Two experiments were performed to evaluate the role of the thyroid gland as a mediator of circadian rhythms in the hamster. In experiment 1, the antithyroid drug propylthiouracil (PTU) lengthened the circadian period (τ), increased thyroid weight, and eliminated detectable thyroxine (T 4 ) and triiodothyronine (T 3 ) from blood. A low-iodine diet greatly reduced T 4 levels but had no effect on T 3 or τ. Treatment with 500 μCi of 131 I failed to alter any parameter of physiology or thythmicity measured. In this experiment, some animals in the low-iodine and PTU groups had greatly reduced testes sizes, and testses size was inversely correlated with change in τ. In experiment 2, T 4 and T 3 levels detected 11 wk after surgical thyroidectomy were significantly less than those found in sham-operated ammals, but concentrations of the two hormones varied widely across the thyroidectomized group. Thyroidectomy did not increase τ either 4 or 11 wk after surgery, nor was there evidence from individuals that level of thyroid function was associated with change in τ. The results from these experiments suggest that diminished thyroid function is not causal of lengthened circadian period
Mieda, Michihiro; Okamoto, Hitoshi; Sakurai, Takeshi
As the central pacemaker in mammals, the circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus is a heterogeneous structure consisting of multiple types of GABAergic neurons with distinct chemical identities [1, 2]. Although individual cells have a cellular clock driven by autoregulatory transcriptional/translational feedback loops of clock genes, interneuronal communication among SCN clock neurons is likely essential for the SCN to generate a highly robust, coherent circadian rhythm . However, neuronal mechanisms that determine circadian period length remain unclear. The SCN is composed of two subdivisions: a ventral core region containing vasoactive intestinal peptide (VIP)-producing neurons and a dorsal shell region characterized by arginine vasopressin (AVP)-producing neurons. Here we examined whether AVP neurons act as pacemaker cells that regulate the circadian period of behavior rhythm in mice. The deletion of casein kinase 1 delta (CK1δ) specific to AVP neurons, which was expected to lengthen the period of cellular clocks [3-6], lengthened the free-running period of circadian behavior as well. Conversely, the overexpression of CK1δ specific to SCN AVP neurons shortened the free-running period. PER2::LUC imaging in slices confirmed that cellular circadian periods of the SCN shell were lengthened in mice without CK1δ in AVP neurons. Thus, AVP neurons may be an essential component of circadian pacemaker cells in the SCN. Remarkably, the alteration of the shell-core phase relationship in the SCN of these mice did not impair the generation per se of circadian behavior rhythm, thereby underscoring the robustness of the SCN network. Copyright © 2016 Elsevier Ltd. All rights reserved.
Butler, Matthew P; Smales, Carolina; Wu, Huijuan; Hussain, Mohammad V; Mohamed, Yusef A; Morimoto, Miki; Shea, Steven A
To test the hypothesis that respiratory event duration exhibits an endogenous circadian rhythm. Within-subject and between-subjects. Inpatient intensive physiologic monitoring unit at the Brigham and Women's Hospital. Seven subjects with moderate/severe sleep apnea and four controls, age 48 (SD = 12) years, 7 males. Subjects completed a 5-day inpatient protocol in dim light. Polysomnography was recorded during an initial control 8-h night scheduled at the usual sleep time, then through 10 recurrent cycles of 2 h 40 min sleep and 2 h 40 min wake evenly distributed across all circadian phases, and finally during another 8-h control sleep period. Event durations, desaturations, and apnea-hypopnea index for each sleep opportunity were assessed according to circadian phase (derived from salivary melatonin), time into sleep, and sleep stage. Average respiratory event durations in NREM sleep significantly lengthened across both control nights (21.9 to 28.2 sec and 23.7 to 30.2 sec, respectively). During the circadian protocol, event duration in NREM increased across the circadian phases that corresponded to the usual sleep period, accounting for > 50% of the increase across normal 8-h control nights. AHI and desaturations were also rhythmic: AHI was highest in the biological day while desaturations were greatest in the biological night. The endogenous circadian system plays an important role in the prolongation of respiratory events across the night, and might provide a novel therapeutic target for modulating sleep apnea. © 2015 Associated Professional Sleep Societies, LLC.
Eastman, Charmane I; Suh, Christina; Tomaka, Victoria A; Crowley, Stephanie J
Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period, and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals.
Yagita, Kazuhiro; Yamanaka, Iori; Koinuma, Satoshi; Shigeyoshi, Yasufumi; Uchiyama, Yasuo
In mammalian circadian rhythms, the transcriptional-translational feedback loop (TTFL) consisting of a set of clock genes is believed to elicit the circadian clock oscillation. The TTFL model explains that the accumulation and degradation of mPER and mCRY proteins control the period-length (tau) of the circadian clock. Although recent studies revealed that the Casein Kinase Iεδ (CKIεδ) regurates the phosphorylation of mPER proteins and the circadian period-length, other kinases are also likely to contribute the phosphorylation of mPER. Here, we performed small scale screening using 84 chemical compounds known as kinase inhibitors to identify candidates possibly affecting the circadian period-length in mammalian cells. Screening by this high-throughput real-time bioluminescence monitoring system revealed that the several chemical compounds apparently lengthened the cellular circadian clock oscillation. These compounds are known as inhibitors against kinases such as Casein Kinase II (CKII), PI3-kinase (PI3K) and c-Jun N-terminal Kinase (JNK) in addition to CKIεδ. Although these kinase inhibitors may have some non-specific effects on other factors, our mini screening identified new candidates contributing to period-length control in mammalian cells
Touitou, Yvan; Mauvieux, Benoit; Reinberg, Alain; Dispersyn, Garance
The circadian time structure of an organism can be desynchronized in a large number of instances, including the intake of specific drugs. We have previously found that propofol, which is a general anesthetic, induces a desynchronization of the circadian time structure in rats, with a 60-80 min significant phase advance of body temperature circadian rhythm. We thus deemed it worthwhile to examine whether this phase shift of body temperature was related to a modification of the circadian period Tau. Propofol was administered at three different Zeitgeber Times (ZTs): ZT6 (middle of the rest period), ZT10 (2 h prior to the beginning of activity period), ZT16 (4 h after the beginning of the activity period), with ZT0 being the beginning of the rest period (light onset) and ZT12 being the beginning of the activity period (light offset). Control rats (n = 20) were injected at the same ZTs with 10% intralipid, which is a control lipidic solution. Whereas no modification of the circadian period of body temperature was observed in the control rats, propofol administration resulted in a significant shortening of the period by 96 and 180 min at ZT6 and ZT10, respectively. By contrast, the period was significantly lengthened by 90 min at ZT16. We also found differences in the time it took for the rats to readjust their body temperature to the original 24-h rhythm. At ZT16, the speed of readjustment was more rapid than at the two other ZTs that we investigated. This study hence shows (i) the disruptive effects of the anesthetic propofol on the body temperature circadian rhythm, and it points out that (ii) the period Tau for body temperature responds to this anesthetic drug according to a Tau-response curve. By sustaining postoperative sleep-wake disorders, the disruptive effects of propofol on circadian time structure might have important implications for the use of this drug in humans.
Helm, B.; Visser, M.E.
Timing is essential, but circadian clocks, which play a crucial role in timekeeping, are almost unaddressed in evolutionary ecology. A key property of circadian clocks is their free-running period length (τ), i.e. the time taken for a full cycle under constant conditions. Under laboratory
Hirota, Tsuyoshi; Lewis, Warren G; Liu, Andrew C; Lee, Jae Wook; Schultz, Peter G; Kay, Steve A
The circadian clock controls daily oscillations of gene expression at the cellular level. We report the development of a high-throughput circadian functional assay system that consists of luminescent reporter cells, screening automation, and a data analysis pipeline. We applied this system to further dissect the molecular mechanisms underlying the mammalian circadian clock using a chemical biology approach. We analyzed the effect of 1,280 pharmacologically active compounds with diverse structures on the circadian period length that is indicative of the core clock mechanism. Our screening paradigm identified many compounds previously known to change the circadian period or phase, demonstrating the validity of the assay system. Furthermore, we found that small molecule inhibitors of glycogen synthase kinase 3 (GSK-3) consistently caused a strong short period phenotype in contrast to the well-known period lengthening by lithium, another presumed GSK-3 inhibitor. siRNA-mediated knockdown of GSK-3beta also caused a short period, confirming the phenotype obtained with the small molecule inhibitors. These results clarify the role of GSK-3beta in the period regulation of the mammalian clockworks and highlight the effectiveness of chemical biology in exploring unidentified mechanisms of the circadian clock.
Eastman, Charmane I; Tomaka, Victoria A; Crowley, Stephanie J
The endogenous, free-running circadian period (τ) determines the phase relationship that an organism assumes when entrained to the 24-h day. We found a shorter circadian period in African Americans compared to non-Hispanic European Americans (24.07 versus 24.33 h). We speculate that a short circadian period, closer to 24 h, was advantageous to humans living around the equator, but when humans migrated North out of Africa, where the photoperiod changes with seasons, natural selection favoured people with longer circadian periods. Recently, in evolutionary terms, immigrants came from Europe and Africa to America ('the New World'). The Europeans were descendents of people who had lived in Europe for thousands of years with changing photoperiods (and presumably longer periods), whereas Africans had ancestors who had always lived around the equator (with shorter periods). It may have been advantageous to have a longer circadian period while living in Europe early in the evolution of humans. In our modern world, however, it is better to have a shorter period, because it helps make our circadian rhythms earlier, which is adaptive in our early-bird-dominated society. European American women had a shorter circadian period than men (24.24 versus 24.41), but there was no sex difference in African Americans (24.07 for both men and women). We speculate that selection pressures in Europe made men develop a slightly longer period than women to help them track dawn which could be useful for hunters, but less important for women as gatherers. © 2017 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.
Narishige, Seira; Kuwahara, Mari; Shinozaki, Ayako; Okada, Satoshi; Ikeda, Yuko; Kamagata, Mayo; Tahara, Yu; Shibata, Shigenobu
Background and Purpose Caffeine is one of the most commonly used psychoactive substances. Circadian rhythms consist of the main suprachiasmatic nucleus (SCN) clocks and peripheral clocks. Although caffeine lengthens circadian rhythms and modifies phase changes in SCN-operated rhythms, the effects on caffeine on the phase, period and amplitude of peripheral organ clocks are not known. In addition, the role of cAMP/Ca2+ signalling in effects of caffeine on rhythm has not been fully elucidated. Experimental Approach We examined whether chronic or transient application of caffeine affects circadian period/amplitude and phase by evaluating bioluminescence rhythm in PER2::LUCIFERASE knock-in mice. Circadian rhythms were monitored in vitro using fibroblasts and ex vivo and in vivo for monitoring of peripheral clocks. Key Results Chronic application of caffeine (0.1–10 mM) increased period and amplitude in vitro. Transient application of caffeine (10 mM) near the bottom of the decreasing phase of bioluminescence rhythm caused phase advance in vitro. Caffeine (0.1%) intake caused a phase delay under light–dark or constant dark conditions, suggesting a period-lengthening effect in vivo. Caffeine (20 mg·kg−1) at daytime or at late night-time caused phase advance or delay in bioluminescence rhythm in the liver and kidney respectively. The complicated roles of cAMP/Ca2+ signalling may be involved in the caffeine-induced increase of period and amplitude in vitro. Conclusions and Implications Caffeine affects circadian rhythm in mice by lengthening the period and causing a phase shift of peripheral clocks. These results suggest that caffeine intake with food/drink may help with food-induced resetting of peripheral circadian clocks. PMID:25160990
Durakoğlugil, Murtaza Emre; Kocaman, Sinan Altan; Ciçek, Yüksel; Cetin, Mustafa
Exercise electrocardiography (ECG) is one of the most commonly utilized tests in cardiology. Despite the drawbacks, exercise ECG is widely preferred due to low cost, standardization, and strong prognostic information. A prolonged PR interval during recovery has recently been proposed as an indicator of mortality. Herein, we report an interesting case of a patient who presented with the complaint of exertional dyspnea and exhibited PR lengthening during the recovery period on the exercise ECG. The patient had a PR interval of 240 ms before exercise, which decreased to 160 ms at peak stress. However, during recovery, the PR interval prolonged gradually, reaching 320 ms at the second minute and persisting at that length until the end of the recovery period. The patient achieved 87% of the age predicted maximum heart rate, and experienced non-disabling shortness of breath and a pressure sensation in the chest, with no apparent ST segment depression. Recovery parameters, including heart rate recovery and systolic blood pressure recovery, were also within normal limits. The patient underwent coronary angiography with the suspicion of CAD which revealed severe multi-vessel disease. This rare case emphasizes the importance of PR lengthening in the recovery period as a sign of severe ischemia, in addition to other signs, such as prominent ST-segment changes, chronotropic incompetence, impaired hemodynamic response, and poor exercise capacity during stress ECG evaluation.
Noreen, Shumaila; Pegoraro, Mirko; Nouroz, Faisal; Tauber, Eran; Kyriacou, Charalambos P
The level of rescue of clock function in genetically arrhythmic Drosophila melanogaster hosts using interspecific clock gene transformation was used to study the putative intermolecular coevolution between interacting clock proteins. Among them PER and TIM are the two important negative regulators of the circadian clock feedback loop. We transformed either the D. pseudoobscura per or tim transgenes into the corresponding arrhythmic D. melanogaster mutant (per01 or tim01) and observed >50% rhythmicity but the period of activity rhythm was either longer (D. pseudoobscura-per) or shorter than 24 h (D. pseudoobscura-tim) compared to controls. By introducing both transgenes simultaneously into double mutants, we observed that the period of the activity rhythm was rescued by the pair of hemizygous transgenes (~24 h). These flies also showed a more optimal level of temperature compensation for the period. Under LD 12:12 these flies have a D. pseudoobscura like activity profile with the absence of morning anticipation as well as a very prominent earlier evening peak of activity rhythm. These observation are consistent with the view that TIM and PER form a heterospecific coevolved module at least for the circadian period of activity rhythms. However the strength of rhythmicity was reduced by having both transgenes present, so while evidence for a coevolution between PER and TIM is observed for some characters it is not for others. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
Full Text Available A key step in the analysis of circadian data is to make an accurate estimate of the underlying period. There are many different techniques and algorithms for determining period, all with different assumptions and with differing levels of complexity. Choosing which algorithm, which implementation and which measures of accuracy to use can offer many pitfalls, especially for the non-expert. We have developed the BioDare system, an online service allowing data-sharing (including public dissemination, data-processing and analysis. Circadian experiments are the main focus of BioDare hence performing period analysis is a major feature of the system. Six methods have been incorporated into BioDare: Enright and Lomb-Scargle periodograms, FFT-NLLS, mFourfit, MESA and Spectrum Resampling. Here we review those six techniques, explain the principles behind each algorithm and evaluate their performance. In order to quantify the methods' accuracy, we examine the algorithms against artificial mathematical test signals and model-generated mRNA data. Our re-implementation of each method in Java allows meaningful comparisons of the computational complexity and computing time associated with each algorithm. Finally, we provide guidelines on which algorithms are most appropriate for which data types, and recommendations on experimental design to extract optimal data for analysis.
Takekata, Hiroki; Matsuura, Yu; Goto, Shin G.; Satoh, Aya; Numata, Hideharu
The clock mechanism for circatidal rhythm has long been controversial, and its molecular basis is completely unknown. The mangrove cricket, Apteronemobius asahinai, shows two rhythms simultaneously in its locomotor activity: a circatidal rhythm producing active and inactive phases as well as a circadian rhythm modifying the activity intensity of circatidal active phases. The role of the clock gene period (per), one of the key components of the circadian clock in insects, was investigated in t...
Frank A J L Scheer
Full Text Available Human expeditions to Mars will require adaptation to the 24.65-h Martian solar day-night cycle (sol, which is outside the range of entrainment of the human circadian pacemaker under lighting intensities to which astronauts are typically exposed. Failure to entrain the circadian time-keeping system to the desired rest-activity cycle disturbs sleep and impairs cognitive function. Furthermore, differences between the intrinsic circadian period and Earth's 24-h light-dark cycle underlie human circadian rhythm sleep disorders, such as advanced sleep phase disorder and non-24-hour sleep-wake disorders. Therefore, first, we tested whether exposure to a model-based lighting regimen would entrain the human circadian pacemaker at a normal phase angle to the 24.65-h Martian sol and to the 23.5-h day length often required of astronauts during short duration space exploration. Second, we tested here whether such prior entrainment to non-24-h light-dark cycles would lead to subsequent modification of the intrinsic period of the human circadian timing system. Here we show that exposure to moderately bright light ( approximately 450 lux; approximately 1.2 W/m(2 for the second or first half of the scheduled wake episode is effective for entraining individuals to the 24.65-h Martian sol and a 23.5-h day length, respectively. Estimations of the circadian periods of plasma melatonin, plasma cortisol, and core body temperature rhythms collected under forced desynchrony protocols revealed that the intrinsic circadian period of the human circadian pacemaker was significantly longer following entrainment to the Martian sol as compared to following entrainment to the 23.5-h day. The latter finding of after-effects of entrainment reveals for the first time plasticity of the period of the human circadian timing system. Both findings have important implications for the treatment of circadian rhythm sleep disorders and human space exploration.
Full Text Available BACKGROUND: Diurnal behavior in humans is governed by the period length of a circadian clock in the suprachiasmatic nuclei of the brain hypothalamus. Nevertheless, the cell-intrinsic mechanism of this clock is present in most cells of the body. We have shown previously that for individuals of extreme chronotype ("larks" and "owls", clock properties measured in human fibroblasts correlated with extreme diurnal behavior. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have measured circadian period in human primary fibroblasts taken from normal individuals and, for the first time, compared it directly with physiological period measured in vivo in the same subjects. Human physiological period length was estimated via the secretion pattern of the hormone melatonin in two different groups of sighted subjects and one group of totally blind subjects, each using different methods. Fibroblast period length was measured via cyclical expression of a lentivirally delivered circadian reporter. Within each group, a positive linear correlation was observed between circadian period length in physiology and in fibroblast gene expression. Interestingly, although blind individuals showed on average the same fibroblast clock properties as sighted ones, their physiological periods were significantly longer. CONCLUSIONS/SIGNIFICANCE: We conclude that the period of human circadian behaviour is mostly driven by cellular clock properties in normal individuals and can be approximated by measurement in peripheral cells such as fibroblasts. Based upon differences among sighted and blind subjects, we also speculate that period can be modified by prolonged unusual conditions such as the total light deprivation of blindness.
Zlinszky, Andras; Barfod, Anders
in amplitude and 2-6hour periodicity. Sub-circadian process dynamics of plants were so far not in focus of research, but here we compare the findings with other published cases of short-term periodicity in leaf turgor, sap flow and especially trunk diameter. Several authors have noted overnight variations...
Zlinszky, Andras; Barfod, Anders
in amplitude and 2-6hour periodicity. Sub-circadian process dynamics of plants were so far not in focus of research, but here we compare the findings with other published cases of short-term periodicity in leaf turgor, sap flow and especially trunk diameter. Several authors have noted overnight variations...
