these methods and is still widely used. Different software packages for cosinor-based rhythmometry exist, but lack certain functionalities and require data in different, non-unified input formats.ResultsWe present CosinorPy, a Python implementation of cosinor-based methods for rhythmicity detection and analysis. CosinorPy merges and extends the functionalities of existing cosinor packages. It supports the analysis of rhythmic data using single- or multi-component cosinor models, automatic selection of the best model, population-mean cosinor regression, and differential rhythmicity assessment. Moreover, it implements functions that can be used in a design of experiments, a synthetic data generator, and import and export of data in different formats.ConclusionCosinorPy is an easy-to-use Python package for straightforward detection and analysis of rhythmicity requiring minimal statistical knowledge, and produces publication-ready figures. Its code, examples, and documentation are available to download from https://github.com/mmoskon/CosinorPy. CosinorPy can be installed manually or by using pip, the package manager for Python packages. The implementation reported in this paper corresponds to the software release v1.1.

Circadian Analysis of the Mouse Cerebellum Proteome.

The cerebellum contains a circadian clock, generating internal temporal signals. The daily oscillations of cerebellar proteins were investigated in mice using a large-scale two-dimensional difference in gel electrophoresis (2D-DIGE). Analysis of 2D-DIGE gels highlighted the rhythmic variation in the intensity of 27/588 protein spots (5%) over 24 h based on cosinor regression. Notably, the rhythmic expression of most abundant cerebellar proteins was clustered in two main phases (i.e., midday and midnight), leading to bimodal distribution. Only six proteins identified here to be rhythmic in the cerebellum are also known to oscillate in the suprachiasmatic nuclei, including two proteins involved in the synapse activity (Synapsin 2 [SYN2] and vesicle-fusing ATPase [NSF]), two others participating in carbohydrate metabolism (triosephosphate isomerase (TPI1] and alpha-enolase [ENO1]), Glutamine synthetase (GLUL), as well as Tubulin alpha (TUBA4A). Most oscillating cerebellar proteins were not previously identified in circadian proteomic analyses of any tissue. Strikingly, the daily accumulation of mitochondrial proteins was clustered to the mid-resting phase, as previously observed for distinct mitochondrial proteins in the liver. Moreover, a number of rhythmic proteins, such as SYN2, NSF and TPI1, were associated with non-rhythmic mRNAs, indicating widespread post-transcriptional control in cerebellar oscillations. Thus, this study highlights extensive rhythmic aspects of the cerebellar proteome.

Circadian and wake-dependent changes in human plasma polar metabolites during prolonged wakefulness: A preliminary analysis

Establishing circadian and wake-dependent changes in the human metabolome are critical for understanding and treating human diseases due to circadian misalignment or extended wake. Here, we assessed endogenous circadian rhythms and wake-dependent changes in plasma metabolites in 13 participants (4 females) studied during 40-hours of wakefulness. Four-hourly plasma samples were analyzed by hydrophilic interaction liquid chromatography (HILIC)-LC-MS for 1,740 metabolite signals. Group-averaged (relative to DLMO) and individual participant metabolite profiles were fitted with a combined cosinor and linear regression model. In group-level analyses, 22% of metabolites were rhythmic and 8% were linear, whereas in individual-level analyses, 14% of profiles were rhythmic and 4% were linear. We observed metabolites that were significant at the group-level but not significant in a single individual, and metabolites that were significant in approximately half of individuals but not group-significant. Of the group-rhythmic and group-linear metabolites, only 7% and 12% were also significantly rhythmic or linear, respectively, in ≥50% of participants. Owing to large inter-individual variation in rhythm timing and the magnitude and direction of linear change, acrophase and slope estimates also differed between group- and individual-level analyses. These preliminary findings have important implications for biomarker development and understanding of sleep and circadian regulation of metabolism.

LimoRhyde: A Flexible Approach for Differential Analysis of Rhythmic Transcriptome Data.

