Altered circadian rhythmicity in patients in the ICU.
Ontology highlight
ABSTRACT:
SUBMITTER: Gazendam JAC
PROVIDER: S-EPMC3734886 | biostudies-other | 2013 Aug
REPOSITORIES: biostudies-other
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Project description:Like neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in the brain, single fibroblasts can function as independent oscillators. In the SCN, synaptic and paracrine signaling among cells creates a robust, synchronized circadian oscillation, whereas there is no evidence for such integration in fibroblast cultures. However, interactions among single-cell fibroblast oscillators cannot be completely excluded, because fibroblasts were not isolated in previous work. In this study, we tested the autonomy of fibroblasts as single-cell circadian oscillators in high- and low-density culture, by single-cell imaging of cells from PER2::LUC circadian reporter mice. We found greatly reduced PER2::LUC rhythmicity in low-density cultures, which could result from lack of either constitutive or rhythmic paracrine signals from neighboring fibroblasts. To discriminate between these 2 possibilities, we mixed PER2::LUC wild-type (WT) cells with nonluminescent, nonrhythmic Bmal1-/- cells, so that density of rhythmic cells was low but overall cell density remained high. In this condition, WT cells showed clear rhythmicity similar to high-density cultures. We also mixed PER2::LUC WT cells with nonluminescent, long period Cry2-/- cells. In this condition, WT cells showed a period no different from cells cultured with rhythmic WT cells or nonrhythmic Bmal1-/- cells. In previous work, we found that low K? suppresses fibroblast rhythmicity, and we and others have found that either low K? or low Ca²? suppresses SCN rhythmicity. Therefore, we attempted to rescue rhythmicity of low-density fibroblasts with high K? (21 mM), high Ca²? (3.6 mM), or conditioned medium. Conditioned medium from high-density fibroblast cultures rescued rhythmicity of low-density cultures, whereas high K? or Ca²? medium did not consistently rescue rhythmicity. These data suggest that fibroblasts require paracrine signals from adjacent cells for normal expression of rhythmicity, but that these signals do not have to be rhythmic, and that rhythmic signals from other cells do not affect the intrinsic periods of fibroblasts.
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Project description:Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY-deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY-less oscillations are variable in their expression and have shorter periods than wild-type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY-mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post-translational.
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Project description:Many physiological processes of living organisms show circadian rhythms, governed by an endogenous clock. This clock has a genetic basis and is entrained by external cues, such as light and temperature. Other physiological processes exhibit seasonal rhythms, that are also responsive to light and temperature. We previously reported a natural latitudinal cline of photoperiodic diapause induction in the parasitic wasp Nasonia vitripennis in Europe and a correlated haplotype frequency for the circadian clock gene period (per). To evaluate if this correlation is reflected in circadian behaviour, we investigated the circadian locomotor activity of seven populations from the cline. We found that the proportion of rhythmic males was higher than females in constant darkness, and that mating decreased rhythmicity of both sexes. Only for virgin females, the free running period (τ) increased weakly with latitude. Wasps from the most southern locality had an overall shorter free running rhythm and earlier onset, peak, and offset of activity during the 24 h period, than wasps from the northernmost locality. We evaluated this variation in rhythmicity as a function of period haplotype frequencies in the populations and discussed its functional significance in the context of local adaptation.
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Project description:OBJECTIVES: Sleep disorders are common in patients with HIV/AIDS, and can lead to poor quality of life. Although many studies have investigated the aetiology of these disorders, it is still unclear whether impaired sleep quality is associated with HIV itself, social problems, or side effects of antiretroviral therapy (ART). Moreover, despite its known neurological associations, little is known about the role of the trans-activator of transcription (Tat) protein in sleep disorders in patients with HIV/AIDS. The purpose of this study was to test the hypothesis that the sleep quality of patients with HIV/AIDS affected by an altered circadian rhythm correlates with cerebrospinal HIV Tat protein concentration. METHODS: Ninety-six patients with HIV/AIDS between 20 and 69 years old completed the Pittsburgh Sleep Quality Index. Their circadian rhythm parameters of blood pressure, Tat concentration in cerebrospinal fluid, melatonin concentration, CD4 cell count and HIV RNA viral load in serum were measured. RESULTS: The circadian amplitude of systolic blood pressure and the score for sleep quality (Pittsburgh Sleep Quality Index) were negatively correlated with HIV Tat protein concentration, while the melatonin value was positively correlated with Tat protein concentration. CONCLUSIONS: The HIV Tat protein affects circadian rhythmicity by interfering with the circadian system in patients with HIV/AIDS and further increases the melatonin excretion value. A Tat protein-related high melatonin value may counteract HIV-related poor sleep quality during the progression of HIV infection. This study provides the first clinical evidence offering an explanation for why sleep quality did not show an association with progression of HIV infection in previous studies.
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Project description:Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c-fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated.
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Project description:CONTEXT:Quality of life (QoL) is increasingly recognized as an important outcome of cancer treatment. Previous studies have examined clinical predictors of QoL, but with the increasing prevalence of wearable sensors that monitor sleep and activity patterns, further investigation into whether these behaviors are predictive of post-treatment QoL is now feasible. Among patients receiving aggressive cancer treatment such as hematopoietic cell transplantation (HCT), analysis of circadian rhythms (24-hour patterns of sleep and activity) via wearable sensors is limited. OBJECTIVE:To evaluate the relationship between overall QoL and circadian rhythms in patients receiving allogeneic HCT. METHODS:Patients wore an ActiGraph GT3X (Pensacola, FL) activity monitor for at least 72 hours before the initiation of conditioning chemotherapy and transplantation and completed a QoL (Functional Assessment of Cancer Therapy-General [FACT-G]) assessment. QoL assessments were also completed 1, 3, and 6 months after HCT. RESULTS:Patients (n = 45, M age = 55) were mostly male (66%) with a total FACT-G score of 80.96 (SD = 16.05) before HCT. Mixed models revealed robust cross-sectional associations between overall QoL and multiple circadian rhythmicity parameters, including durations of high physical activity, overall circadian rhythmicity, and earlier starts of daily activity (P's < .01). Recovery of QoL after transplant was predicted by longer pre-transplant durations of high physical activity (P = .04) and earlier evening retirement (P = .04). CONCLUSION:Our findings suggest that wearable sensor information is a promising method of predicting recovery of QoL after HCT. Additional studies are needed to confirm these findings in a larger sample.
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