Ohnishi, Isao; Kurokawa, Takahide; Sato, Wakyo; Nakamura, Kozo
The purpose of this study was to investigate the effects of lengthening frequency on mechanical environment in limb lengthening. Tensile forces were continuously monitored using a load sensor attached to a unilateral external fixator. Twenty patients were monitored. Ten patients were with acquired femoral shortening, and five of them underwent quasi-continuous lengthening of 1440 steps per day, and the other five received step lengthening twice a day. The other 10 patients were with achondropalsia. Five of them underwent the same quasi-continuous lengthening, and the other five received the same step lengthening. The circadian change and the daily course of the tensile forces were assessed and compared between quasi-continuous lengthening and step lengthening. As for circadian change, an acute increase in the force took place simultaneously with each step of lengthening in the step-lengthening group, but very little change of the baseline force level was seen during quasi-continuous lengthening. As for daily course of the tensile force, it increased almost linearly in both lengthening frequency groups in the initial stage of lengthening. No significant difference of the average force increment rate in this phase was recognized between the quasi-continuous and step lengthening groups irrespective of the etiologies. The lengthening frequency greatly affected the circadian change of the tensile force, but did not affect the increment rate of the force in the linear phase.
Julie S Pendergast
Full Text Available The mammalian circadian system, which is composed of a master pacemaker in the suprachiasmatic nuclei (SCN as well as other oscillators in the brain and peripheral tissues, controls daily rhythms of behavior and physiology. Lesions of the SCN abolish circadian rhythms of locomotor activity and transplants of fetal SCN tissue restore rhythmic behavior with the periodicity of the donor's genotype, suggesting that the SCN determines the period of the circadian behavioral rhythm. According to the model of timekeeping in the SCN, the Period (Per genes are important elements of the transcriptional/translational feedback loops that generate the endogenous circadian rhythm. Previous studies have investigated the functions of the Per genes by examining locomotor activity in mice lacking functional PERIOD proteins. Variable behavioral phenotypes were observed depending on the line and genetic background of the mice. In the current study we assessed both wheel-running activity and Per1-promoter-driven luciferase expression (Per1-luc in cultured SCN, pituitary, and lung explants from Per2(-/- and Per3(-/- mice congenic with the C57BL/6J strain. We found that the Per2(-/- phenotype is enhanced in vitro compared to in vivo, such that the period of Per1-luc expression in Per2(-/- SCN explants is 1.5 hours shorter than in Per2+/+ SCN, while the free-running period of wheel-running activity is only 11 minutes shorter in Per2(-/- compared to Per2+/+ mice. In contrast, circadian rhythms in SCN explants from Per3(-/- mice do not differ from Per3+/+ mice. Instead, the period and phase of Per1-luc expression are significantly altered in Per3(-/- pituitary and lung explants compared to Per3+/+ mice. Taken together these data suggest that the function of each Per gene may differ between tissues. Per2 appears to be important for period determination in the SCN, while Per3 participates in timekeeping in the pituitary and lung.
Oklejewicz, M; Overkamp, GJF; Stirland, JA; Daan, S
The variation in spontaneous meal patterning was studied in three genotypes (tau +/+, tau +/- and tau -/-) of the Syrian hamster with an altered circadian period. Feeding activity was monitored continuously in 13 individuals from each genotype in constant dim light conditions. All three genotypes
Yamashita, Shuhei; Uehara, Tomoe; Matsuo, Minako; Kikuchi, Yo; Numano, Rika
The biochemical, physiological and behavioral processes are under the control of internal clocks with the period of approximately 24 hr, circadian rhythms. The expression of clock gene Period1 (Per1) oscillates autonomously in cells and is induced immediately after a light pulse. Per1 is an indispensable member of the central clock system to maintain the autonomous oscillator and synchronize environmental light cycle. Per1 expression could be detected by Per1∷luc and Per1∷GFP plasmid DNA in which firefly luciferase and Green Fluorescence Protein were rhythmically expressed under the control of the mouse Per1 promoter in order to monitor mammalian circadian rhythms. Membrane protein, MELANOPSIN is activated by blue light in the morning on the retina and lead to signals transduction to induce Per1 expression and to reset the phase of circadian rhythms. In this report Per1 induction was measured by reporter signal assay in Per1∷luc and Per1∷GFP fibroblast cell at the input process of circadian rhythms. To the result all process to reset the rhythms by Melanopsin is completed in single cell like in the retina projected to the central clock in the brain. Moreover, the phase of circadian rhythm in Per1∷luc cells is synchronized by photo-activated Melanopsin, because the definite peak of luciferase activity in one dish was found one day after light illumination. That is an available means that physiological circadian rhythms could be real-time monitor as calculable reporter (bioluminescent and fluorescent) chronological signal in both single and groups of cells.
Seggio, Joseph A; Fixaris, Michael C; Reed, Jeffrey D; Logan, Ryan W; Rosenwasser, Alan M
Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes.
Gu, Changgui; Rohling, Jos H. T.; Liang, Xiaoming; Yang, Huijie
The dominant endogenous clock, named the suprachiasmatic nucleus (SCN), regulates circadian rhythms of behavioral and physiological activity in mammals. One of the main characteristics of the SCN is that the animal maintains a circadian rhythm with a period close to 24 h in the absence of a daily light-dark cycle (called the free running period). The free running period varies among species due to heterogeneity of the SCN network. Previous studies have shown that the heterogeneity in cellular coupling as well as in intrinsic neuronal periods shortens the free running period. Furthermore, as derived from experiments, one neuron's coupling strength is negatively associated with its period. It is unknown what the effects of this association between coupling strength and period are on the free running period and how the heterogeneity in coupling strength influences this free running period. In the present study we found that in the presence of a negative relationship between one neuron's coupling strength and its period, surprisingly, the dispersion of coupling strengths increases the free running period. Our present finding may shed new light on the understanding of the heterogeneous SCN network and provides an alternative explanation for the diversity of free running periods between species.
Full Text Available Accumulating evidence suggests that the circadian clock is closely associated with metabolic regulation. However, whether an impaired circadian clock is a direct cause of metabolic dysregulation such as body weight gain is not clearly understood. In this study, we demonstrate that body weight gain in mice is not significantly changed by restricting feeding period to daytime or nighttime. The expression of peripheral circadian clock genes was altered by feeding period restriction, while the expression of light-regulated hypothalamic circadian clock genes was unaffected by either a normal chow diet (NCD or a high-fat diet (HFD. In the liver, the expression pattern of circadian clock genes, including Bmal1, Clock, and Per2, was changed by different feeding period restrictions. Moreover, the expression of lipogenic genes, gluconeogenic genes, and fatty acid oxidation-related genes in the liver was also altered by feeding period restriction. Given that feeding period restriction does not affect body weight gain with a NCD or HFD, it is likely that the amount of food consumed might be a crucial factor in determining body weight. Collectively, these data suggest that feeding period restriction modulates the expression of peripheral circadian clock genes, which is uncoupled from light-sensitive hypothalamic circadian clock genes.
Full Text Available The pathogenesis of fibromyalgia (FM has not been clearly elucidated, but central sensitization, which plays an important role in the development of neuropathic pain, is considered to be the main mechanism. The cutaneous silent period (CSP, which is a spinal reflex mediated by A-delta cutaneous afferents, is useful for the evaluation of sensorimotor integration at the spinal and supraspinal levels. To understand the pathophysiology of FM, we compared CSP patterns between patients with FM and normal healthy subjects. Twenty-four patients with FM diagnosed in accordance with the 1990 American College of Rheumatology classification system and 24 age- and sex-matched healthy volunteers were recruited. The CSP was measured from the abductor pollicis brevis muscle. Demographic data, number of tender points, and visual analog scale and FM impact questionnaire scores were collected. The measured CSP and clinical parameters of the patient and control groups were compared. In addition, possible correlations between the CSP parameters and the other clinical characteristics were analyzed. Mean CSP latencies did not differ between patients (55.50 ± 10.97 ms and healthy controls (60.23 ± 11.87 ms; p = 0.158, although the mean CSP duration was significantly longer in patients (73.75 ± 15.67 ms than in controls (63.50 ± 14.05 ms; p = 0.021. CSP variables did not correlate with any clinical variables. The significantly longer CSP duration in FM patients suggests central dysregulation at the spinal and supraspinal levels, rather than peripheral small fiber dysfunction.
Laranjeiro, Ricardo; Tamai, T Katherine; Letton, William; Hamilton, Noémie; Whitmore, David
Studies from a number of model systems have shown that the circadian clock controls expression of key cell cycle checkpoints, thus providing permissive or inhibitory windows in which specific cell cycle events can occur. However, a major question remains: Is the clock actually regulating the cell cycle through such a gating mechanism or, alternatively, is there a coupling process that controls the speed of cell cycle progression? Using our light-responsive zebrafish cell lines, we address this issue directly by synchronizing the cell cycle in culture simply by changing the entraining light-dark (LD) cycle in the incubator without the need for pharmacological intervention. Our results show that the cell cycle rapidly reentrains to a shifted LD cycle within 36 h, with changes in p21 expression and subsequent S phase timing occurring within the first few hours of resetting. Reentrainment of mitosis appears to lag S phase resetting by 1 circadian cycle. The range of entrainment of the zebrafish clock to differing LD cycles is large, from 16 to 32 hour periods. We exploited this feature to explore cell cycle entrainment at both the population and single cell levels. At the population level, cell cycle length is shortened or lengthened under corresponding T-cycles, suggesting that a 1:1 coupling mechanism is capable of either speeding up or slowing down the cell cycle. However, analysis at the single cell level reveals that this, in fact, is not true and that a gating mechanism is the fundamental method of timed cell cycle regulation in zebrafish. Cell cycle length at the single cell level is virtually unaltered with varying T-cycles.
Choi, I H; Chung, M S; Baek, G H; Cho, T J; Chung, C Y
We retrospectively reviewed and compared the outcomes of 15 one-stage metatarsal lengthenings with intercalary bone graftings in 10 patients with those of nine metatarsal lengthenings by callotasis in five patients younger than 15 years. In the one-stage lengthening group, the diaphyseal osteotomy site was gradually distracted intraoperatively for 20-30 min to relax the surrounding soft tissues. In the callotasis group, lengthening was achieved with mini-Orthofix M-100. There was little difference in the outcomes between the two groups in terms of length gain, percentage increase, and complications. However, the period to achieve bony consolidation was longer in the callotasis group (2.7 months/cm) than in the one-stage lengthening group (1.5 months/cm). No case of neurovascular impairment was found in both groups.
Oklejewicz, M; Hut, RA; Daan, S
Homozygous tau mutant Syrian hamsters (tau-/-) have a free-running circadian period (tau) around 20 h and a proportionally higher metabolic rate compared with wild-type hamsters (tau+/+) with a period of circa 24 h. In this study, we applied deuterium oxide (D2O) to hamsters to test whether
Kubota, Masaya; Shinozaki, Masako; Sasaki, Hideo.
We report a 19-year-old man suffering from circadian sleep-wake (S-W) rhythm disturbance after total tumor resection and whole brain irradiation. The patient was diagnosed as having astrocytoma in the right temporal lobe by CT scan and angiography at the age of 6 months. After total tumor resection and whole brain irradiation ( 60 Co 60 Gy), he showed profound psychomotor retardation, endoclinologic dysfunction including hypothyroidism and growth hormone deficiency, and S-W rhythm disturbance. At the age of 19, brain MRI revealed asymmetrical low intensity in the hypothalamic region. On endoclinological examination panhypopituitarism due to primary hypothalamic lesion was evident. His S-W rhythm was disturbed; i.e., sleep periods were dispersedly distributed throughout 24 hours. So he showed a lethargic tendency in the daytime. All-day polysomnography revealed abnormal sleep structure such as the absence of sleep spindle and hump, peripheral apnea, snoring and low oxygen saturation. After L-thyroxine supplementation his daily activity improved gradually. The decrease in short time sleep and tendency of a free-running rhythm were observed and oxygen saturation improved remarkably. Peripheral apnea and snoring disappeared. This wakening effect of L-thyroxine administration may be due to improvement of hypothyroidism symptom such as myxoedematous pharynx. It also seems related to the alteration of the central S-W rhythm regulation, because free-running rhythm appeared after L-thyroxine administration. Vitamin B 12 (VB 12 ), which has been reported to be effective for S-W rhythm disorders, was not effective for our patient's free-running rhythm. Compared with the patients responding to VB 12 , our patient's organic brain damage was more evident radiologically and endoclinologically. Following the hypothesis that VB 12 has a potential to reinforce the entrainment of circadian rhythm, our patient's organic brain damage may include entrainment system. (author)
Louisa M-C Wang
Full Text Available Genes responsible for generating circadian oscillations are expressed in a variety of brain regions not typically associated with circadian timing. The functions of this clock gene expression are largely unknown, and in the present study we sought to explore the role of the Per2 (Period 2 gene in hippocampal physiology and learned behaviour. We found that PER2 protein is highly expressed in hippocampal pyramidal cell layers and that the expression of both protein and mRNA varies with a circadian rhythm. The peaks of these rhythms occur in the late night or early morning and are almost 180° out-of-phase with the expression rhythms measured from the suprachiasmatic nucleus of the same animals. The rhythms in Per2 expression are autonomous as they are present in isolated hippocampal slices maintained in culture. Physiologically, Per2-mutant mice exhibit abnormal long-term potentiation. The underlying mechanism is suggested by the finding that levels of phosphorylated cAMP-response-element-binding protein, but not phosphorylated extracellular-signal-regulated kinase, are reduced in hippocampal tissue from mutant mice. Finally, Per2-mutant mice exhibit deficits in the recall of trace, but not cued, fear conditioning. Taken together, these results provide evidence that hippocampal cells contain an autonomous circadian clock. Furthermore, the clock gene Per2 may play a role in the regulation of long-term potentiation and in the recall of some forms of learned behaviour.
Laurinová, Kristýna; Kováčiková, Zuzana; Sládek, Martin; Bendová, Zdena; Illnerová, Helena; Sumová, Alena
Roč. 272, č. S1 (2005), s. 554-555 ISSN 1474-3833. [FEBS Congress /30./ and IUBMB Conference /9./. 02.07.2005-07.07.2005, Budapest] R&D Projects: GA ČR(CZ) GA309/05/0350; GA ČR(CZ) GP309/02/D093 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian rhythm s * Period1 * suprachiasmatic nucleus * development Subject RIV: FH - Neurology
Eskes, G.A.; Zucker, I.
The testes of hamsters exposed to short days (10 hr of light per day) regress within 13 weeks. Administration of 7.5 percent deuterium oxide to hamsters lengthens the period of free running circadian activity rhythms by 2.2 percent and prevents testicular regression during short-day exposure. This is consistent with predictions derived from an external coincidence model for photoperiodic time measurement: Deuterium oxide changes phase relationships between the light-dark cycle and the circadian system, the hamster's daily photosensitive phase is stimulated with light during short days, and the testes remain large. Conservation of the period of circadian rhythms within narrow limits has adaptive significance for hamster photoperiodism and for the occurrence and phasing of the annual reproductive cycle
Volpi, Alexander D; Fragomen, Austin T
Brachymetacarpia is a condition manifesting a shortened metacarpal that is caused by early closure of the epiphyseal plate and believed to arise idiopathically. The correction for brachymetacarpia is usually for cosmetic reasons as brachymetacarpia does not impair function. The literature indicates several different approaches to lengthening digits, including single-stage lengthening and rapid distraction lengthening with a bone graft. However, gradual distraction is the preferred method due to excellent cosmetic outcomes and few postoperative complications. This article reports a case of brachymetacarpia treated with distraction lengthening using a minimally invasive, percutaneous approach. A 16-year-old girl presented with a shortened left ring finger and underwent surgery to correct the deformity. The left ring finger measured 12 mm shorter than her right ring finger; however, there was normal mobility at the joints. In the operating room, an external fixator was attached using 4 self-drilling, self-tapping pins through several 3-mm skin incisions. The total fixation time was 14 weeks; however, the achieved length of 12 mm was achieved 6 weeks postoperatively. The healing index of the fixation period was 81 days/cm. The postoperative course and fixation period were uneventful, with no complications except for 2 pin infections that were treated with oral antibiotics. The method of gradual distraction lengthening in this case successfully achieved the desired length and yielded an excellent cosmetic result. Copyright 2011, SLACK Incorporated.
La Spada, F.
Humans spend one third of their life sleeping, then we could raise the basic question: Why do we sleep? Despite the fact that we still don't fully understand its function, we made much progress in understanding at different levels how sleep is regulated. One model suggests that sleep is regulated by two processes: a homeostatic process that tracks the need for sleep and by a circadian rhythm that determines the preferred time-of-day sleep occurs. At the molecular level circadian rhythms ar...
Beersma, DGM; Daan, S; Hut, RA
The accuracy with which a circadian pacemaker can entrain to an environmental 24-h zeitgeber signal depends on (a) characteristics of the entraining signal and (b) response characteristics and intrinsic stability of the pacemaker itself. Position of the sun, weather conditions, shades, and
Walton, K. M.; Fisher, K.; Rubitski, D.; Marconi, M.; Meng, Q.-J.; Sládek, Martin; Adams, J.; Bass, M.; Chandrasekaran, R.; Butler, T.; Griffor, M.; Rajamohan, F.; Serpa, M.; Chen, Y.; Claffey, M.; Hastings, M.; Loudon, A.; Maywood, E.; Ohren, J.; Doran, A.; Wager, T. T.
Roč. 330, č. 2 (2009), s. 430-439 ISSN 0022-3565 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * casein kinase 1 epsilon * inhibitor Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.093, year: 2009
Dani M. Long
Full Text Available Circadian clocks consist of molecular negative feedback loops that coordinate physiological, neurological, and behavioral variables into “circa” 24-h rhythms. Rhythms in behavioral and other circadian outputs tend to weaken during aging, as evident in progressive disruptions of sleep-wake cycles in aging organisms. However, less is known about the molecular changes in the expression of clock genes and proteins that may lead to the weakening of circadian outputs. Western blot studies have demonstrated that the expression of the core clock protein PERIOD (PER declines in the heads of aged Drosophila melanogaster flies. This age-related decline in PER does not occur in the central pacemaker neurons but has been demonstrated so far in retinal photoreceptors. Besides photoreceptors, clock proteins are also expressed in fly glia, which play important roles in neuronal homeostasis and are further categorized into subtypes based on morphology and function. While previous studies of mammalian glial cells have demonstrated the presence of functional clocks in astrocytes and microglia, it is not known which glial cell types in Drosophila express clock proteins and how their expression may change in aged individuals. Here, we conducted immunocytochemistry experiments to identify which glial subtypes express PER protein suggestive of functional circadian clocks. Glial cell subtypes that showed night-time accumulation and day-time absence in PER consistent with oscillations reported in the pacemaker neurons were selected to compare the level of PER protein between young and old flies. Our data demonstrate that some glial subtypes show rhythmic PER expression and the relative PER levels become dampened with advanced age. Identification of glial cell types that display age-related dampening of PER levels may help to understand the cellular changes that contribute to the loss of homeostasis in the aging brain.