Unraveling the effects of genetic or environmental perturbations on biological rhythms requires detecting changes in rhythmicity across multiple conditions. Although methods to detect rhythmicity in genome-scale data are well established, methods to detect changes in rhythmicity or changes in average expression between experimental conditions are often ad hoc and statistically unreliable. Here we present LimoRhyde (linear models for rhythmicity, design), a flexible approach for analyzing transcriptome data from circadian systems. Borrowing from cosinor regression, LimoRhyde decomposes circadian or zeitgeber time into multiple components to fit a linear model to the expression of each gene. The linear model can accommodate any number of additional experimental variables, whether discrete or continuous, making it straightforward to detect differential rhythmicity and differential expression using state-of-the-art methods for analyzing microarray and RNA-seq data. In this approach, differential rhythmicity corresponds to a statistical interaction between an experimental variable and circadian time, whereas differential expression corresponds to the main effect of an experimental variable while accounting for circadian time. To validate LimoRhyde’s performance, we applied it to simulated data. To demonstrate LimoRhyde’s versatility, we applied it to murine and human circadian transcriptome datasets acquired under various experimental designs. Our results show how LimoRhyde systematizes the analysis of such data, and suggest that LimoRhyde could prove valuable for assessing how circadian systems respond to perturbations.

Does seasonality of births in diabetes mellitus reflect pathogenetic differences?

This study indicates that the seasonality of births of patients with DM1 and DM2 has occurred in their adolescence or adulthood. Patients with Diabetes mellitus type 2 (DM2) with the maturity onset have different seasonal birth patterns from those with Diabetes mellitus type 1 (DM1) with the maturity onset, or DM1children. Monthly numbers of births of 81 and 236 children with DM1 and DM2, respectively, in adolescent or adult age, were adapted to different actual length of calendar months. The 12- and 6-month rhythm was tested using the cosinor regression with 95% confidence interval versus the hypothesis of null seasonality. Regarding DM1 with maturity onset, annual and semiannual rhythm was significant in both genders, with the increase in birth numbers from November to January and decrease in March, April and August. In DM2, only female data displayed a significant annual rhythm, with an increase in birth from April to August and decrease from October to December. CONCLUSION: The birth seasonality related to DM1 in adolescent or adult age appears to be reciprocal, compared to DM1 in childhood. For DM2, the seasonality of births was found only in females. The increase in female fecundity seems to be related to an increase in the risk of DM2 in female offspring. The outcomes could help in identifying environmental and endogenous factors related to seasonality cycle (Tab. 1, Fig. 1, Ref. 18).

Seasonal trends in tinnitus symptomatology: evidence from Internet search engine query data.

The primary aim of this study was to test the hypothesis that the symptom of tinnitus demonstrates a seasonal pattern with worsening in the winter relative to the summer using Internet search engine query data. Normalized search volume for the term 'tinnitus' from January 2004 through December 2013 was retrieved from Google Trends. Seasonal effects were evaluated using cosinor regression models. Primary countries of interest were the United States and Australia. Secondary exploratory analyses were also performed using data from Germany, the United Kingdom, Canada, Sweden, and Switzerland. Significant seasonal effects for 'tinnitus' search queries were found in the United States and Australia (p < 0.00001 for both countries), with peaks in the winter and troughs in the summer. Secondary analyses demonstrated similarly significant seasonal effects for Germany (p < 0.00001), Canada (p < 0.00001), and Sweden (p = 0.0008), again with increased search volume in the winter relative to the summer. Our findings indicate that there are significant seasonal trends for Internet search queries for tinnitus, with a zenith in winter months. Further research is indicated to determine the biological mechanisms underlying these findings, as they may provide insights into the pathophysiology of this common and debilitating medical symptom.

Old Forestry Traditions and Modern Chronobiological Research: Lunar-Cycle-Related Sowing Time Influences Effectively Initial Plant Growth

After a preliminary trial, 12 successive sowings (with 4 repetitions each) of the panafrican tree Maesopsis eminii had been realized, at alternating dates 2 days before Full Moon (FM) and 2 days before New Moon (NM) [1]. The mean height of the young plants 4 months after sowing was by 3 centimeters (= ca. 19%) larger for sowings before FM compared to sowings before NM. This phenomenon, now re-evaluated by Halberg´s cosinor regression, was statistically significant partly on the level a = 0.05, partly 0.1.