John C Means
Full Text Available While circadian dysfunction and neurodegeneration are correlated, the mechanism for this is not understood. It is not known if age-dependent circadian dysfunction leads to neurodegeneration or vice-versa, and the proteins that mediate the effect remain unidentified. Here, we show that the knock-down of a regulator (spag of the circadian kinase Dbt in circadian cells lowers Dbt levels abnormally, lengthens circadian rhythms and causes expression of activated initiator caspase (Dronc in the optic lobes during the middle of the day or after light pulses at night. Likewise, reduced Dbt activity lengthens circadian period and causes expression of activated Dronc, and a loss-of-function mutation in Clk also leads to expression of activated Dronc in a light-dependent manner. Genetic epistasis experiments place Dbt downstream of Spag in the pathway, and Spag-dependent reductions of Dbt are shown to require the proteasome. Importantly, activated Dronc expression due to reduced Spag or Dbt activity occurs in cells that do not express the spag RNAi or dominant negative Dbt and requires PDF neuropeptide signaling from the same neurons that support behavioral rhythms. Furthermore, reduction of Dbt or Spag activity leads to Dronc-dependent Drosophila Tau cleavage and enhanced neurodegeneration produced by human Tau in a fly eye model for tauopathy. Aging flies with lowered Dbt or Spag function show markers of cell death as well as behavioral deficits and shortened lifespans, and even old wild type flies exhibit Dbt modification and activated caspase at particular times of day. These results suggest that Dbt suppresses expression of activated Dronc to prevent Tau cleavage, and that the circadian clock defects confer sensitivity to expression of activated Dronc in response to prolonged light. They establish a link between the circadian clock factors, light, cell death pathways and Tau toxicity, potentially via dysregulation of circadian neuronal remodeling in
Chilbule, Sanjay K; Dutt, Vivek; Madhuri, Vrisha
Background: Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive s...
Sanjay K Chilbule
Full Text Available Background: Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive stature lengthening performed at our center. Materials and Methods: Eight achondroplasic and one hypochondroplasic patient underwent bilateral transverse lengthening for tibiae, humeri and femora. Tibia lengthening was carried out using a ring fixator and bifocal corticotomy, while a monolateral pediatric limb reconstruction system with unifocal corticotomy was used for the femur and humerus. Lengthening of each bone segment, height gain, healing index and complications were assessed. Subgroup analysis was carried out to assess the effect of age and bone segment on the healing index. Results: Nine patients aged five to 25 years (mean age 10.2 years underwent limb lengthening procedures for 18 tibiae, 10 femora and 8 humeri. Four patients underwent bilateral lengthening of all three segments. The mean length gain for the tibia, femur and humerus was 15.4 cm (100.7%, 9.9 cm (52.8% and 9.6 cm (77.9%, respectively. Healing index was 25.7, 25.6 and 20.6 days/cm, respectively, for the tibia, femur and humerus. An average of 33.3% height gain was attained. Lengthening of both tibia and femur added to projected height achieved as the 3 rd percentile of standard height in three out of four patients. In all, 33 complications were encountered (0.9 complications per segment. Healing index was not affected by age or bone segment. Conclusion: Extensive limb lengthening (more than 50% over initial length carries significant risk and should be undertaken only after due
Chilbule, Sanjay K; Dutt, Vivek; Madhuri, Vrisha
Stature lengthening in skeletal dysplasia is a contentious issue. Specific guidelines regarding the age and sequence of surgery, methods and extent of lengthening at each stage are not uniform around the world. Despite the need for multiple surgeries, with their attendant complications, parents demanding stature lengthening are not rare, due to the social bias and psychological effects experienced by these patients. This study describes the outcome and complications of extensive stature lengthening performed at our center. Eight achondroplasic and one hypochondroplasic patient underwent bilateral transverse lengthening for tibiae, humeri and femora. Tibia lengthening was carried out using a ring fixator and bifocal corticotomy, while a monolateral pediatric limb reconstruction system with unifocal corticotomy was used for the femur and humerus. Lengthening of each bone segment, height gain, healing index and complications were assessed. Subgroup analysis was carried out to assess the effect of age and bone segment on the healing index. Nine patients aged five to 25 years (mean age 10.2 years) underwent limb lengthening procedures for 18 tibiae, 10 femora and 8 humeri. Four patients underwent bilateral lengthening of all three segments. The mean length gain for the tibia, femur and humerus was 15.4 cm (100.7%), 9.9 cm (52.8%) and 9.6 cm (77.9%), respectively. Healing index was 25.7, 25.6 and 20.6 days/cm, respectively, for the tibia, femur and humerus. An average of 33.3% height gain was attained. Lengthening of both tibia and femur added to projected height achieved as the 3(rd) percentile of standard height in three out of four patients. In all, 33 complications were encountered (0.9 complications per segment). Healing index was not affected by age or bone segment. Extensive limb lengthening (more than 50% over initial length) carries significant risk and should be undertaken only after due consideration.
Full Text Available BackgroundIn mammals, the master circadian pacemaker is localized in an area of the ventral hypothalamus known as the suprachiasmatic nucleus (SCN. Previous studies have shown that pacemaker neurons in the SCN are highly coupled to one another, and this coupling is crucial for intrinsic self-sustainability of the SCN central clock, which is distinguished from peripheral oscillators. One plausible mechanism underlying the intercellular communication may involve direct electrical connections mediated by gap junctions.MethodsWe examined the effect of mefloquine, a neuronal gap junction blocker, on circadian Period 2 (Per2 gene oscillation in SCN slice cultures prepared from Per2::luciferase (PER2::LUC knock-in mice using a real-time bioluminescence measurement system.ResultsAdministration of mefloquine causes instability in the pulse period and a slight reduction of amplitude in cyclic PER2::LUC expression. Blockade of gap junctions uncouples PER2::LUC-expressing cells, in terms of phase transition, which weakens synchrony among individual cellular rhythms.ConclusionThese findings suggest that neuronal gap junctions play an important role in synchronizing the central pacemaker neurons and contribute to the distinct self-sustainability of the SCN master clock.
Iwahana, Eiko; Hamada, Toshiyuki; Uchida, Ayumi; Shibata, Shigenobu
Lithium is one of the most commonly used drugs in the prophylaxis and treatment of bipolar disorder. It is also known to lengthen circadian period in several organisms. Previously, we reported that there was the association between lengthening circadian period by lithium and GSK-3 protein and its enzyme activity in the mouse suprachiasmatic nucleus (SCN). In this study, we show that lithium affects the circadian oscillator in young and old hamster SCN, in an age-dependent manner. We found that basal levels of phosphorylated GSK-3 (pGSK-3) protein expression in old hamsters are much lower than that in young hamsters. Furthermore, in the old hamsters, lithium did not affect the period of the locomotor activity rhythm or pGSK-3 expression, while changing period and pGSK-3 in the younger animals. These results indicate that the content of pGSK-3 in the SCN has an important role in age-dependent effects of lithium on the circadian oscillator
Long, Dani M.; Giebultowicz, Jadwiga M.
Circadian clocks consist of molecular negative feedback loops that coordinate physiological, neurological, and behavioral variables into “circa” 24-h rhythms. Rhythms in behavioral and other circadian outputs tend to weaken during aging, as evident in progressive disruptions of sleep-wake cycles in aging organisms. However, less is known about the molecular changes in the expression of clock genes and proteins that may lead to the weakening of circadian outputs. Western blot studies have demo...
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Sharma, Vijay Kumar; Daan, Serge
We report period response curves (tauRC) for two nocturnal Murid species from India, Mus booduga and Mus platythrix. We further discuss the method of phase shift estimation in the presence of tau-changes, because such changes pose a serious methodological problem in the estimation of phase shifts.
Ionică, A.M.; Matei, I.A.; D'Amico, G.; Bel, L.; Dumitrache, M.O.; Modrý, David; Mihalca, A. D.
Roč. 10, FEB 28 (2017), č. článku 116. ISSN 1756-3305 Institutional support: RVO:60077344 Keywords : periodicity * microfilariae * co-infection * Dirofilaria immitis * Dirofilaria repens Subject RIV: GJ - Animal Vermins ; Diseases, Veterinary Medicine OBOR OECD: Veterinary science Impact factor: 3.080, year: 2016
Cain, Sean W; Yoon, Jeena; Shrestha, Tenjin C; Ralph, Martin R
Circadian rhythmic expression of conditioned place avoidance (CPA) was produced in Syrian hamsters homozygous for the circadian short period mutation, tau. In constant dim red light neither the 20 h endogenous period, nor a 20 h place conditioning schedule eliminated the 24 h modulation of CPA behavior described previously for wild type (wt) hamsters and other species. Tau mutants exhibited a 20 h rhythm superimposed on the 24 h modulation. The 20 h component was removed selectively with lesions of the suprachiasmatic nucleus. Wt animals conditioned on a 20 h schedule did not produce a 20 h rhythm, but still expressed the 24 h modulation. The results show that the context entrainable oscillator (CEO) underlying memory for the timing of an unconditioned stimulus, retains a period of about 24 h regardless of clock gene background (tau mutation) and/or the conditioning schedule (24 vs 20 h). Therefore the CEO responsible for time memory is distinct from the biological clock controlling activity; the underlying circadian molecular mechanisms may differ from the ubiquitous transcription-translation feedback oscillator; and time memory itself is not classically conditioned. Copyright © 2014 Elsevier Inc. All rights reserved.
Correll, J; Held, P
Limb lengthening in dwarfism has become a standardised procedure with a good prognosis. In most cases external fixation is used. Gain of leg length up to 15 cm and more is possible in the lower leg and the femur and 8.5 cm in the humerus. Limb lengthening is useful in many cases of dwarfism due to skeletal dysplasia. There are a number of risks and possible complications involved and the procedure also requires considerable time. We report the results of 48 patients with dwarfism operated on in the Orthopädische Kinderklinik Aschau (Orthopaedic Hospital for Children). It must not be recommended as a normal tool in handling the problems of dwarfism, but it makes sense in some cases of dwarfism. We describe and discuss the prerequisites for the operative treatment.
Ushirogawa, H; Abe, Y; Tomioka, K
The optic lobe is essential for circadian locomotor rhythms in the cricket, Gryllodes sigillatus. We examined potential interactions between the bilaterally paired optic lobes in circadian rhythm generation. When one optic lobe was removed, the free-running period of the locomotor rhythm slightly but significantly lengthened. When exposed to light-dark cycles (LD) with 26 hr period, intact and sham operated animals were clearly entrained to the light cycle, but a large number of animals receiving unilateral optic nerve severance showed rhythm dissociation. In the dissociation, two rhythmic components appeared; one was readily entrained to the given LD and the other free-ran with a period shorter than 24 hr, and activity was expressed only when they were inphase. The period of the free-running component was significantly longer than that of the animals with a single blinded pacemaker kept in LD13:13, suggesting that the pacemaker on the intact side had some influence on the blinded pacemaker even in the dissociated state. The ratio of animals with rhythm dissociation was greater with the lower light intensity of the LD. The results suggest that the bilaterally distributed pacemakers are only weakly coupled to one another but strongly suppress the activity driven by the partner pacemaker during their subjective day. The strong suppression of activity would be advantageous to keep a stable nocturnality for this cricket living indoors.
Wong, C C; Döhler, K D; Geerlings, H; von zur Mühlen, A
The influence of age, strain and season on the circadian pattern of serum levels of LH, FSH, prolactin androgens and corticosterone was studied in five groups of male laboratory rats. Significant 24-hour periodicity was observed for serum levels of corticosterone in all five groups, for androgen levels in four, for prolactin levels in three, for LH levels in two and for FSH levels in one group of rats. There were significant influences of age, strain and season on the temporal patterns and/or on 24-hour mean serum hormone levels. The results indicate that some of the disagreements on existence or nonexistence of circadian rhythms and on rhythm patterns in serum hormone levels may be explained by the fact that animals of different ages or strains had been used or that experiments were performed at different times of the year.
Cerovac, S; Miranda, B H
Tendon defect reconstruction is amongst the most technically challenging areas in hand surgery. Tendon substance deficiency reconstruction techniques include lengthening, grafting, two-stage reconstruction and tendon transfers, however each is associated with unique challenges over and above direct repair. We describe a novel 'turnover lengthening' technique for hand tendons that has successfully been applied to the repair of several cases, including a case of attritional flexor and traumatic extensor tendon rupture in two presented patients where primary tenorrhaphy was not possible. In both cases a good post-operative outcome was achieved, as the patients were happy having returned back to normal activities of daily living such that they were discharged 12 weeks post-operatively. Our technique avoids the additional morbidity and complications associated with grafting, transfers and two stage reconstructions. It is quick, simple and reproducible for defects not exceeding 3-4 cm, provides a means of immediate one stage reconstruction, no secondary donor site morbidity and does not compromise salvage by tendon transfer and/or two-stage reconstruction in cases of failure. To our knowledge no such technique has been previously been described to reconstruct such hand tendon defects. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.
Full Text Available Abstract The present paper reflects a work in progress toward a definition of circadian light, one that should be informed by the thoughtful, century-old evolution of our present definition of light as a stimulus for the human visual system. This work in progress is based upon the functional relationship between optical radiation and its effects on nocturnal melatonin suppression, in large part because the basic data are available in the literature. Discussed here are the fundamental differences between responses by the visual and circadian systems to optical radiation. Brief reviews of photometry, colorimetry, and brightness perception are presented as a foundation for the discussion of circadian light. Finally, circadian light (CLA and circadian stimulus (CS calculation procedures based on a published mathematical model of human circadian phototransduction are presented with an example.
Legan, Sandra J.; Donoghue, Kathleen M.; Franklin, Kathleen M.; Duncan, Marilyn J.
The suprachiasmatic nucleus (SCN) controls the timing of the preovulatory luteinizing hormone (LH) surge in laboratory rodents. Barbiturate administration during a critical period on proestrus delays the surge and prolongs the estrous cycle 1 day. Because a nonphotic timing signal (zeitgeber) during the critical period that phase advances activity rhythms can also induce the latter effect, we hypothesized that barbiturates delay the LH surge by phase-advancing its circadian timing signal beyond the critical period. In experiment 1, locomotor rhythms and estrous cycles were monitored in hamsters for 2–3 wk preinjection and postinjection of vehicle or phenobarbital and after transfer to darkness at zeitgeber time (ZT) 6 on proestrus. Phenobarbital delayed estrous cycles in five of seven hamsters, which exhibited phase shifts that averaged twofold greater than those exhibited by vehicle controls or phenobarbital-injected hamsters with normal cycles. Experiment 2 used a similar protocol, but injections were at ZT 5, and blood samples for LH determination were collected from 1200 to 1800 on proestrus and the next day via jugular cannulae inserted the day before proestrus. Phenobarbital delayed the LH surge 1 day in all six hamsters, but it occurred at an earlier circadian time, supporting the above hypothesis. Experiment 3 investigated whether phenobarbital, like other nonphotic zeitgebers, suppresses SCN Period1 and Period2 transcription. Two hours postinjection, phenobarbital decreased SCN expression of only Period1 mRNA, as determined by in situ hybridization. These results suggest that phenobarbital advances the SCN pacemaker, governing activity rhythms and hormone release in part by decreasing its Period1 gene expression. PMID:19297538
Mickley, H; Pless, P; Nielsen, J R
with a peak activity occurring in the evening hours (p less than 0.01). Thus, 43% of ischemic episodes and 42% of ischemic time occurred between 6 P.M. and 12 midnight. The characteristics of morning and evening episodes were similar, except for the heart rate at maximal ST-segment depression, which...... was significantly higher during morning episodes (p less than 0.02). Patients with transient myocardial ischemia had a diurnal distribution similar to the circadian variation displayed during ischemic activity. Thus, 16 of the 21 patients had ischemic episodes from 6 P.M. to 12 midnight versus 10 patients from 6 A...
Cansü, Eren; Ünal, Mehmet Bekir; Parmaksızoğlu, Fatih; Gürcan, Serkan
Thumb amputation is a major cause of hand dysfunction, and the treatment for distal thumb amputations remains controversial. Although finger reconstruction methods using distraction lengthening are known to restore finger length and function, we found no reports in the literature regarding phalangeal lengthening in thumb amputations. We aimed to evaluate proximal phalangeal lengthening in thumb amputations at or near the interphalangeal (IP) joint. We retrospectively evaluated patients who had undergone distraction lengthening of the proximal phalanx of the thumb. All patients underwent osteotomy, either during the initial procedure or as a second-stage procedure. Distraction began 10 days after osteotomy with the use of an external fixator that remained in place until ossification of the gap occurred without bone grafting. Patients were evaluated using the QuickDASH score. Fourteen patients with a mean age of 27 years and a mean follow-up period of 7 years were enrolled. The mean phalangeal lengthening achieved was 20 mm. Ossification occurred at all distraction sites, and the fixators were maintained for a mean of 85 days. The mean healing index was 42.5 days/cm. All 14 patients achieved the desired amount of phalangeal lengthening without major complications such as nonunion, premature union, or gross infection. For reconstruction in cases of distal thumb amputations, distraction lengthening of the proximal phalanx can be used to improve absolute length, web space, and grip distance. The technique is safe and effective, improves functionality/cosmesis, and offers a low complication risk.
Schulz, Pierre; Steimer, Thierry
Time is a dimension tightly associated with the biology of living species. There are cycles of varied lengths in biological activities, from very short (ultradian) rhythms to rhythms with a period of approximately one day (circadian) and rhythms with longer cycles, of a week, a month, a season, or even longer. These rhythms are generated by endogenous biological clocks, i.e. time-keeping structures, rather than being passive reactions to external fluctuations. In mammals, the suprachiasmatic nucleus (SCN) is the major pacemaker. The pineal gland, which secretes melatonin, is the major pacemaker in other phyla. There also exist biological clocks generating circadian rhythms in peripheral tissues, for example the liver. A series of clock genes generates the rhythm through positive and negative feedback effect of proteins on their own synthesis, and this system oscillates with a circadian period. External factors serve as indicators of the astronomical (solar) time and are called zeitgebers, literally time-givers. Light is the major zeitgeber, which resets daily the SCN circadian clock. In the absence of zeitgebers, the circadian rhythm is said to be free running; it has a period that differs from 24 hours. The SCN, together with peripheral clocks, enables a time-related homeostasis, which can become disorganized in its regulation by external factors (light, social activities, food intake), in the coordination and relative phase position of rhythms, or in other ways. Disturbances of rhythms are found in everyday life (jet lag, shift work), in sleep disorders, and in several psychiatric disorders including affective disorders. As almost all physiological and behavioural functions in humans occur on a rhythmic basis, the possibility that advances, delays or desynchronization of circadian rhythms might participate in neurological and psychiatric disorders has been a theme of research. In affective disorders, a decreased circadian amplitude of several rhythms as well as a
Jasiewicz, Barbara; Kacki, Wojciech; Koniarski, Arkadiusz; Kasprzyk, Marcin; Zarzycka, Maja; Tesiorowski, Maciej
Background. Anisomelia in patients with congenital fibular deficiencies is a difficult orthopedic problem due to concomitant deformities of the angle and knee. The goal of the present study was to analyze outcomes of tibia lengthening in these patients. Material and methods. In the period 1989-2001 we performed lengthening of 26 limbs in 21 patients with congenital fibular deficiency (11 female, 10 male, average age 10.1 years). Under the Achterman-Kalamchi classification, 8 tibiae were Type 1, 3 were Type 1b, and 10 were Type 2 (including one case with bilateral defect). The average baseline shortening was 4.6 cm, i.e. 15.3%. The Ilizarov method was used in 24 cases, chondrial lengthening in the others. We measured time of lengthening, time of stabilization, total healing time, amount of lengthening, and the lengthening index, as well as the range of ankle and knee movement, the positioning of the foot, and the axis of the tibia at each stage. Problems and complications were classified according to Paley. The average follow-up was 4.9 years Results. The mean time of lengthening was 101 days, stabilization time 177 days, total healing time 269 days, mean lengthening 5.6 cm (22.9%). As of the last examination only 7 patients did not require follow-up surgery, 6 with Type 1a and 1 with Type 1b. Conclusions. Tibia lengthening with axis correction constitutes an alternative to amputation in congenital fibular deficiency. It is a difficult procedure, however, encumbered by a significant risk of complications.