Seasonal trends in sleep-disordered breathing: evidence from Internet search engine query data

The primary aim of the current study was to test the hypothesis that there is a seasonal component to snoring and obstructive sleep apnea (OSA) through the use of Google search engine query data. Internet search engine query data were retrieved from Google Trends from January 2006 to December 2012. Monthly normalized search volume was obtained over that 7-year period in the USA and Australia for the following search terms: "snoring" and "sleep apnea". Seasonal effects were investigated by fitting cosinor regression models. In addition, the search terms "snoring children" and "sleep apnea children" were evaluated to examine seasonal effects in pediatric populations. Statistically significant seasonal effects were found using cosinor analysis in both USA and Australia for "snoring" (p < 0.00001 for both countries). Similarly, seasonal patterns were observed for "sleep apnea" in the USA (p = 0.001); however, cosinor analysis was not significant for this search term in Australia (p = 0.13). Seasonal patterns for "snoring children" and "sleep apnea children" were observed in the USA (p = 0.002 and p < 0.00001, respectively), with insufficient search volume to examine these search terms in Australia. All searches peaked in the winter or early spring in both countries, with the magnitude of seasonal effect ranging from 5 to 50%. Our findings indicate that there are significant seasonal trends for both snoring and sleep apnea internet search engine queries, with a peak in the winter and early spring. Further research is indicated to determine the mechanisms underlying these findings, whether they have clinical impact, and if they are associated with other comorbid medical conditions that have similar patterns of seasonal exacerbation.

The Derer´s biological - cosmic week and the Halberg´s circaseptan chronome.

There are three common periodic intervals in the life of each human being from time immemorial: the day, the week and the year. The first one is given by the Earth´s rotation, the latter one by its revolution around the Sun. These both do have clear biomedical counterparts. The 7-day week, basically linguistically "period of change" (or a similar period, e.g.10 days in Egypt or 8 days in Etrutria) was obviously originally considered mainly as a product of a societal agreement. Two groups of Czechoslovak clinicians-scientists, however, noted in forties of the XXth century an approximately week period in human laboratory data, after similar attempts abroad a few years earlier. In fifties, L.Dérer, respecting the mathematical and biological principles in medicine and supported by the mathematician A.Huťa, demonstrated the presence of the "6-day" rhythm in blood leukocyte counts in patients with leukemia, treated by cytostatics. Posing the question "Where is it from?", he considered also cosmic influences but was unable to study this issue more deeply due to his premature decease. Two decades later, the "Dérer´s circaseptans" found wide confirmation not only in human medicine but also in biology. The pioneering role here belongs to Franz Halberg, USA, the godfather of the "circadians" (originally "Halberg´s paranoia") since the fifties. The possible geocosmic roots of circaseptans are supposed in the geomagnetic activity from interplanetary space, generating under the influence of the Sun rotation the periods around 6-7 days. This is presently documented, surprisingly, also by analysing the Dérer´s original data using more advanced, inferentially statistical method - the Halberg cosinor regression. Thus, the optimal approximation has been achieved for the period of 6.75 days - the 4th harmonics of the Bartels solar rotation cycle. Accordingly, the week can be now, after Dérer and Halberg, understood also - same as day and year - as a biological - geocosmic phenomenon, a geomagnetic week, genetically acquired in the course of billions years´ of evolution, encoded in our chronome. The personality of Ladislav Dérer should, in the history of the Czech and Slovak biomedical sciences, be permanenly standing by such giants as the well known Jan Evangelista Purkyně ("Purkinje") or as Bohumil Němec, discoverer of the mechanism of positive geotropism of plant roots (Fig. 3, Ref. 28).