Daly, Rónán; Edwards, Kieron D.; O'Neill, John S.; Aitken, Stuart; Millar, Andrew J.; Girolami, Mark
Modelling gene regulatory networks in organisms is an important task that has recently become possible due to large scale assays using technologies such as microarrays. In this paper, the circadian clock of Arabidopsis thaliana is modelled by fitting dynamic Bayesian networks to luminescence data gathered from experiments. This work differs from previous modelling attempts by using higher-order dynamic Bayesian networks to explicitly model the time lag between the various genes being expressed. In order to achieve this goal, new techniques in preprocessing the data and in evaluating a learned model are proposed. It is shown that it is possible, to some extent, to model these time delays using a higher-order dynamic Bayesian network.
Park, Kwang-Won; Garcia, Rey-an Niño; Rejuso, Chastity Amor; Choi, Jung-Woo; Song, Hae-Ryong
Although bilateral lower-limb lengthening has been performed on patients with achondroplasia, the outcomes for the tibia and femur in terms of radiographic parameters, clinical results, and complications have not been compared with each other. We proposed 1) to compare the radiological outcomes of femoral and tibial lengthening and 2) to investigate the differences of complications related to lengthening. We retrospectively reviewed 28 patients (average age, 14 years 4 months) with achondroplasia who underwent bilateral limb lengthening between 2004 and 2012. All patients first underwent bilateral tibial lengthening, and at 9-48 months (average, 17.8 months) after this procedure, bilateral femoral lengthening was performed. We analyzed the pixel value ratio (PVR) and characteristics of the callus of the lengthened area on serial radiographs. The external fixation index (EFI) and healing index (HI) were computed to compare tibial and femoral lengthening. The complications related to lengthening were assessed. The average gain in length was 8.4 cm for the femur and 9.8 cm for the tibia. The PVR, EFI, and HI of the tibia were significantly better than those of the femur. Fewer complications were found during the lengthening of the tibia than during the lengthening of the femur. Tibial lengthening had a significantly lower complication rate and a higher callus formation rate than femoral lengthening. Our findings suggest that bilateral limb lengthening (tibia, followed by femur) remains a reasonable option; however, we should be more cautious when performing femoral lengthening in selected patients.
Serchov, Tsvetan; Jilg, Antje; Wolf, Christian T; Radtke, Ina; Stehle, Jörg H; Heumann, Rolf
Circadian rhythms, generated in the mouse suprachiasmatic nucleus (SCN), are synchronized to the environmental day-night changes by photic input. The activation of the extracellular signal-regulated kinases 1 and 2 (ERK1,2) and cAMP response element-binding protein (CREB)-mediated transcription play a critical role in this photoentrainment. The small GTPase Ras is one of the major upstream regulators of the ERK1,2/CREB pathway. In contrast to the well-described role of Ras in structural and functional synaptic plasticity in the adult mouse brain, the physiological regulation of Ras by photic sensory input is yet unknown. Here, we describe for the first time a circadian rhythm of Ras activity in the mouse SCN. Using synRas transgenic mice, expressing constitutively activated V12-Ha-Ras selectively in neurons, we demonstrate that enhanced Ras activation causes shortening of the circadian period length. We found upregulated expression and decreased inhibitory phosphorylation of the circadian period length modulator, glycogen synthase kinase-3 beta (GSK3β), in the SCN of synRas mice. Conversely, downregulation of Ras activity by blocking its function with an antibody in oscillating cell cultures reduced protein levels and increased phosphorylation of GSK3β and lengthened the period of BMAL1 promoter-driven luciferase activity. Furthermore, enhanced Ras activity in synRas mice resulted in a potentiation of light-induced phase delays at early subjective night, and increased photic induction of pERK1,2/pCREB and c-Fos. In contrast, at late subjective night, photic activation of Ras/ERK1,2/CREB in synRas mice was not sufficient to stimulate c-Fos protein expression and phase advance the clock. Taken together, our results demonstrate that Ras activity fine tunes the period length and modulates photoentrainment of the circadian clock.
Rawashdeh, Oliver; Jilg, Antje; Maronde, Erik
, the presence of PER1 in hippocampal neurons is a prerequisite for the time-of-day-dependent phosphorylation of CREB, as it regulates the shuttling of pP90RSK into the nucleus. Representative immunofluorescence images show a temporal difference in phosphorylated cAMP response element-binding protein (p...... activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility......CREB; green color) levels in all regions of the dorsal hippocampus between a wild-type C3H mouse (WT; left) and a Period1-knockout (Per1−/−; right) mouse. Images were taken 2 h after lights on, thus, when fluctuating levels of pCREB peak in WT mouse hippocampus. Insets show a representative hippocampal neuron...
Rawashdeh, Oliver; Jilg, Antje; Maronde, Erik; Fahrenkrug, Jan; Stehle, Jörg H
Memory performance varies over a 24-h day/night cycle. While the detailed underlying mechanisms are yet unknown, recent evidence suggests that in the mouse hippocampus, rhythmic phosphorylation of mitogen-activated protein kinase (MAPK) and cyclic adenosine monophosphate response element-binding protein (CREB) are central to the circadian (~ 24 h) regulation of learning and memory. We recently identified the clock protein PERIOD1 (PER1) as a vehicle that translates information encoding time of day to hippocampal plasticity. We here elaborate how PER1 may gate the sensitivity of memory-relevant hippocampal signaling pathways. We found that in wild-type mice (WT), spatial learning triggers CREB phosphorylation only during the daytime, and that this effect depends on the presence of PER1. The time-of-day-dependent induction of CREB phosphorylation can be reproduced pharmacologically in acute hippocampal slices prepared from WT mice, but is absent in preparations made from Per1-knockout (Per1(-/-) ) mice. We showed that the PER1-dependent CREB phosphorylation is regulated downstream of MAPK. Stimulation of WT hippocampal neurons triggered the co-translocation of PER1 and the CREB kinase pP90RSK (pMAPK-activated ribosomal S6 kinase) into the nucleus. In hippocampal neurons from Per1(-/-) mice, however, pP90RSK remained perinuclear. A co-immunoprecipitation assay confirmed a high-affinity interaction between PER1 and pP90RSK. Knocking down endogenous PER1 in hippocampal cells inhibited adenylyl cyclase-dependent CREB activation. Taken together, the PER1-dependent modulation of cytoplasmic-to-nuclear signaling in the murine hippocampus provides a molecular explanation for how the circadian system potentially shapes a temporal framework for daytime-dependent memory performance, and adds a novel facet to the versatility of the clock gene protein PER1. We provide evidence that the circadian clock gene Period1 (Per1) regulates CREB phosphorylation in the mouse hippocampus
Liu, Lin; Bailey, Susan M; Okuka, Maja; Muñoz, Purificación; Li, Chao; Zhou, Lingjun; Wu, Chao; Czerwiec, Eva; Sandler, Laurel; Seyfang, Andreas; Blasco, Maria A; Keefe, David L
Stem cells and cancer cells maintain telomere length mostly through telomerase. Telomerase activity is high in male germ line and stem cells, but is low or absent in mature oocytes and cleavage stage embryos, and then high again in blastocysts. How early embryos reset telomere length remains poorly understood. Here, we show that oocytes actually have shorter telomeres than somatic cells, but their telomeres lengthen remarkably during early cleavage development. Moreover, parthenogenetically activated oocytes also lengthen their telomeres, thus the capacity to elongate telomeres must reside within oocytes themselves. Notably, telomeres also elongate in the early cleavage embryos of telomerase-null mice, demonstrating that telomerase is unlikely to be responsible for the abrupt lengthening of telomeres in these cells. Coincident with telomere lengthening, extensive telomere sister-chromatid exchange (T-SCE) and colocalization of the DNA recombination proteins Rad50 and TRF1 were observed in early cleavage embryos. Both T-SCE and DNA recombination proteins decrease in blastocyst stage embryos, whereas telomerase activity increases and telomeres elongate only slowly. We suggest that telomeres lengthen during the early cleavage cycles following fertilization through a recombination-based mechanism, and that from the blastocyst stage onwards, telomerase only maintains the telomere length established by this alternative mechanism.
Hwang, So-Min; Song, Jennifer Kim; Kim, Hui-Taek
Brachymetatarsia is a rare clinical entity that presents a challenging problem for surgeons. One-stage lengthening with an autologous bone graft has been preferred for metatarsals that require a limited lengthening. With a gradual lengthening of metatarsals, callus distraction (callotasis) can achieve a greater length gain and a concomitant lengthening of the soft tissue. This article presents results of callotasis for adults with first brachymetatarsia. The outcomes of nine cases of first brachymetatarsia in five adult patients who underwent metatarsal lengthening by callotasis between March 1999 and February 2005 were retrospectively reviewed and analyzed. The average length gain was 16.4 mm and the average lengthening percentage was 43.7%. In addition, the average healing index was calculated as 3.8 months/cm, which was higher than that reported previously in the fourth brachymetatarsia. It was concluded that the period of bony consolidation following callotasis is longer in the first brachymetatarsia than in the fourth brachymetatarsia. Presumably, this might be because of the anatomically larger osteotomized cut surface and its weight-bearing function.
Burghardt, Rolf D; Yoshino, Koichi; Kashiwagi, Naoya; Yoshino, Shigeo; Bhave, Anil; Paley, Dror; Herzenberg, John E
Outcome assessment after double level tibial lengthening in patients with dwarfism. Fourteen patients with dwarfism were analyzed after bilateral simultaneous double level tibial lengthening. Average age was 15.1 years. Average lengthening was 13.5 cm. The two levels were lengthened by an average of 7.5 cm proximally and 6.0 cm distally. Concomitant deformities were also addressed during lengthening. External fixation treatment time averaged 8.8 months. Healing index averaged 0.7 months/cm. Bilateral tibial lengthening for dwarfism is difficult, but the results are usually quite gratifying.
Kubota, Masaya; Shinozaki, Masako (Metropolitan Medical Center for the Severely Handicapped, Fuchu, Tokyo (Japan)); Sasaki, Hideo
We report a 19-year-old man suffering from circadian sleep-wake (S-W) rhythm disturbance after total tumor resection and whole brain irradiation. The patient was diagnosed as having astrocytoma in the right temporal lobe by CT scan and angiography at the age of 6 months. After total tumor resection and whole brain irradiation ([sup 60]Co 60 Gy), he showed profound psychomotor retardation, endoclinologic dysfunction including hypothyroidism and growth hormone deficiency, and S-W rhythm disturbance. At age 19, brain MRI revealed asymmetrical low intensity in the hypothalamic region. On endoclinological examination panhypopituitarism due to primary hypothalamic lesion was evident. His S-W rhythm was disturbed; i.e., sleep periods were dispersedly distributed throughout 24 hours. He showed a lethargic tendency in the daytime. All-day polysomnography revealed abnormal sleep structure such as the absence of sleep spindle and hump, peripheral apnea, snoring and low oxygen saturation. After L-thyroxine supplementation his daily activity improved gradually. The decrease in short time sleep and tendency of a free-running rhythm were observed and oxygen saturation improved remarkably. Peripheral apnea and snoring disappeared. This wakening effect of L-thyroxine administration may be due to improvement of hypothyroidism symptom such as myxoedematous pharynx. It also seems related to the alteration of the central S-W rhythm regulation, because free-running rhythm appeared after L-thyroxine administration. Vitamin B[sub 12] (VB[sub 12]), which has been reported to be effective for S-W rhythm disorders, was not effective for our patient's free-running rhythm. Compared with the patients responding to VB[sub 12], our patient's organic brain damage was more evident radiologically and endoclinologically. Following the hypothesis that VB[sub 12] has a potential to reinforce the entrainment of circadian rhythm, our patient's organic brain damage may include entrainment
Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 11. Circadian Rhythms ... M Vaze1 Vijay Kumar Sharma1. Chronobiology Laboratory Evolutionary and Organismal Biology Unit, Jawaharlal Nehru Centre for Advanced Scientific Research Jakkur, PO Box 6436, Bangalore 560 064, India.
Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 2. Circadian Rhythms: Why do ... Nikhil Vijay Kumar Sharma1. Chronobiology Laboratory Evolutionary and Organismal Biology Unit Jawaharlal Nehru Centre for Advanced Scientific Research Jakkur, PO Box 6436, Bangalore 560 064, India.
and clocks driving such rhythms have been studied for a long time now, our ... passage of time using near 24 h oscillation as a reference process, and (iii) Output .... Bünning's work on circadian rhythms across model systems ranging from ..... E Bünning, The Physiological Clock, Revised 3rd Edition, The English. Universities ...
Early studies on circadian rhythms focussed on unravelling the fundamental .... careful analysis revealed that deaths of most arrhythmic indi- viduals were due to .... is no more a sci-fi movie script and is achievable through a technique called ...
Taghinia, Amir H; Al-Sheikh, Ayman A; Panossian, Andre E; Upton, Joseph
Single-stage lengthening of the forearm using callus distraction is well described; however, forearm lengthening using a 2-stage technique of distraction followed by bone grafting has received less attention. A 2-staged technique can be a better alternative in cases where the surgeon desires extensive lengthening. A retrospective review was undertaken of eleven 2-stage forearm lengthening procedures performed by 1 surgeon over a 15-year period. Indications were radial longitudinal deficiency (8 patients), neonatal ischemic contractures (2 patients), and septic growth arrest (1 patient). Average follow-up was 2.8 years. Distraction was performed on patients an average of 82 mm over an average duration of 24 weeks. Average time to union from the time of distractor removal and grafting was 87 days. Average healing index was 32.1 d/cm. Distraction problems were common and related to the length of time that the distractor was in place; they included pain, pin-related infections, and multiple mechanical device difficulties. Three patients had nonunion, and another had delayed union; however, additional procedures resulted in ultimate bony union in all patients. Demineralized bone matrix and autologous corticocancellous bone grafts yielded predictable healing and good functional results in short-distance distractions. For longer distractions, free vascularized fibula transfer produced the best outcomes. Intercalary cortical allografts did not heal well. Patients with neonatal Volkmann contractures had the most difficulty with distraction and healing, ultimately obtaining little to no lengthening and poor functional outcomes.
Dodd, Antony N; Salathia, Neeraj; Hall, Anthony; Kévei, Eva; Tóth, Réka; Nagy, Ferenc; Hibberd, Julian M; Millar, Andrew J; Webb, Alex A R
Circadian clocks are believed to confer an advantage to plants, but the nature of that advantage has been unknown. We show that a substantial photosynthetic advantage is conferred by correct matching of the circadian clock period with that of the external light-dark cycle. In wild type and in long- and short-circadian period mutants of Arabidopsis thaliana, plants with a clock period matched to the environment contain more chlorophyll, fix more carbon, grow faster, and survive better than plants with circadian periods differing from their environment. This explains why plants gain advantage from circadian control.
Zou, Pei; Li, Junhui; Li, Zhuyi
To investigate the feature and regularity of the collagen change in bone healing during bone lengthening. Bone lengthening model was made in the middle segment of the rabbit tibia. Five days after the model was established, the bone was lengthened 1.5 mm per day for 14 days. The rabbits were put to death after elongation, 7, 14, 21, 30, 40, 50, 60 and 70 days after elongation. The distracted area of the bone was imbedded with paraffin. After being stained by the picric acid-sirius red staining, the slice was observed under polarized microscope. The features of the collagen change in the distracted bone were as follows: (1) In the fibrous tissue of the distracted area during lengthening period and the early stage after lengthening, there was not only collagen III but also much collagen I. (2) Collagen I , II and III were observed in the cartilage. (3) Collagen I, II and III were also observed in the pseudo-growth plate. (4) Collagen I took the dominance during lengthening period and the late stage after lengthening. New bone formation in bone lengthening is under the distracted force, so the collagen changes have different features compared with that in fracture healing. Collagen I, II and III can be identified by picric acid-sirius red staining and polarized microscope, so a new method for studying the collagen typing in bone repairing is provided.
Kanemitsu, Takumi; Tsurudome, Yuya; Kusunose, Naoki; Oda, Masayuki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro
Xanthine oxidase (XOD), also known as xanthine dehydrogenase, is a rate-limiting enzyme in purine nucleotide degradation, which produces uric acid. Uric acid concentrations in the blood and liver exhibit circadian oscillations in both humans and rodents; however, the underlying mechanisms remain unclear. Here, we demonstrate that XOD expression and enzymatic activity exhibit circadian oscillations in the mouse liver. We found that the orphan nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) transcriptionally activated the mouse XOD gene and that bile acids suppressed XOD transactivation. The synthesis of bile acids is known to be under the control of the circadian clock, and we observed that the time-dependent accumulation of bile acids in hepatic cells interfered with the recruitment of the co-transcriptional activator p300 to PPARα, thereby repressing XOD expression. This time-dependent suppression of PPARα-mediated transactivation by bile acids caused an oscillation in the hepatic expression of XOD, which, in turn, led to circadian alterations in uric acid production. Finally, we also demonstrated that the anti-hyperuricemic effect of the XOD inhibitor febuxostat was enhanced by administering it at the time of day before hepatic XOD activity increased. These results suggest an underlying mechanism for the circadian alterations in uric acid production and also underscore the importance of selecting an appropriate time of day for administering XOD inhibitors. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
In Neurospora crassa, the cel mutation lengthens the period of the circadian rhythm when the medium is supplemented with linoleic acid (18:2). Double mutant strains were constructed between cel and the clock mutants prd-1 and four alleles at the frq locus. It was found that: (1) the effect of 18:2 on cel was blocked by prd-1, i.e., prd-1 is epistatic to cel. (2) cel and frq interact such that the percent increase in the period produced by 18:2 was inversely proportional to the period of the frq parent. (3) Data from the literature on period effects in double mutant strains support a multiplicative rather than an additive model. A biochemical interpretation of these interactions is discussed, based on the control of flux through metabolic pathways. Because the cel strain is known to be deficient in the pantothenate derivative normally attached to the fatty acid synthetase (FAS) complex, the possibility that cel may affect other pantothenate-modified proteins was investigated. It was found that in the cel + strain, five proteins of molecular weights (M/sub r/) 9000, 19,000, 22,000, 140,000, and 200,000 were labelled with [ 14 C]pantothenate. In the cel strain, only the 200 k (FAS) label was reduced in amount. Therefore, there is no evidence that cel affects circadian rhythmicity through any deficiency other than FAS. A biochemical model for circadian rhythmicity in Neurospora is presented. Oscillations in cytoplasmic and mitochondrial Ca 2+ are proposed; clock mutations are postulated to affect Ca 2+ transporters and the mitochondrial membrane; and phase-shifting effects are accounted for by changes in Ca 2+ or ATP levels
Daniela Eleutério Diniz
Full Text Available OBJECTIVE: The purpose of this study was to perform a radiographic follow-up evaluation after a 12-month healing period, following crown lengthening surgery. MATERIAL AND METHODS: Twenty-three periodontally healthy subjects (mean age 32.5 years that required crown lengthening surgery in premolars were recruited. In a total of 30 premolars, full thickness flaps, osseous resection, and flap suturing were performed. The restorative margin was defined in the pre-surgical phase and maintained unaltered during the healing period, serving as a reference point. Standardized bitewing radiographs were taken before and after osseous reduction, and at 2, 3, 6, and 12-month healing periods. RESULTS: Intact lamina dura was observed at both mesial and distal alveolar crests only from the 3rd month. At 12-months, all alveolar crests presented lamina dura. The overall mean distance from the restorative margin to the alveolar crest achieved after osseous resection was 3.28±0.87 mm at mesial and 2.81±0.51 mm at distal sites. No significant radiographic changes in the bone crest were observed during a 12-month healing period. CONCLUSION: The findings of this study suggest that the radiographic proximal bone level observed on bitewing radiographs following crown lengthening surgery can be used as a reference to predict the future level of the healed alveolar crest.
Full Text Available Farikou Ibrahima,1,2 Pius Fokam,2 Félicien Faustin Mouafo Tambo11Department of Surgery and Specialties, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, 2Department of Surgery, Douala General Hospital, Douala, CameroonBackground: We present a case of lengthening of a tibia to treat postosteomyelitis pseudarthrosis and limb length discrepancy by the Ilizarov device.Objective: The objective was to treat the pseudarthrosis and correct the consequent limb length discrepancy of 50 mm.Materials and methods: The patient was a 5-year-old boy. Osteotomy of the tibia, excision of fibrosis, and decortications were carried out. After a latency period of 5 days, the lengthening started at a rate of 1 mm per day.Results: The pseudarthrosis healed and the gained correction was 21.73%. The index consolidation was 49 days/cm. Minor complications were reported.Discussion: Osteomyelitis of long bones is a common poverty-related disease in Africa. The disease usually is diagnosed at an advanced stage with complications. In these conditions, treatment is much more difficult. Most surgical procedures treating this condition use the Ilizarov device. The most common reported surgical complications are refractures and recurrence of infection.Conclusion: This technique should be popularized in countries with limited resources because it would be an attractive alternative to the amputations that are sometimes performed.Keywords: Limb length discrepancy (LLD, bone gap, Ilizarov device
de Goede, Paul; Wefers, Jakob; Brombacher, Eline Constance; Schrauwen, P; Kalsbeek, A.
Many physiological processes are regulated with a 24h periodicity to anticipate the environmental changes of day to nighttime and vice versa. These 24h regulations, commonly termed circadian rhythms, amongst others control the sleep-wake cycle, locomotor activity and preparation for food
Mori, Tetsuya; Mchaourab, Hassane; Johnson, Carl Hirschie
A circadian oscillation can be reconstituted in vitro from three proteins that cycles with a period of ∼ 24 h. Two recent studies provide surprising biochemical answers to why this remarkable oscillator has such a long time constant and how it can switch effortlessly between alternating enzymatic modes. Copyright © 2015 Elsevier Ltd. All rights reserved.
Mori, Tetsuya; Mchaourab, Hassane; Johnson, Carl Hirschie
A circadian oscillation can be reconstituted in vitro from three proteins that cycles with a period of ~24 h. Two recent studies provide surprising biochemical answers to why this remarkable oscillator has such a long time constant and how it can switch effortlessly between alternating enzymatic modes.
Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M.; Giebultowicz, Jadwiga M.
Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging-related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exerci...
Month, M.; Messerschmid, E.
A new theory of bunch lengthening in electron storage rings is proposed. The equilibrium bunch length is that length which stabilizes the bunch against the onset of ''fast'' resistive instability, caused by the combination of many high frequency resonators such as vacuum flanges. The heat dissipated in these impedance sources follows immediately from the bunch length. It is found that the anomalous bunch length is determined by a scaling parameter g = (hVcos phi/sub s/)/I. Data taken in SPEAR I and II, data in which g extends in value by more than three orders of magnitude, can be fit with an appropriate choice of high frequency, large width coupling impedance. The impedance functions for SPEAR I and II are taken to be the same, a reflection of the fact that the high frequency sources are chamber discontinuities rather than structures connected with the rf systems. A parameter search leads to an impedance characterized by a central frequency approximately 5 GHz, a width (FWHM) approximately 1.8 GHz and a peak impedance approximately 0.2 M OMEGA. The expected and observed higher mode resistance (i.e., heat dissipated) for SPEAR are compared and found to be in agreement. Predictions are given for PEP and PETRA
Guerreschi, P; Labbé, D
First described by Labbé in 1997, the lengthening temporalis myoplasty (LTM) ensures the transfer of the entire temporal muscle from the coronoid process to the upper half of the lip without interposition of aponeurotic tissue. Thanks to brain plasticity, the temporal muscle is able to change its function because it is entirely mobilized towards another effector: the labial commissure. After 6 months of speech rehabilitation, the muscle loses its chewing function and it acquires its new smiling function. We describe as far as possible all the technical points to guide surgeons who would like to perform this powerful surgical procedure. We show the coronoid process approaches both through an upper temporal fossa approach and a lower nasolabial fold approach. Rehabilitation starts 3 weeks after the surgery following a standardized protocol to move from a mandibular smile to a voluntary smile, and then a spontaneous smile in 3 steps. The LTM is the main part of a one-stage global treatment of the paralyzed face. It constitutes a dynamic palliative treatment usually started at the sequelae stage, 18 months after the outcome of a peripheral facial paralysis. This one-stage procedure is a reproducible and relevant surgical technique in the difficult treatment of peripheral facial paralysis. An active muscle is transferred to reanimate the labial commissure and to recreate a mobile nasolabial fold. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
level of the apices of the six maxillary anterior teeth. Maxillary canines and ... requires osseous resection surgeries whereas excessive gingival display due to ... this case included complete oral prophylaxis along aesthetic crown lengthening ...
Rikimaru, Hideaki; Kiyokawa, Kensuke; Watanabe, Koichi; Koga, Noriyuki; Nishi, Yukiko
Correction of severe short nose is a distressing problem for plastic surgeons. It is difficult to simultaneously lengthen the 3 components of the nose, which are the outer skin envelope, the framework, and the mucosal lining. We developed a new method to lengthen the nose more than 10 mm definitively and safely, which was performed using the technique of distraction osteogenesis. The procedure involves a 2-stage operation. At the first stage, boat-shaped iliac bone is grafted on the dorsum. More than 6 months later, the second-stage operation is performed. The grafted bone is cut horizontally in the center, and the distraction device is applied to it. Distraction osteogenesis is started after a latency period of 14 days and performed at a rate of 0.6 mm once daily. The distraction device is replaced by a special attachment (Ribbond; Ribbond Inc) during the 3-month consolidation period. Our method was applied for 2 patients with congenitally and posttraumatic severe short nose, respectively. The total amount of distraction osteogenesis was 12.6 and 13.8 mm, respectively. The profiles of both of the patients improved, and they were satisfied with the results. The method we developed is an entirely new approach to the correction of severe short nose. Furthermore, it was determined that nonvascularized grafted iliac bone could be lengthened by distraction osteogenesis. Our new method was a very effective and definitive technique and could become a mainstream procedure for the correction of severe short nose.
Kim, J S; Baek, G H; Chung, M S; Yoon, P W
We performed nine metatarsal and three proximal phalangeal lengthenings in five patients with congenital brachymetatarsia of the first and one or two other metatarsal bones, by a one-stage combined shortening and lengthening procedure using intercalcary autogenous bone grafts from adjacent shortened metatarsal bones. Instead of the isolated lengthening of the first and the other metatarsal bones, we shortened the adjacent normal metatarsal and used the excised bone to lengthen the short toes, except for the great toe, to restore the normal parabola. One skin incision was used. All the operations were performed bilaterally and the patients were followed up for a mean period of 69.5 months (29 to 107). They all regained a nearly normal parabola and were satisfied with the cosmetic results. Our technique is straightforward and produces good cosmetic results. Satisfactory, bony union is achieved, morbidity is low, and no additional surgery is required for the removal of metal implants.
Yeim, S; Boudebesse, C; Etain, B; Belliviera, F
Bipolar disorder is a severe and complex multifactorial disease, characterized by alternance of acute episodes of depression and mania/hypomania, interspaced by euthymic periods. The etiological determinants of bipolar disorder yet, are still poorly understood. For the last 30 years, chronobiology is an important field of investigation to better understand the pathophysiology of bipolar disorder. We conducted a review using Medline, ISI Database, EMBase, PsyInfo up to January 2015, using the following keywords combinations: "mood disorder", "bipolar disorder", "depression", "unipolar disorder", "major depressive disorder", "affective disorder", for psychiatric conditions; and "circadian rhythms", "circadian markers", "circadian gene", "clock gene", "melatonin" for circadian rhythms. The search critera was presence of word in any field of the article. Quantitative and qualitative circadian abnormalities are associated with bipolar disorders both during acute episodes and euthymic periods, suggesting that these altered circadian rhythms may represent biological trait markers of the disorder. These circadian dysfunctions were assessed by various validated tools including polysomnography, actigraphy, sleep diaries, chronotype assessments and blood melatonin/cortisol measures. Other altered endogenous circadian activities have also been reported in bipolar patients, such as hormones secretion, core body temperature or fibroblasts activity. Moreover, these markers were also altered in healthy relatives of bipolar patients, suggesting a degree of heritability. Several genetic association studies have also showed associations between multiple circadian genes and bipolar disorder, such as CLOCK, ARTNL1, GSK3β, PER3, NPAS2, NR1D1, TIMELESS, RORA, RORB, and CSNK1ε. Thus, these circadian gene variants may contribute to the genetic susceptibility of the disease. Furthermore, the study of the clock system may help to better understand some phenotypic aspects like the
M. A. Stepanov
Full Text Available Elimination of congenital shortening of lower limb still remains a complex and unsolved orthopaedic task which requires an improved fixation technique as well as adjusted tactics of treatment and rehabilitation procedures.Purpose of the study — experimental approval of femur lengthening technique by external fixation with Ilizarov apparatus and internal fixation by plate.Materials and methods. Femur lengthening was performed in 6 mongrel dogs. Average animal age was 1,5±0,3 years, average weight — 20±5 kg, femur length — 22±2 sm. External apparatus with two supports and a titanium plate of an original design were applied under general anesthesia on the right femur of animals. Lengthening was performed manually at a rate of1 mm per day in 4 stages at a distance of 10% from initial segment length. External apparatus was removed on the last day of distraction after locking the plate. X-ray examination was done on the day of surgery, in 7, 14 and 25 days from the onset of distraction as well as in 14, 30, 60 and 90 days after completion of distraction and removal of external apparatus. Three animals were taken out of experiment in 30 days of fixation, remaining three animals — in 90 days. After euthanasia the authors performed autopsy of the organic femur complex and tissues contacting the plate.Results. The use of operated limb was not restricted during the whole distraction period. The authors observed first roentgenological signs of distraction osteogenesis on 7th day of lengthening. By the end of distraction period, at 25th day, shadows of regenerates demonstrated longitudinal striated structures in all cases. Median lucency area of 1–5 mm was located diagonally and across the regenerate or was intermittent. In 60 days of fixation X-rays demonstrated homogeneous regenerate. External fixation index was 13,9±1,5 days/sm (p≤0,05. The authors observed no cases of implants fracture or deformity during the experiment
Birch, John G
In the last 35 years, orthopaedic surgeons have witnessed 3 major advances in the technique of limb lengthening: "distraction osteogenesis" facilitated by Gavriil Ilizarov method and infinitely-adaptable circular fixator with fine-wire bone fragment fixation; the introduction of the "6-strut" computer program-assisted circular fixators to effect complex deformity correction simultaneously; and the development of motorized intramedullary lengthening nails. However, the principles and associated complications of these techniques are on the basis of observations by Codivilla, Putti, and Abbott from as much as 110 years ago. This review notes the contribution of these pioneers in limb lengthening, and the contribution of Thor Heyerdahl principles of tolerance and diversity to the dissemination of Ilizarov principles to the Western world.
) in urine the first night after both minor and major surgery. This delay after major surgery was correlated to the duration of surgery. The amplitude in the melatonin rhythm was unchanged the first night but increased in the second night after major surgery. The amplitude in AMT6s was reduced the first...... night after minimally invasive surgery. The core body temperature rhythm was disturbed after both major and minor surgery. There was a change in the sleep wake cycle with a significantly increased duration of REM-sleep in the day and evening time after major surgery compared with preoperatively....... There was also a shift in the autonomic nervous balance after major surgery with a significantly increased number of myocardial ischaemic episodes during the nighttime period. The circadian activity rhythm was also disturbed after both minor and major surgery. The daytime AMT6s excretion in urine after major...
Full Text Available Abstract Background The central circadian pacemaker is a remarkably robust regulator of daily rhythmic variations of cardiovascular, endocrine, and neural physiology. Environmental lighting conditions are powerful modulators of circadian rhythms, but regulation of circadian rhythms by disease states is less clear. Here, we examine the effect of ischemic stroke on circadian rhythms in rats using high-resolution pineal microdialysis. Methods Rats were housed in LD 12:12 h conditions and monitored by pineal microdialysis to determine baseline melatonin timing profiles. After demonstration that the circadian expression of melatonin was at steady state, rats were subjected to experimental stroke using two-hour intralumenal filament occlusion of the middle cerebral artery. The animals were returned to their cages, and melatonin monitoring was resumed. The timing of onset, offset, and duration of melatonin secretion were calculated before and after stroke to determine changes in circadian rhythms of melatonin secretion. At the end of the monitoring period, brains were analyzed to determine infarct volume. Results Rats demonstrated immediate shifts in melatonin timing after stroke. We observed a broad range of perturbations in melatonin timing in subsequent days, with rats exhibiting onset/offset patterns which included: advance/advance, advance/delay, delay/advance, and delay/delay. Melatonin rhythms displayed prolonged instability several days after stroke, with a majority of rats showing a day-to-day alternation between advance and delay in melatonin onset and duration. Duration of melatonin secretion changed in response to stroke, and this change was strongly determined by the shift in melatonin onset time. There was no correlation between infarct size and the direction or amplitude of melatonin phase shifting. Conclusion This is the first demonstration that stroke induces immediate changes in the timing of pineal melatonin secretion, indicating
Agrawal, Hemendra Kumar; Singh, Balvinder; Garg, Mohit; Khatkar, Vipin; Batra, Sumit; Sharma, Vinod Kumar
Upper limb length discrepancy is a rare occurrence. Humerus shortening may need specialized treatment to restore the functional and cosmetic status of upper limb. We report a case of humerus lengthening of 9 cm with a monorail external fixator and the result was observed during a 2-year follow-up. Humerus lengthening needs specialized focus as it is not only a cosmetic issue but also a functional demand. The monorail unilateral fixator is more functional and cosmetically acceptable, and thus becomes an effective treatment option.
Duffy, Jeanne F.; Zitting, Kirsi-Marja; Chinoy, Evan D.
Aging is associated with numerous changes, including changes in sleep timing, duration, and quality. The circadian timing system interacts with a sleep-wake homeostatic system to regulate human sleep, including sleep timing and structure. Here, we review key features of the human circadian timing system, age-related changes in the circadian timing system, and how those changes may contribute to the observed alterations in sleep. PMID:26568120
Lee, Hong Gil; Lee, Kyounghee; Jang, Kiyoung; Seo, Pil Joon
The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock.
Nathani, Suneeti; Oller, D. Kimbrough; Cobo-Lewis, Alan B.
Sought to verify research findings that suggest there may be a U-shaped developmental trajectory for final syllable lengthening (FSL). Attempted to determine whether vocal maturity and deafness influence FSL . Eight normally hearing infants and eight deaf infants were examined at three levels of prelinguistic vocal development. (Author/VWL)
Rabinovich Gabriel A
Full Text Available Abstract Background Recent evidence suggests a two-way interaction between the immune and circadian systems. Circadian control of immune factors, as well as the effect of immunological variables on circadian rhythms, might be key elements in both physiological and pathological responses to the environment. Among these relevant factors, galectin-1 is a member of a family of evolutionarily-conserved glycan-binding proteins with both extracellular and intracellular effects, playing important roles in immune cell processes and inflammatory responses. Many of these actions have been studied through the use of mice with a null mutation in the galectin-1 (Lgals1 gene. To further analyze the role of endogenous galectin-1 in vivo, we aimed to characterize the circadian behavior of galectin-1 null (Lgals1-/- mice. Methods We analyzed wheel-running activity in light-dark conditions, constant darkness, phase responses to light pulses (LP at circadian time 15, and reentrainment to 6 hour shifts in light-dark schedule in wild-type (WT and Lgals1-/- mice. Results We found significant differences in free-running period, which was longer in mutant than in WT mice (24.02 vs 23.57 h, p alpha (14.88 vs. 12.35 circadian h, p Conclusions Given the effect of a null mutation on circadian period and entrainment, we indicate that galectin-1 could be involved in the regulation of murine circadian rhythmicity. This is the first study implicating galectin-1 in the mammalian circadian system.
Nakano-Matsuoka, Natsuko; Fukiage, Kenichi; Harada, Yuki; Kashiwagi, Naoya; Futami, Tohru
The aim of this study is to evaluate the complications of humeral lengthening and their associated factors. Fifty-four achondroplastic patients were treated by bilateral humeral lengthening. Our original shoulder sling was sufficient to prevent shoulder dislocation. Pre-existing radial head dislocation was observed in 18 patients. Lengthening was accomplished in all cases without a decrease in the elbow function. Seven humeri fractured after the fixator removal. The risk factors for postoperative fracture were a waiting period of less than 5 days, a healing index less than 25, and the concave shape of the callus. There was no radial nerve palsy.
Full Text Available The circadian rhythm sleep disorders define the clinical conditions where sleep and ndash;wake rhythm is disrupted despite optimum environmental and social conditions. They occur as a result of the changes in endogenous circadian hours or non-compatibility of environmental factors or social life with endogenous circadian rhythm. The sleep and ndash;wake rhythm is disrupted continuously or in repeating phases depending on lack of balance between internal and external cycles. This condition leads to functional impairments which cause insomnia, excessive sleepiness or both in people. Application of detailed sleep anamnesis and sleep diary with actigraphy record, if possible, will be sufficient for diagnosis. The treatment aims to align endogenous circadian rhythm with environmental conditions. The purpose of this article is to review pathology, clinical characteristics, diagnosis and treatment of circadian rhythm disorder. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2016; 8(2: 178-189
Tamai, T Katherine; Nakane, Yusuke; Ota, Wataru; Kobayashi, Akane; Ishiguro, Masateru; Kadofusa, Naoya; Ikegami, Keisuke; Yagita, Kazuhiro; Shigeyoshi, Yasufumi; Sudo, Masaki; Nishiwaki-Ohkawa, Taeko; Sato, Ayato; Yoshimura, Takashi
Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA Dietary administration of DHEA to mice shortened free-running circadian period and accelerated re-entrainment to advanced light-dark (LD) cycles, thereby reducing jet-lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.