Circulating Clusterin (Apolipoprotein J) Levels Do Not Have Any Day/Night Variability and Are Positively Associated with Total and LDL Cholesterol Levels in Young Healthy Individuals

Clusterin has been associated with several pathologies, including cardiovascular disease and neoplasias. However, little is known about its physiology and its association with metabolic and anthropometric parameters in humans. The aim of the study was to examine whether circulating clusterin levels exhibit a day/night variation pattern and whether clusterin is associated with anthropometric and metabolic parameters. Study A was a frequent sampling study to evaluate potential periodicity in clusterin secretion. Study B was an observational study to evaluate the cross-sectional and prospective associations of clusterin with anthropometric and metabolic parameters. Study A participants were healthy males (n = 6) and females (n = 6), aged 22.3 ± 3.1 and 22.8 ± 3.4 yr, respectively. Study B participants were 186 healthy males aged 18.4 ± 0.14 yr. Ninety-one of the study B subjects were studied again 2 yr later and clusterin's associations with change of anthropometric and metabolic parameters were thus investigated prospectively. Samples in study A were collected every 15 min during an overnight admission, and subsequently pooled every hour. Samples in study B were collected during a screening visit. Circulating clusterin levels were measured. In study A, spectral domain and cosinor regression analysis failed to reveal any day/night variation pattern. In study B, clusterin was positively correlated with total and low-density lipoprotein cholesterol (r = 0.23, P = 0.002; and r = 0.20, P = 0.005). Baseline clusterin did not predict change of any anthropometric, biochemical, or metabolic parameters prospectively. We report for the first time that circulating clusterin does not have a day/night variation pattern in healthy young individuals. Clusterin levels are associated with total and low-density lipoprotein cholesterol cross-sectionally but do not predict short-term changes in metabolic parameters in healthy young males.

An association between seasonal fluctuation ‘cycling’ of 25(OH)D and increased bone resorption but not BMD or BMC in UK South Asian and Caucasian women living at 51on

It has been hypothesised that the U shaped association between 25(OH)D and some health outcomes may be due to large seasonal fluctuations of 25(OH)D1. It is unknown whether such fluctuation of 25(OH)D (‘cycling’) influences bone health. This is an important issue, because if ‘cycling’ is detrimental for bone, then winter only rather than year round vitamin D supplementation may be useful for bone health to ‘blunt’ the rhythm. In the D-FINES study, n = 373 women (South Asian/Caucasian) had repeated measurements in four seasons for serum 25(OH)D and PTH, as well as a DXA scan in autumn and spring. Serum C-telopeptide (sCTX) was also measured in a random subset (n = 66). Cosinor regression analysis was used to identify individuals showing a significant rhythm (p 0.05) between ‘cyclers’ and ‘non-cyclers’ for any of the bone indices in either ethnic group. However, there were trends for a higher CTX and PTH in ‘cyclers’ versus ‘non-cyclers’ in both ethnic groups in every season, but no differences for BMD or BMC (Figs. 1–4). This suggests tentatively that ‘cycling’ could be associated with changes in bone metabolism but may not translate into structural changes. In summary, there is no clear evidence here to suggest that ‘cycling’ is detrimental to bone health, although there are trends in PTH and CTX that warrant further investigation with a larger sample.

Leptin secretion rate increases with higher CAG repeat number in Huntington’s disease patients

Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by an increased number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. To perform a detailed analysis of adipose tissue function in HD patients as abnormal fat tissue function could contribute to the weight loss. In a clinical research laboratory, 24-h plasma concentrations of leptin, adiponectin and resistin were studied in nine early-stage, medication-free HD patients and nine age-, gender- and body mass index (BMI)-matched controls. Leptin was measured every 20 min whereas adiponectin and resistin were measured hourly. Autodeconvolution and cosinor regression were applied to quantify secretion characteristics of leptin and diurnal variations in leptin, adiponectin and resistin levels. Plasma levels and diurnal rhythmicity of leptin, adiponectin and resistin were not significantly different between HD patients and controls. However, although leptin production increased with higher BMI and fat mass in controls, no such relation was present in HD patients. Moreover, when corrected for fat mass, mean plasma leptin concentration as well as basal, pulsatile and total secretion rates increased with the size of the CAG repeat mutation (r = +0.72 to r = +0.80; all P < 0.05). Both higher pulsatile leptin secretion and higher mean adiponectin levels were associated with a greater degree of motor and functional impairment in HD patients. CAG-repeat size-dependent interference of the HD mutation with adipose tissue function may contribute to weight loss in HD patients.

Circadian and ultradian extrasystole rhythms in healthy individuals at elevated versus lowland altitudes

We defined chronobiologic norms for supraventricular and ventricular single extrasystoles (SV and VE, respectively) in healthy older males in lowland areas. The study was extended to higher altitudes, where hypobaric hypoxia was expected to increase extrasystole frequency, while perhaps not changing rhythmicity. In healthy men (lowland n = 37, altitude n = 22), aged 49-72 years, mean numbers of SVs and VEs were counted over a 24-h period. Cosinor regression was used to test the 24-h rhythm and its 2nd-10th harmonics. The resulting approximating function for either extrasystole type includes its point, 95% confidence interval of the mean, and 95% tolerance for single measurement estimates. Separate hourly differences (delta) between altitude and lowland (n = 59) were also analysed. Hourly means were significantly higher in the mountains versus lowland, by +0.8 beats/h on average for SVs, and by +0.9 beats/h for VEs. A relatively rich chronogram for VEs in mountains versus lowland exists. Delta VEs clearly display a 24-h component and its 2nd, 3rd, 4th and 7th harmonics. This results in significantly higher accumulation of VEs around 8.00 a.m., 11.00 a.m. and 3.00 p.m. in the mountains. The increase in extrasystole occurrence in the mountains is probably caused by higher hypobaric hypoxia and resulting sympathetic drive. Healthy men at elevated altitudes show circadian and several ultradian rhythms of single VEs dependent on the hypoxia level. This new methodological approach--evaluating the differences between two locations using delta values--promises to provide deeper insight into the occurrence of premature beats.

Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

Abstract Context: Huntington’s disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. Objective: The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. Design, Setting, and Participants: Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. Main Outcome Measures: Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. Results: Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 ± 320 vs. 2500 ± 220 nmol/liter/24 h, P = 0.023; and 111 ± 14 vs. 64 ± 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. Conclusions: HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.

Increased Hypothalamic-Pituitary-Adrenal Axis Activity in Huntington’s Disease

Huntington's disease (HD) is a fatal hereditary neurodegenerative disorder characterized by motor, cognitive, and behavioral disturbances. Hypothalamic-pituitary-adrenal (HPA) axis dysfunction could contribute to a number of HD signs and symptoms; however, no data are available on cortisol diurnal variations and secretory dynamics in HD patients. The aim of the study was to perform a detailed analysis of HPA axis function in HD patients in relation to clinical signs and symptoms. Twenty-four-hour cortisol secretion was studied in eight early-stage, medication-free HD patients and eight age-, sex-, and body mass index-matched controls in a clinical research laboratory. Cortisol levels were measured every 10 min. Multiparameter autodeconvolution and cosinor regression were applied to quantify basal, pulsatile, and total cortisol secretion rates as well as diurnal variations in cortisol levels. Total cortisol secretion rate and the amplitude of the diurnal cortisol profile were both significantly higher in HD patients compared with controls (3490 +/- 320 vs. 2500 +/- 220 nmol/liter/24 h, P = 0.023; and 111 +/- 14 vs. 64 +/- 8 nmol/liter, P = 0.012, respectively). Cortisol concentrations in patients were particularly increased in the morning and early afternoon period. In HD patients, mean 24-h cortisol levels significantly correlated with total motor score, total functional capacity, as well as body mass index. HPA axis hyperactivity is an early feature of HD and is likely to result from a disturbed central glucocorticoid feedback due to hypothalamic pathology. HPA axis dysfunction may contribute to some signs and symptoms in HD patients.