Circadian rhythms, biochemical or developmental processes with a period length of approximately 24 hours, are thoroughly documented in plants and animals. However, virtually all of what is currently known about circadian rhythms in fungi is derived from the model fungus, Neurospora crassa, including...
Hundahl, Christian A; Fahrenkrug, Jan; Hay-Schmidt, Anders
on circadian behavior. Ngb-deficient and wild-type (wt) mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1) and the immediate early gene Fos was determined after light...
Kowalska, Elzbieta; Ripperger, Juergen A; Hoegger, Dominik C; Bruegger, Pascal; Buch, Thorsten; Birchler, Thomas; Mueller, Anke; Albrecht, Urs; Contaldo, Claudio; Brown, Steven A
Mammalian circadian clocks restrict cell proliferation to defined time windows, but the mechanism and consequences of this interrelationship are not fully understood. Previously we identified the multifunctional nuclear protein NONO as a partner of circadian PERIOD (PER) proteins. Here we show that it also conveys circadian gating to the cell cycle, a connection surprisingly important for wound healing in mice. Specifically, although fibroblasts from NONO-deficient mice showed approximately normal circadian cycles, they displayed elevated cell doubling and lower cellular senescence. At a molecular level, NONO bound to the p16-Ink4A cell cycle checkpoint gene and potentiated its circadian activation in a PER protein-dependent fashion. Loss of either NONO or PER abolished this activation and circadian expression of p16-Ink4A and eliminated circadian cell cycle gating. In vivo, lack of NONO resulted in defective wound repair. Because wound healing defects were also seen in multiple circadian clock-deficient mouse lines, our results therefore suggest that coupling of the cell cycle to the circadian clock via NONO may be useful to segregate in temporal fashion cell proliferation from tissue organization.
Herbert, A J; Herzenberg, J E; Paley, D
As recently as 1986, limb lengthening in children was considered by most North American orthopedic surgeons to be both dangerous and impractical. Previous attempts were plagued by unacceptably high rates of serious complications such as nerve palsy, deep infection, malunion, broken hardware, and stiff joints. With the recent introduction of the Russian Ilizarov method and apparatus for limb lengthening, a tremendous groundswell of interest has risen. Despite a steep learning curve, many Western centers have now reproduced Ilizarov's clinical results. The important advances over prior methods are partly biologic and partly hardware related. Ilizarov's principles require a minimally invasive, low-energy osteotomy, stable external fixation, a latency period before commencing distraction, and gradual lengthening of 1 mm/d in divided doses (0.25 mm four times per day). The article reviews the background of this new technique and provides an update on results reported over the past year. There is disagreement regarding precise indications for limb salvage (lengthening) of congenital limb deficiencies versus amputation. The role of extended lengthening in dwarfism also remains controversial.
Schmal, Christoph; Herzog, Erik D; Herzel, Hanspeter
Modern imaging techniques allow the monitoring of circadian rhythms of single cells. Coupling between these single cellular circadian oscillators can generate coherent periodic signals on the tissue level that subsequently orchestrate physiological outputs. The strength of coupling in such systems of oscillators is often unclear. In particular, effects on coupling strength by varying cell densities, by knockouts, and by inhibitor applications are debated. In this study, we suggest to quantify the relative coupling strength via analyzing period, phase, and amplitude distributions in ensembles of individual circadian oscillators. Simulations of different oscillator networks show that period and phase distributions become narrower with increasing coupling strength. Moreover, amplitudes can increase due to resonance effects. Variances of periods and phases decay monotonically with coupling strength, and can serve therefore as measures of relative coupling strength. Our theoretical predictions are confirmed by studying recently published experimental data from PERIOD2 expression in slices of the suprachiasmatic nucleus during and after the application of tetrodotoxin (TTX). On analyzing the corresponding period, phase, and amplitude distributions, we can show that treatment with TTX can be associated with a reduced coupling strength in the system of coupled oscillators. Analysis of an oscillator network derived directly from the data confirms our conclusions. We suggest that our approach is also applicable to quantify coupling in fibroblast cultures and hepatocyte networks, and for social synchronization of circadian rhythmicity in rodents, flies, and bees.
Muscles and subcutaneous cellular tissue of upper and lower limbs have been studied in 14 patients with achondroplasia treated after Ilizarov in various periods of lengthening employing contrast roentgenography. The technique applied has allowed to reveal anatomic and topographic features of muscles and subcutaneous cellular tissue in achodroplasia cases and observe changes of morphological parameters in different stages of elongation. 8 refs.; 8 figs
Larsen, Bjørn Strøier; Kumarathurai, Preman; Nielsen, Olav W
AIMS: The aim of the study was to assess a possible circadian variation of premature atrial contractions (PACs) in a community-based population and to determine if the daily variation could be used to assess a more vulnerable period of PACs in predicting later incidence of atrial fibrillation (AF...... variation in heart rate. After adjusting for relevant risk factors, the risk of AF was equal in all time intervals throughout the day. CONCLUSION: Premature atrial contractions showed a circadian variation in subjects with frequent PACs. No specific time interval of the day was more predictive of AF than...
Atanasov, Nenad; Poposka, Anastasika; Samardziski, Milan; Kamnar, Viktor
Radiographic examination of extremities in surgical lengthening and/or correction of deformities is of crucial importance for the assessment of new bone formation. The purpose of this study is to confirm the diagnostic value of radiography in precise detection of bone parameters in various lengthening or correction stages in patients treated by limb-lengthening and deformity correction. 50 patients were treated by the Ilizarov method of limb lengthening or deformity correction at the University Orthopaedic Surgery Clinic in Skopje, and analysed over the period from 2006 to 2012. The patients were divided into two groups. The first group consisted of 27 patients with limb-lengthening because of congenital shortening. The second group consisted of 23 patients treated for acquired limb deformities. The results in both groups were received in three stages of new bone formation and were based on the appearance of 3 radiographic parameters at the distraction/compression site. The differences between the presence of all radiographic bone parameters in different stages of new bone formation were statistically signficant in both groups, especially the presence of the cortical margin in the first group (Cochran Q=34.43, df=2, p=0.00000). The comparative analysis between the two groups showed a statistically significant difference in the presence of initial bone elements and cystic formations only in the first stage. Almost no statistical significance in the differences between both groups of patients with regard to 3 radiographic parameters in 3 stages of new bone formation, indicates a minor influence of the etiopathogenetic background on the new bone formation in patients treated by gradual lengthening or correction of limb deformities.
Full Text Available Leaf senescence is an integral part of plant development, and the timing and progressing rate of senescence could substantially affect the yield and quality of crops. It has been known that a circadian rhythm synchronized with external environmental cues is critical for the optimal coordination of various physiological and metabolic processes. However, the reciprocal interactions between the circadian clock and leaf senescence in plants remain unknown. Here, through measuring the physiological and molecular senescence related markers of several circadian components mutants, we found that CIRCADIAN CLOCK-ASSOCIATED 1 inhibits leaf senescence. Further molecular and genetic studies revealed that CCA1 directly activates GLK2 and suppresses ORE1 expression to counteract leaf senescence. As plants age, the expression and periodic amplitude of CCA1 declines and thus weakens the inhibition of senescence. Our findings reveal an age-dependent circadian clock component of the process of leaf senescence.
Truong, Kimberly K; Lam, Michael T; Grandner, Michael A; Sassoon, Catherine S; Malhotra, Atul
Physiological and cellular functions operate in a 24-hour cyclical pattern orchestrated by an endogenous process known as the circadian rhythm. Circadian rhythms represent intrinsic oscillations of biological functions that allow for adaptation to cyclic environmental changes. Key clock genes that affect the persistence and periodicity of circadian rhythms include BMAL1/CLOCK, Period 1, Period 2, and Cryptochrome. Remarkable progress has been made in our understanding of circadian rhythms and their role in common medical conditions. A critical review of the literature supports the association between circadian misalignment and adverse health consequences in sepsis, obstructive lung disease, obstructive sleep apnea, and malignancy. Circadian misalignment plays an important role in these disease processes and can affect disease severity, treatment response, and survivorship. Normal inflammatory response to acute infections, airway resistance, upper airway collapsibility, and mitosis regulation follows a robust circadian pattern. Disruption of normal circadian rhythm at the molecular level affects severity of inflammation in sepsis, contributes to inflammatory responses in obstructive lung diseases, affects apnea length in obstructive sleep apnea, and increases risk for cancer. Chronotherapy is an underused practice of delivering therapy at optimal times to maximize efficacy and minimize toxicity. This approach has been shown to be advantageous in asthma and cancer management. In asthma, appropriate timing of medication administration improves treatment effectiveness. Properly timed chemotherapy may reduce treatment toxicities and maximize efficacy. Future research should focus on circadian rhythm disorders, role of circadian rhythm in other diseases, and modalities to restore and prevent circadian disruption.
Atkinson, G; Reilly, T
Chronobiology is the science concerned with investigations of time-dependent changes in physiological variables. Circadian rhythms refer to variations that recur every 24 hours. Many physiological circadian rhythms at rest are endogenously controlled, and persist when an individual is isolated from environmental fluctuations. Unlike physiological variables, human performance cannot be monitored continuously in order to describe circadian rhythmicity. Experimental studies of the effect of circadian rhythms on performance need to be carefully designed in order to control for serial fatigue effects and to minimise disturbances in sleep. The detection of rhythmicity in performance variables is also highly influenced by the degree of test-retest repeatability of the measuring equipment. The majority of components of sports performance, e.g. flexibility, muscle strength, short term high power output, vary with time of day in a sinusoidal manner and peak in the early evening close to the daily maximum in body temperature. Psychological tests of short term memory, heart rate-based tests of physical fitness, and prolonged submaximal exercise performance carried out in hot conditions show peak times in the morning. Heart rate-based tests of work capacity appear to peak in the morning because the heart rate responses to exercise are minimal at this time of day. Post-lunch declines are evident with performance variables such as muscle strength, especially if measured frequently enough and sequentially within a 24-hour period to cause fatigue in individuals. More research work is needed to ascertain whether performance in tasks demanding fine motor control varies with time of day. Metabolic and respiratory rhythms are flattened when exercise becomes strenuous whilst the body temperature rhythm persists during maximal exercise. Higher work-rates are selected spontaneously in the early evening. At present, it is not known whether time of day influences the responses of a set
Popa-Wagner, Aurel; Buga, Ana-Maria; Dumitrascu, Dinu Iuliu; Uzoni, Adriana; Thome, Johannes; Coogan, Andrew N
Circadian rhythms are recurring patterns in a host of physiological and other parameters that recur with periods of near 24 h. These rhythms reflect the temporal organization of an organism's homeostatic control systems and as such are key processes in ensuring optimal physiological performance. Dysfunction of circadian processes is linked with adverse health conditions. In this review we highlight the evidence that normal, healthy aging is associated with changes in the circadian system; we examine the molecular mechanisms through which such changes may arise, discuss whether more robust circadian function is a predictor of longevity and highlight the role of circadian rhythms in age-related diseases. Overall, the literature shows that aging is associated with marked changes in circadian processes, both at the behavioral and molecular levels, and the molecular mechanisms through which such changes arise remain to be elucidated, but may involve inflammatory process, redox homeostasis and epigenetic modifications. Understanding the nature of age-related circadian dysfunction will allow for the design of chronotherapeutic intervention strategies to attenuate circadian dysfunction and thus improve health and quality of life.
Shanahan, T. L.; Czeisler, C. A.
The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.
Andrew J Zele
Full Text Available Intrinsically photosensitive retinal ganglion cells (ipRGC signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central or intrinsic (retinal network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC and outer retina (cone photoreceptors was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux. Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin retinal ganglion cells mediate this circadian variation.
Eleftheriou, Andreas; Ulander, Martin; Lundin, Fredrik
The pathogenesis of idiopathic normal pressure hydrocephalus (iNPH) takes place in structures close to the cerebral ventricular system. Suprachiasmatic nucleus (SCN), situated close to the third ventricle, is involved in circadian rhythm. Diurnal disturbances are well-known in demented patients. The cognitive decline in iNPH is potentially reversible after a shunt operation. Diurnal rhythm has never been studied in iNPH. We hypothesize that there is a disturbance of circadian rhythm in iNPH-patients and the aim was to study any changes of the diurnal rhythm (mesor and circadian period) as well as any changes of the diurnal amplitude and acrophase of the activity in iNPH-patients before and after a shunt operation. Twenty consecutive iNPH-patients fulfilling the criteria of the American iNPH-guidelines, 9 males and 11 females, mean age 73 (49-81) years were included. The patients underwent a pre-operative clinical work-up including 10m walk time (w10mt) steps (w10ms), TUG-time (TUGt) and steps (TUGs) and for cognitive function an MMSE score was measured. In order to receive circadian rhythm data actigraphic recordings were performed using the SenseWear 2 (BodyMedia Inc Pittsburgh, PA, USA) actigraph. Cosinor analyses of accelerometry data were performed in "R" using non-linear regression with Levenburg- Marquardt estimation. Pre- and post-operative data regarding mesor, amplitude and circadian period were compared using Wilcoxon-Mann-Whitney test for paired data. Twenty patients were evaluated before and three month post-operatively. Motor function (w10mt, w10ms, TUGt, TUGs) was significantly improved while MMSE was not significantly changed. Actigraphic measurements (mesor, amplitude and circadian period) showed no significant changes after shunt operation. This is the first systematic study of circadian rhythm in iNPH-patients. We found no significant changes in circadian rhythm after shunt surgery. The conceptual idea of diurnal rhythm changes in hydrocephalus is
Park, Hoon; Shin, Soowan; Shin, Han Sol; Kim, Hyun Woo; Kim, Dong Wook; Lee, Dong Hoon
at any time during the study period. VAS scores were no different between the patients who received BtX-A and those who received saline. Local injection of 200 IU BtX-A in the quadriceps muscles does not appear to reduce distraction-induced pain nor enhance ROM in the hip or knee during femoral lengthening. Additional studies are needed to evaluate the effect of larger doses or different injection methods. Based on our findings, we do not recommend routine use of botulinum injections during limb lengthening and believe any further use of this drug should only be in the context of a controlled trial. Level II, therapeutic study.
Bodenstein, C; Heiland, I; Schuster, S
To anticipate daily variations in the environment and coordinate biological activities into a daily cycle many organisms possess a circadian clock. In the absence of external time cues the circadian rhythm persists with a period of approximately 24 h. The clock phase can be shifted by single pulses of light, darkness, chemicals, or temperature and this allows entrainment of the clock to exactly 24 h by cycles of these zeitgebers. On the other hand, the period of the circadian rhythm is kept relatively constant within a physiological range of constant temperatures, which means that the oscillator is temperature compensated. The mechanisms behind temperature compensation and temperature entrainment are not fully understood, neither biochemically nor mathematically. Here, we theoretically investigate the interplay of temperature compensation and entrainment in general oscillatory systems. We first give an analytical treatment for small temperature shifts and derive that every temperature-compensated oscillator is entrainable to external small-amplitude temperature cycles. Temperature compensation ensures that this entrainment region is always centered at the endogenous period regardless of possible seasonal temperature differences. Moreover, for small temperature cycles the entrainment region of the oscillator is potentially larger for rectangular pulses. For large temperature shifts we numerically analyze different circadian clock models proposed in the literature with respect to these properties. We observe that for such large temperature shifts sinusoidal or gradual temperature cycles allow a larger entrainment region than rectangular cycles. (paper)
A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark. Copyright © 2016, American Association for the Advancement of Science.
Golden, Susan S.
SUMMARY Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718
Boden, Michael J; Kennaway, David J
There is a growing recognition that the circadian timing system, in particular recently discovered clock genes, plays a major role in a wide range of physiological systems. Microarray studies, for example, have shown that the expression of hundreds of genes changes many fold in the suprachiasmatic nucleus, liver heart and kidney. In this review, we discuss the role of circadian rhythmicity in the control of reproductive function in animals and humans. Circadian rhythms and clock genes appear to be involved in optimal reproductive performance, but there are sufficient redundancies in their function that many of the knockout mice produced do not show overt reproductive failure. Furthermore, important strain differences have emerged from the studies especially between the various Clock (Circadian Locomotor Output Cycle Kaput) mutant strains. Nevertheless, there is emerging evidence that the primary clock genes, Clock and Bmal1 (Brain and Muscle ARNT-like protein 1, also known as Mop3), strongly influence reproductive competency. The extent to which the circadian timing system affects human reproductive performance is not known, in part, because many of the appropriate studies have not been done. With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans.
Abecassis, M; Berreby, S; Boccara, D
The male genitalia cosmetic surgery matches an ever growing need. The aim of this study is to describe our penile lengthening and widening procedures, the benefits and complications that could result from it. We perform these procedures since 1992 and treated close to 2000 patients. Thanks to our expertise and after succeeding in standardizing our techniques, we achieved a retrospective survey on 103 patients operated between 2004 and 2006. We describe here the two processes of our operating technique and we analyse the results obtained 1 month, 3 months and 1 year after the surgery. In most cases, combining a penis adipose tissue grafting, a suspensory ligament section and an adequate skin plasty is proven to be necessary in order to obtain both lengthening and widening increases. One year later, the increase is about 2.7 cm in length, corresponding to 28%, and 2.6 cm in circumference, corresponding to 27%. The complications (cutaneous necrosis, haematoma, lymphoedema, disharmonies), whenever they may exist, are most of the time spontaneously resolutive. Combining a penile fat tissue grafting with a suspensory ligament section allows us to answer to most of patients' expectations. However, several liposculpturing sessions might be necessary in order to get satisfactory results. Copyright 2009 Elsevier Masson SAS. All rights reserved.
Zheng, Xiangzhong; Sehgal, Amita
In most organisms, an intrinsic circadian (~24-h) timekeeping system drives rhythms of physiology and behavior. Within cells that contain a circadian clock, specific transcriptional activators and repressors reciprocally regulate each other to generate a basic molecular oscillator. A mismatch of the period generated by this oscillator with the external environment creates circadian disruption, which can have adverse effects on neural function. Although several clock genes have been extensively characterized, a fundamental question remains: how do these genes work together to generate a ~24-h period? Period-altering mutations in clock genes can affect any of multiple regulated steps in the molecular oscillator. In this review, we examine the regulatory mechanisms that contribute to setting the pace of the circadian oscillator. Copyright © 2012 Elsevier Ltd. All rights reserved.
Thorey, Fritz; Bruenger, Jens; Windhagen, Henning; Witte, Frank
Continuous lengthening of intact muscles during distraction osteogenesis leads to an increase of sarcomeres and enhances the regeneration of tendons and blood vessels. A high distraction rate leads to an excessive leg and muscle lengthening and might cause damages of muscle fibers with fibrosis, necrosis, and muscle weakness. Complications like muscle contractures or atrophy after postoperative immobilization emphazize the importance of muscles and their function in the clinical outcome. In an animal model of distraction osteogenesis, 18 sheep were operated with an external fixator followed by 4 days latency, 21 days distraction (1.25 mm per day) and 51 days consolidation. The anatomical location (gastrocnemius, peroneus tertius, and first flexor digitorum longus muscle), dimension and occurrence of muscular defects were characterized histologically. The callus formation and leg axis was monitored by weekly X-rays. Additionally, serum creatine kinase was analyzed during a distraction and consolidation period. Significant signs of muscle lesions in all three observed muscles can be found postoperatively, whereas normal callus formation and regular leg axis was observed radiologically. The peroneus tertius and first flexor digitorum longus muscles were found to have significantly more signs of fibrosis, inflammatory, and necrosis. Creatine kinase showed two peaks: 4 and 39 days postoperative as an indication of muscle damage and regeneration. The study implicates that muscle damages should be considered when a long-distance distraction osteogenesis is planned. The surgeon should consider these muscle responses and individually discuss a two-stage treatment or additional muscle tendon releases to minimize the risk of muscle damages.
Lengthening of the lateral column for adduction of forefoot and restoration of the medial arch. Stabilization of the ankle joint complex. Supple flatfoot deformity (posterior tibial tendon dysfunction stage II). Instability of the medial ankle joint complex (superficial deltoid and spring ligament). Posttraumatic valgus and pronation deformity of the foot. Rigid flatfoot deformity (posterior tibial tendon dysfunction stage III and IV). Talocalcaneal and naviculocalcaneal coalition. Osteoarthritis of calcaneocuboid joint. Exposition of calcaneus at sinus tarsi. Osteotomy through sinus tarsi and widening until desired correction of the foot is achieved. Insertion of bone graft. Screw fixation. Immobilization in a cast for 6 weeks. Weight-bearing as tolerated from the beginning. In the majority of cases, part of hindfoot reconstruction. Reliable and stable correction. Safe procedure with few complications.
Robertson, Laura; Jones, M. Gail
The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…
Zheng, Li; Seon, Yoon Ji; Mourão, Marcio A; Schnell, Santiago; Kim, Doohak; Harada, Hidemitsu; Papagerakis, Silvana; Papagerakis, Petros
Ameloblasts, the cells responsible for making enamel, modify their morphological features in response to specialized functions necessary for synchronized ameloblast differentiation and enamel formation. Secretory and maturation ameloblasts are characterized by the expression of stage-specific genes which follows strictly controlled repetitive patterns. Circadian rhythms are recognized as key regulators of the development and diseases of many tissues including bone. Our aim was to gain novel insights on the role of clock genes in enamel formation and to explore the potential links between circadian rhythms and amelogenesis. Our data shows definitive evidence that the main clock genes (Bmal1, Clock, Per1 and Per2) oscillate in ameloblasts at regular circadian (24 h) intervals both at RNA and protein levels. This study also reveals that the two markers of ameloblast differentiation i.e. amelogenin (Amelx; a marker of secretory stage ameloblasts) and kallikrein-related peptidase 4 (Klk4, a marker of maturation stage ameloblasts) are downstream targets of clock genes. Both, Amelx and Klk4 show 24h oscillatory expression patterns and their expression levels are up-regulated after Bmal1 over-expression in HAT-7 ameloblast cells. Taken together, these data suggest that both the secretory and the maturation stages of amelogenesis might be under circadian control. Changes in clock gene expression patterns might result in significant alterations of enamel apposition and mineralization. Copyright © 2013 Elsevier Inc. All rights reserved.
Background and purpose Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with acondroplasia. Methods We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Results Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Interpretation Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence—especially when lengthening of more than 50% is attempted. PMID:22489887
Ibrahima F; Fokam P; Mouafo Tambo FF
Farikou Ibrahima,1,2 Pius Fokam,2 Félicien Faustin Mouafo Tambo11Department of Surgery and Specialties, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, 2Department of Surgery, Douala General Hospital, Douala, CameroonBackground: We present a case of lengthening of a tibia to treat postosteomyelitis pseudarthrosis and limb length discrepancy by the Ilizarov device.Objective: The objective was to treat the pseudarthrosis and correc...
Full Text Available There are a few rhythms of our daily lives that we are under the influence. One of them is characterized by predictable changes over a 24-hour timescale called circadian clock. This cellular clock is coordinated by the suprachiasmatic nucleus in the anterior hypothalamus. The clock consist of an autoregulatory transcription-translation feedback loop compose of four genes/proteins; BMAL1, Clock, Cyrptochrome, and Period. BMAL 1 and Clock are transcriptional factors and Period and Cyrptochrome are their targets. Period and Cyrptochrome dimerize in the cytoplasm to enter the nucleus where they inhibit Clock/BMAL activity.It has been demonstrate that circadian clock plays an important role cellular proliferation, DNA damage and repair mechanisms, checkpoints, apoptosis and cancer.
Laubscher, M; Mitchell, C; Timms, A; Goodier, D; Calder, P
Patients undergoing femoral lengthening by external fixation tolerate treatment less well when compared to tibial lengthening. Lengthening of the femur with an intramedullary device may have advantages. We reviewed all cases of simple femoral lengthening performed at our unit from 2009 to 2014. Cases of nonunions, concurrent deformities, congenital limb deficiencies and lengthening with an unstable hip were excluded, leaving 33 cases (in 22 patients; 11 patients had bilateral procedures) for review. Healing index, implant tolerance and complications were compared. In 20 cases (15 patients) the Precice lengthening nail was used and in 13 cases (seven patients) the LRS external fixator system. The desired length was achieved in all cases in the Precice group and in 12 of 13 cases in the LRS group. The mean healing index was 31.3 days/cm in the Precice and 47.1 days/cm in the LRS group (p < 0.001). This was associated with an earlier ability to bear full weight without aids in the Precice group. There were more complications with LRS lengthening, including pin site infections and regenerate deformity. Implant tolerance and the patients' perception of the cosmetic result were better with the Precice treatment. Femoral lengthening with the Precice femoral nail achieved excellent functional results with fewer complications and greater patient satisfaction when compared with the LRS system in our patients. Cite this article: Bone Joint J 2016;98-B:1382-8. ©2016 The British Editorial Society of Bone & Joint Surgery.
Wagner, Lucas; Schmal, Christoph; Staiger, Dorothee; Danisman, Selahattin
The analysis of circadian leaf movement rhythms is a simple yet effective method to study effects of treatments or gene mutations on the circadian clock of plants. Currently, leaf movements are analysed using time lapse photography and subsequent bioinformatics analyses of leaf movements. Programs that are used for this purpose either are able to perform one function (i.e. leaf tip detection or rhythm analysis) or their function is limited to specific computational environments. We developed a leaf movement analysis tool-PALMA-that works in command line and combines image extraction with rhythm analysis using Fast Fourier transformation and non-linear least squares fitting. We validated PALMA in both simulated time series and in experiments using the known short period mutant sensitivity to red light reduced 1 ( srr1 - 1 ). We compared PALMA with two established leaf movement analysis tools and found it to perform equally well. Finally, we tested the effect of reduced iron conditions on the leaf movement rhythms of wild type plants. Here, we found that PALMA successfully detected period lengthening under reduced iron conditions. PALMA correctly estimated the period of both simulated and real-life leaf movement experiments. As a platform-independent console-program that unites both functions needed for the analysis of circadian leaf movements it is a valid alternative to existing leaf movement analysis tools.
Lyons, Lisa C; Roman, Gregg
Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term associative memory formation using a negatively reinforced olfactory-learning paradigm in Drosophila melanogaster. We found that memory formation was regulated in a circadian manner. The peak performance in short-term memory (STM) occurred during the early subjective night with a twofold performance amplitude after a single pairing of conditioned and unconditioned stimuli. This rhythm in memory is eliminated in both timeless and period mutants and is absent during constant light conditions. Circadian gating of sensory perception does not appear to underlie the rhythm in short-term memory as evidenced by the nonrhythmic shock avoidance and olfactory avoidance behaviors. Moreover, central brain oscillators appear to be responsible for the modulation as cryptochrome mutants, in which the antennal circadian oscillators are nonfunctional, demonstrate robust circadian rhythms in short-term memory. Together these data suggest that central, rather than peripheral, circadian oscillators modulate the formation of short-term associative memory and not the perception of the stimuli.
Zhou, Mian; Wang, Wei; Karapetyan, Sargis; Mwimba, Musoki; Marqués, Jorge; Buchler, Nicolas E; Dong, Xinnian
Recent studies have shown that in addition to the transcriptional circadian clock, many organisms, including Arabidopsis, have a circadian redox rhythm driven by the organism's metabolic activities. It has been hypothesized that the redox rhythm is linked to the circadian clock, but the mechanism and the biological significance of this link have only begun to be investigated. Here we report that the master immune regulator NPR1 (non-expressor of pathogenesis-related gene 1) of Arabidopsis is a sensor of the plant's redox state and regulates transcription of core circadian clock genes even in the absence of pathogen challenge. Surprisingly, acute perturbation in the redox status triggered by the immune signal salicylic acid does not compromise the circadian clock but rather leads to its reinforcement. Mathematical modelling and subsequent experiments show that NPR1 reinforces the circadian clock without changing the period by regulating both the morning and the evening clock genes. This balanced network architecture helps plants gate their immune responses towards the morning and minimize costs on growth at night. Our study demonstrates how a sensitive redox rhythm interacts with a robust circadian clock to ensure proper responsiveness to environmental stimuli without compromising fitness of the organism.
Full Text Available Background: Surgical crown lengthening is needed for teeth with subgingival caries, fractured teeth, insufficient crown length, and deep subgingival margin of failed restorations. Since there is no agreement on the effects of crown lengthening surgery on gingival parameters, the purpose of this study was to evaluate periodontal parameters in patients who needed crown lengthening surgery. Methods: Twenty patients who had healthy periodontium and needed surgical crown lengthening were included in this study. After professional dental cleaning, gingival parameters including gingival index (GI, probing depth (PD, bone level (BL, and transsulcular probing (TSP were recorded in interproximal and keratinized gingiva (KG in mid buccal portion. The patients were evaluated one and three months after the surgery. Results: After one and three months of the surgery, the amount of PD reduced from 2.32 mm to 1.25 mm and 1.17 mm, respectively (P=0.001. The mean of BL reduction was 0.88 mm after one month (P=0.001, but there was no reduction between 1 month and 3 months. Amounts of KG at baseline andone month later were 4.2 mm and 2.9 mm, respectively (P=0.001, and remained at the same level up to three months. TSP significantly reduced (from 3.67 mm at baseline to 2.62 mm after 1 month, and to 2.27 mm after 3 months (P=0.001, P=0.005. Conclusion: The present study suggests that in the presence of good oral hygiene, except BW (biological width, other parameters including PD, BL, KG, and TSP had significant changes after crown lengthening surgery in the period of 1 month and 3 months (P
Mendoza-Vargas, Leonor; Báez-Saldaña, Armida; Alvarado, Ramón; Fuentes-Pardo, Beatriz; Flores-Soto, Edgar; Solís-Chagoyán, Héctor
Melatonin (MEL) is a conserved molecule with respect to its synthesis pathway and functions. In crayfish, MEL content in eyestalks (Ey) increases at night under the photoperiod, and this indoleamine synchronizes the circadian rhythm of electroretinogram amplitude, which is expressed by retinas and controlled by the cerebroid ganglion (CG). The aim of this study was to determine whether MEL content in eyestalks and CG or circulating MEL in hemolymph (He) follows a circadian rhythm under a free-running condition; in addition, it was tested whether MEL might directly influence the spontaneous electrical activity of the CG. Crayfish were maintained under constant darkness and temperature, a condition suitable for studying the intrinsic properties of circadian systems. MEL was quantified in samples obtained from He, Ey, and CG by means of an enzyme-linked immunosorbent assay, and the effect of exogenous MEL on CG spontaneous activity was evaluated by electrophysiological recording. Variation of MEL content in He, Ey, and CG followed a circadian rhythm that peaked at the same circadian time (CT). In addition, a single dose of MEL injected into the crayfish at different CTs reduced the level of spontaneous electrical activity in the CG. Results suggest that the circadian increase in MEL content directly affects the CG, reducing its spontaneous electrical activity, and that MEL might act as a periodical signal to reinforce the organization of the circadian system in crayfish.
Oklejewicz, M; Hut, RA; Daan, S; Loudon, ASI; Stirland, AJ; Loudon, Andrew S.I.; Stirland, Anne J.
The tau mutation in Syrian hamsters (Mesocricetus auratus) is phenotypically expressed in a period of the circadian rhythm of about 20 h in homozygotes (SS) and about 22 h in heterozygotes (S+). The authors investigate whether this well-defined model for variation in circadian period exhibits
Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela
Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural conditions for any eukaryotic organism. We tested this hypothesis in mice bearing a short-period mutation in the enzyme casein kinase 1ε (tau mutation), which accelerates free-running circadian cycles. We compared daily activity (feeding) rhythms, survivorship, and reproduction in six replicate populations in outdoor experimental enclosures, established with wild-type, heterozygous, and homozygous mice in a Mendelian ratio. In the release cohort, survival was reduced in the homozygote mutant mice, revealing strong selection against short-period genotypes. Over the course of 14 mo, the relative frequency of the tau allele dropped from initial parity to 20%. Adult survival and recruitment of juveniles into the population contributed approximately equally to the selection for wild-type alleles. The expression of activity during daytime varied throughout the experiment and was significantly increased by the tau mutation. The strong selection against the short-period tau allele observed here contrasts with earlier studies showing absence of selection against a Period 2 (Per2) mutation, which disrupts internal clock function, but does not change period length. These findings are consistent with, and predicted by the theory that resonance of the circadian system plays an important role in individual fitness.
Danica F Patton
Full Text Available Circadian rhythms of behavior and physiology are generated by central and peripheral circadian oscillators entrained by periodic environmental or physiological stimuli. A master circadian pacemaker in the hypothalamic suprachiasmatic nucleus is directly entrained by daily light-dark cycles, and coordinates the timing of other oscillators by direct and indirect neural, hormonal and behavioral outputs. The daily rhythm of food intake provides stimuli that entrain most peripheral and central oscillators, some of which can drive a daily rhythm of food anticipatory activity if food is restricted to one daily mealtime. The location of food-entrainable oscillators (FEOs that drive food anticipatory rhythms, and the food-related stimuli that entrain these oscillators, remain to be clarified. Here, we critically examine the role of peripheral metabolic hormones as potential internal entrainment stimuli or outputs for FEOs controlling food anticipatory rhythms in rats and mice. Hormones for which data are available include corticosterone, ghrelin, leptin, insulin, glucagon, and glucagon-like peptide 1. All of these hormones exhibit daily rhythms of synthesis and secretion that are synchronized by meal timing. There is some evidence that ghrelin and leptin modulate the expression of food anticipatory rhythms, but none of the hormones examined so far are necessary for entrainment. Ghrelin and leptin likely modulate food-entrained rhythms by actions in hypothalamic circuits utilizing melanocortin and orexin signaling, although again food-entrained behavioral rhythms can persist in lesion and gene knockout models in which these systems are disabled. Actions of these hormones on circadian oscillators in central reward circuits remain to be evaluated. Food-entrained activity rhythms are likely mediated by a distributed system of circadian oscillators sensitive to multiple feeding related inputs. Metabolic hormones appear to play a modulatory role within this
Full Text Available Circadian entrainment is necessary for rhythmic physiological functions to be appropriately timed over the 24-hour day. Disruption of circadian rhythms has been associated with sleep and neuro-behavioral impairments as well as cancer. To date, light is widely accepted to be the most powerful circadian synchronizer, motivating its use as a key control input for phase resetting. Through sensitivity analysis, we identify additional control targets whose individual and simultaneous manipulation (via a model predictive control algorithm out-perform the open-loop light-based phase recovery dynamics by nearly 3-fold. We further demonstrate the robustness of phase resetting by synchronizing short- and long-period mutant phenotypes to the 24-hour environment; the control algorithm is robust in the presence of model mismatch. These studies prove the efficacy and immediate application of model predictive control in experimental studies and medicine. In particular, maintaining proper circadian regulation may significantly decrease the chance of acquiring chronic illness.
Wu, Chi-Chuan; Lee, Zhon-Liau
To assess the effectiveness of a one-stage lengthening using a locked nail technique for the treatment of distal femoral shaft nonunions associated with shortening. Retrospective. University hospital. During a 6-year period, 36 distal femoral shaft nonunions associated with shortening (>1.5 cm) were treated by the one-stage lengthening technique. Indications for this technique were distal femoral shaft aseptic or quiescent infected nonunions, 1.5-5 cm shortening, and a fracture level suitable for the insertion of two distal locked screws. The surgical technique involved skeletal traction using the femoral condyle, local débridement, lengthening by lengthening was 2.5 cm (range 1.5-3.5 cm). One-stage lengthening using the locked nailing technique to treat distal femoral shaft nonunions associated with shortening can achieve a high success rate and low complication rate. The key to successful treatment is the patient's complete cooperation with strictly protected weight bearing until the fracture has healed.
Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disorder that affects over one million individuals in the US alone. PD is characterized by a plethora of motor and non-motor manifestations, resulting from a progressive degeneration of dopaminergic neurons and disbalance of several other neurotransmitters. A growing body of evidence points to significant alterations of the circadian system in PD. This is not surprising given the pivotal role that dopamine plays in circadian regulation as well as the role of circadian influences in dopamine metabolism. In this review we present basic and clinical investigations that examined the function of the circadian system in PD.
Hida, A; Ohsawa, Y; Kitamura, S; Nakazaki, K; Ayabe, N; Motomura, Y; Matsui, K; Kobayashi, M; Usui, A; Inoue, Y; Kusanagi, H; Kamei, Y; Mishima, K
We evaluated the circadian phenotypes of patients with delayed sleep-wake phase disorder (DSWPD) and non-24-hour sleep-wake rhythm disorder (N24SWD), two different circadian rhythm sleep disorders (CRSDs) by measuring clock gene expression rhythms in fibroblast cells derived from individual patients. Bmal1-luciferase (Bmal1-luc) expression rhythms were measured in the primary fibroblast cells derived from skin biopsy samples of patients with DSWPD and N24SWD, as well as control subjects. The period length of the Bmal1-luc rhythm (in vitro period) was distributed normally and was 22.80±0.47 (mean±s.d.) h in control-derived fibroblasts. The in vitro periods in DSWPD-derived fibroblasts and N24SWD-derived fibroblasts were 22.67±0.67 h and 23.18±0.70 h, respectively. The N24SWD group showed a significantly longer in vitro period than did the control or DSWPD group. Furthermore, in vitro period was associated with response to chronotherapy in the N24SWD group. Longer in vitro periods were observed in the non-responders (mean±s.d.: 23.59±0.89 h) compared with the responders (mean±s.d.: 22.97±0.47 h) in the N24SWD group. Our results indicate that prolonged circadian periods contribute to the onset and poor treatment outcome of N24SWD. In vitro rhythm assays could be useful for predicting circadian phenotypes and clinical prognosis in patients with CRSDs.
Christian A Hundahl
Full Text Available Neuroglobin (Ngb, a neuron-specific oxygen-binding globin with an unknown function, has been proposed to play a key role in neuronal survival. We have previously shown Ngb to be highly expressed in the rat suprachiasmatic nucleus (SCN. The present study addresses the effect of Ngb deficiency on circadian behavior. Ngb-deficient and wild-type (wt mice were placed in running wheels and their activity rhythms, endogenous period and response to light stimuli were investigated. The effect of Ngb deficiency on the expression of Period1 (Per1 and the immediate early gene Fos was determined after light stimulation at night and the neurochemical phenotype of Ngb expressing neurons in wt mice was characterized. Loss of Ngb function had no effect on overall circadian entrainment, but resulted in a significantly larger phase delay of circadian rhythm upon light stimulation at early night. A light-induced increase in Per1, but not Fos, gene expression was observed in Ngb-deficient mice. Ngb expressing neurons which co-stored Gastrin Releasing Peptide (GRP and were innervated from the eye and the geniculo-hypothalamic tract expressed FOS after light stimulation. No PER1 expression was observed in Ngb-positive neurons. The present study demonstrates for the first time that the genetic elimination of Ngb does not affect core clock function but evokes an increased behavioural response to light concomitant with increased Per1 gene expression in the SCN at early night.
Robin M Voigt
Full Text Available Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases.
Gerkema, Menno P.; Binder, Marc D.; Hirokawa, Nobutaka; Windhorst, Uwe
One of the defining characteristics of circadian pacemakers and indicates the independence of the speed of circadian clock processes of environmental temperature. Mechanisms involved, so far not elucidated in full detail, entail at least two processes that are similarly affected by temperature
Li, Ying; Liu, Zengrong
MicroRNAs (miRNAs) interact with 3‧untranslated region (UTR) elements of target genes to regulate mRNA stability or translation, and play a crucial role in regulating many different biological processes. bantam, a conserved miRNA, is involved in several functions, such as regulating Drosophila growth and circadian rhythm. Recently, it has been discovered that bantam plays a crucial role in the core circadian pacemaker. In this paper, based on experimental observations, a detailed dynamical model of bantam-regulated circadian clock system is developed to show the post-transcriptional behaviors in the modulation of Drosophila circadian rhythm, in which the regulation of bantam is incorporated into a classical model. The dynamical behaviors of the model are consistent with the experimental observations, which shows that bantam is an important regulator of Drosophila circadian rhythm. The sensitivity analysis of parameters demonstrates that with the regulation of bantam the system is more sensitive to perturbations, indicating that bantam regulation makes it easier for the organism to modulate its period against the environmental perturbations. The effectiveness in rescuing locomotor activity rhythms of mutated flies shows that bantam is necessary for strong and sustained rhythms. In addition, the biological mechanisms of bantam regulation are analyzed, which may help us more clearly understand Drosophila circadian rhythm regulated by other miRNAs.
Deaver, Jessica A; Eum, Sung Y; Toborek, Michal
Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques , a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii , a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances.
Koopman, M. G.; Krediet, R. T.; Zuyderhoudt, F. J.; de Moor, E. A.; Arisz, L.
Circadian variations in proteinuria were studied in 17 patients with different types of glomerulopathies. During 3-4 successive days urine was collected over periods of 3 h under standardized conditions. Thirteen of the 17 patients showed a circadian rhythm of their proteinuria with a maximum
Full Text Available Objectives. We evaluated the results of digital lengthening by distraction and second-stage bone graft. Methods. We treated finger deficiency of 201 digits in 104 patients (68 males, 36 females by digital distraction and second-stage bone graft. The distraction was performed with a rate of 1 mm/day (for the first ten days and 0.5 mm/day followed by using a self-designed bilateral tubal-helical external fixator. The mean follow-up period was 42 months (range 6 to 60 months. Results. The mean lengthening was 29.2 mm (range 25 to 40 mm and 18.7 mm (range 12 to 32 mm for metacarpal bones and phalanges, respectively. The mean elongation rate was 174.4% (range 145% to 202% and 184.8% (range 115% to 283% for metacarpal bones and phalanges, respectively. The static two-point discriminations and SpO2 showed no significant differences before and after distraction. Four complications were observed (two skin ruptures and two phalangeal splitting. No pin tract infection or tendon rupture showed. Digital lengthening improved functions of the hand. Conclusion. Digital distraction and second-stage bone graft is an effective method to compensate disabilities caused by lack of finger length. It could be an alternative plan for patients with thumb deficiency instead of toe-to-thumb transplant and patients with finger deficiency instead of ray resection.
Ding, Zhenyu; Zhu, Xiaozhong; Fu, Kai; Zheng, Xianyou
Objectives. We evaluated the results of digital lengthening by distraction and second-stage bone graft. Methods. We treated finger deficiency of 201 digits in 104 patients (68 males, 36 females) by digital distraction and second-stage bone graft. The distraction was performed with a rate of 1 mm/day (for the first ten days) and 0.5 mm/day followed by using a self-designed bilateral tubal-helical external fixator. The mean follow-up period was 42 months (range 6 to 60 months). Results. The mean lengthening was 29.2 mm (range 25 to 40 mm) and 18.7 mm (range 12 to 32 mm) for metacarpal bones and phalanges, respectively. The mean elongation rate was 174.4% (range 145% to 202%) and 184.8% (range 115% to 283%) for metacarpal bones and phalanges, respectively. The static two-point discriminations and SpO 2 showed no significant differences before and after distraction. Four complications were observed (two skin ruptures and two phalangeal splitting). No pin tract infection or tendon rupture showed. Digital lengthening improved functions of the hand. Conclusion. Digital distraction and second-stage bone graft is an effective method to compensate disabilities caused by lack of finger length. It could be an alternative plan for patients with thumb deficiency instead of toe-to-thumb transplant and patients with finger deficiency instead of ray resection.
Bodenstein, C; Heiland, I; Schuster, S
Many biological species possess a circadian clock, which helps them anticipate daily variations in the environment. In the absence of external stimuli, the rhythm persists autonomously with a period of approximately 24 h. However, single pulses of light, nutrients, chemicals or temperature can shift the clock phase. In the case of light- and temperature-cycles, this allows entrainment of the clock to cycles of exactly 24 h. Circadian clocks have the remarkable property of temperature compensation, that is, the period of the circadian rhythm remains relatively constant within a physiological range of temperatures. For several organisms, temperature-regulated processes within the circadian clock have been identified in recent years. However, how these processes contribute to temperature compensation is not fully understood. Here, we theoretically investigate temperature compensation in general oscillatory systems. It is known that every oscillator can be locally temperature compensated around a reference temperature, if reactions are appropriately balanced. A balancing is always possible if the control coefficient with respect to the oscillation period of at least one reaction in the oscillator network is positive. However, for global temperature compensation, the whole physiological temperature range is relevant. Here, we use an approach which leads to an optimization problem subject to the local balancing principle. We use this approach to analyse different circadian clock models proposed in the literature and calculate activation energies that lead to temperature compensation
Winget, C. M.; Vernikos-Danellis, J.; Cronin, S. E.; Leach, C. S.; Rambaut, P. C.; Mack, P. B.
Posture and exercise were investigated as synchronizers of certain physiologic rhythms in eight healthy male subjects in a defined environment. Four subjects exercised during bed rest. Body temperature (BT), heart rate, plasma thyroid hormone, and plasma steroid data were obtained from the subjects for a 6-day ambulatory equilibration period before bed rest, 56 days of bed rest, and a 10-day recovery period after bed rest. The results indicate that the mechanism regulating the circadian rhythmicity of the cardiovascular system is rigorously controlled and independent of the endocrine system, while the BT rhythm is more closely aligned to the endocrine system.
Jessica W Tsai
Full Text Available Light influences sleep and alertness either indirectly through a well-characterized circadian pathway or directly through yet poorly understood mechanisms. Melanopsin (Opn4 is a retinal photopigment crucial for conveying nonvisual light information to the brain. Through extensive characterization of sleep and the electrocorticogram (ECoG in melanopsin-deficient (Opn4(-/- mice under various light-dark (LD schedules, we assessed the role of melanopsin in mediating the effects of light on sleep and ECoG activity. In control mice, a light pulse given during the habitual dark period readily induced sleep, whereas a dark pulse given during the habitual light period induced waking with pronounced theta (7-10 Hz and gamma (40-70 Hz activity, the ECoG correlates of alertness. In contrast, light failed to induce sleep in Opn4(-/- mice, and the dark-pulse-induced increase in theta and gamma activity was delayed. A 24-h recording under a LD 1-hratio1-h schedule revealed that the failure to respond to light in Opn4(-/- mice was restricted to the subjective dark period. Light induced c-Fos immunoreactivity in the suprachiasmatic nuclei (SCN and in sleep-active ventrolateral preoptic (VLPO neurons was importantly reduced in Opn4(-/- mice, implicating both sleep-regulatory structures in the melanopsin-mediated effects of light. In addition to these acute light effects, Opn4(-/- mice slept 1 h less during the 12-h light period of a LD 12ratio12 schedule owing to a lengthening of waking bouts. Despite this reduction in sleep time, ECoG delta power, a marker of sleep need, was decreased in Opn4(-/- mice for most of the (subjective dark period. Delta power reached after a 6-h sleep deprivation was similarly reduced in Opn4(-/- mice. In mice, melanopsin's contribution to the direct effects of light on sleep is limited to the dark or active period, suggesting that at this circadian phase, melanopsin compensates for circadian variations in the photo sensitivity of
Seo, Pil Joon; Mas, Paloma
The circadian clock is a cellular time-keeper mechanism that regulates biological rhythms with a period of ~24 h. The circadian rhythms in metabolism, physiology, and development are synchronized by environmental cues such as light and temperature. In plants, proper matching of the internal circadian time with the external environment confers fitness advantages on plant survival and propagation. Accordingly, plants have evolved elaborated regulatory mechanisms that precisely control the circadian oscillations. Transcriptional feedback regulation of several clock components has been well characterized over the past years. However, the importance of additional regulatory mechanisms such as chromatin remodeling, protein complexes, protein phosphorylation, and stability is only starting to emerge. The multiple layers of circadian regulation enable plants to properly synchronize with the environmental cycles and to fine-tune the circadian oscillations. This review focuses on the diverse posttranslational events that regulate circadian clock function. We discuss the mechanistic insights explaining how plants articulate a high degree of complexity in their regulatory networks to maintain circadian homeostasis and to generate highly precise waveforms of circadian expression and activity.
Luque-Fernandez, Miguel Angel; Ananth, Cande V.; Sanchez, Sixto E.; Qiu, Chun-fang; Hernandez-Diaz, Sonia; Valdimarsdottir, Unnur; Gelaye, Bizu; Williams, Michelle A.
Purpose Data regarding circadian rhythm in the onset of spontaneous preterm premature rupture of membranes (PROM) and placental abruption (PA) cases are conflicting. We modeled the time of onset of preterm PROM and PA cases and examined if the circadian profiles varied based on the gestational age at delivery. Methods We used parametric and nonparametric methods, including trigonometric regression in the framework of generalized linear models, to test the presence of circadian rhythms in the time of onset of preterm PROM and PA cases, among 395 women who delivered a singleton between 2009 and 2010 in Lima, Peru. Results We found a diurnal circadian pattern, with a morning peak at 07h:32’ (95%CI:05h:46’ – 09h:18’) among moderate preterm PROM cases (P-value<0.001), and some evidence of a diurnal circadian periodicity among PA cases in term infants (P-value=0.067). However, we did not find evidence of circadian rhythms in the time of onset of extremely or very preterm PROM (P-value=0.259) and preterm PA (P-value=0.224). Conclusions The circadian rhythms of the time of onset of preterm PROM and PA cases varied based on gestational weeks at delivery. While circadian rhythms were presented among moderate preterm PROM and term PA cases, there was no evidence of circadian rhythms among preterm PA and very or extremely preterm PROM cases, underlying other mechanisms associated with the time of onset. PMID:25453346
Masri, Selma; Kinouchi, Kenichiro; Sassone-Corsi, Paolo
The interplay between circadian rhythm and cancer has been suggested for more than a decade based on the observations that shift work and cancer incidence are linked. Accumulating evidence implicates the circadian clock in cancer survival and proliferation pathways. At the molecular level, multiple control mechanisms have been proposed to link circadian transcription and cell-cycle control to tumorigenesis.The circadian gating of the cell cycle and subsequent control of cell proliferation is an area of active investigation. Moreover, the circadian clock is a transcriptional system that is intricately regulated at the epigenetic level. Interestingly, the epigenetic landscape at the level of histone modifications, DNA methylation, and small regulatory RNAs are differentially controlled in cancer cells. This concept raises the possibility that epigenetic control is a common thread linking the clock with cancer, though little scientific evidence is known to date.This review focuses on the link between circadian clock and cancer, and speculates on the possible connections at the epigenetic level that could further link the circadian clock to tumor initiation or progression.
Jin Wook Kim
Full Text Available Nocturia is a prevalent condition of waking to void during the night. The concept of nocturia has evolved from being a symptomatic aspect of disease associated with the prostate or bladder to a form of lower urinary tract disorder. However, recent advances in circadian biology and sleep science suggest that it might be important to consider nocturia as a form of circadian dysfunction. In the current review, nocturia is reexamined with an introduction to sleep disorders and recent findings in circadian biology in an attempt to highlight the importance of rediscovering nocturia as a problem of chronobiology.
Borzunov, Dmitry Y
This paper presents experimental findings to substantiate the use of multilevel bone fragment lengthening for managing extensive long bone defects caused by diverse aetiologies and shows its clinical introduction which could provide a solution for the problem of reducing the total treatment time. Both experimental and clinical multilevel lengthening to bridge bone defect gaps was performed with the use of the Ilizarov method only. The experimental findings and clinical outcomes showed that multilevel defect fragment lengthening could provide sufficient bone formation and reduction of the total osteosynthesis time in one stage as compared to traditional Ilizarov bone transport. The method of multilevel regeneration enabled management of critical-size defects that measured on average 13.5 ± 0.7 cm in 78 patients. The experimental and clinical results proved the efficiency of the Ilizarov non-free multilevel bone plasty that can be recommended for practical use.
Zhuo, Qinqiang; Li, Shirong; Wu, Julong; Wang, Zhenxiang; Yang, Dongyun; Tao, Ling
To investigate the clinical application of the scrotal flap on penis lengthening. One hundred and fifty-two patients were operated using the scrotal flap from July 1998 to January 2008 at the Department of Plastic and Aesthetic, Surgery Southwest Hospital, Chongqing, China. The procedure consisted of designing a positive sign shaped incision 1.5cm above the root of the penis, dissect and release the superficial suspensory ligament and part of the deep suspensory ligament, then cover the elongated cavernosum with proper scrotal flap. Six-month to 5-year follow-up showed that all patients were satisfied with the good contour and function of the penis. The operation was successful. The method of using scrotal flap on penis lengthening has the following advantages: simple operation, reliable blood supply of the flap, one-stage operation, and satisfactory postoperative results. It is a preferable operation technique for penis lengthening.
Lee, W-C; Yoo, J H; Moon, J-S
We carried out a retrospective study to assess the clinical results of lengthening the fourth metatarsal in brachymetatarsia in 153 feet of 106 patients (100 female, six males) using three different surgical techniques. In one group lengthening was performed by one-stage intercalary bone grafting secured by an intramedullary Kirschner-wire (45 feet, 35 patients). In the second group lengthening was obtained gradually using a mini-external fixator after performing an osteotomy with a saw (59 feet, 39 patients) and in the third group lengthening was achieved in a gradual manner using a mini-external fixator after undertaking an osteotomy using osteotome through pre-drilled holes (49 feet, 32 patients). The mean age of the patients was 26.3 years (13 to 48). Pre-operatively, the fourth ray of the bone-graft group was longer than that of other two groups (p lengthening in the bone-graft group was 13.9 mm (3.5 to 23.0, 27.1%) which was less than that obtained in the saw group with a mean of 17.8 mm (7.0 to 33.0, 29.9%) and in the pre-drilled osteotome group with a mean of 16.8 mm (6.5 to 28.0, 29.4%, p = 0.001). However, the mean time required for retention of the fixation in the bone-graft group was the shortest of the three groups. Patients were dissatisfied with the result for five feet (11.1%) in the bone-graft group, eight (13.6%) in the saw group and none in the pre-drilled osteotomy group (p lengthening by distraction osteogenesis after osteotomy using an osteotome produces the most reliable results for the treatment of fourth brachymetatarsia.
Gerben van Ooijen
Full Text Available The Earth's rotation has driven the evolution of cellular circadian clocks to facilitate anticipation of the solar cycle. Some evidence for timekeeping mechanism conserved from early unicellular life through to modern organisms was recently identified, but the components of this oscillator are currently unknown. Although very few clock components appear to be shared across higher species, Casein Kinase 1 (CK1 is known to affect timekeeping across metazoans and fungi, but has not previously been implicated in the circadian clock in the plant kingdom. We now show that modulation of CK1 function lengthens circadian rhythms in Ostreococcustauri, a unicellular marine algal species at the base of the green lineage, separated from humans by ~1.5 billion years of evolution. CK1 contributes to timekeeping in a phase-dependent manner, indicating clock-mediated gating of CK1 activity. Label-free proteomic analyses upon overexpression as well as inhibition revealed CK1-responsive phosphorylation events on a set of target proteins, including highly conserved potentially clock-relevant cellular regulator proteins. These results have major implications for our understanding of cellular timekeeping and can inform future studies in any circadian organism.
Bele, Irene Velsvik
It is common practice in vocal training to make use of vocal exercise techniques that involve partial occlusion of the vocal tract. Various techniques are used; some of them form an occlusion within the front part of the oral cavity or at the lips. Another vocal exercise technique involves lengthening the vocal tract; for example, the method of phonation into small tubes. This essay presents some studies made on the effects of various vocal training methods that involve an artificially lengthened and constricted vocal tract. The influence of sufficient acoustic impedance on vocal fold vibration and economical voice production is presented.
Ding, Zhenyu; Zhu, Xiaozhong; Fu, Kai; Zheng, Xianyou
Objectives. We evaluated the results of digital lengthening by distraction and second-stage bone graft. Methods. We treated finger deficiency of 201 digits in 104 patients (68 males, 36 females) by digital distraction and second-stage bone graft. The distraction was performed with a rate of 1 mm/day (for the first ten days) and 0.5 mm/day followed by using a self-designed bilateral tubal-helical external fixator. The mean follow-up period was 42 months (range 6 to 60 months). Results. The mea...
He, Qiankun; Wu, Binbin; Price, Jeffrey L; Zhao, Zhangwu
Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state.
Garibay González, Francisco; Díaz Martínez, Daniel Alberto; Valencia Flores, Alejandro; González Hernández, Miguel Angel
To compare two intestinal lengthening procedures in an experimental dog model. Intestinal lengthening is one of the methods for gastrointestinal reconstruction used for treatment of short bowel syndrome. The modification to the Bianchi's technique is an alternative. The modified technique decreases the number of anastomoses to a single one, thus reducing the risk of leaks and strictures. To our knowledge there is not any clinical or experimental report that studied both techniques, so we realized the present report. Twelve creole dogs were operated with the Bianchi technique for intestinal lengthening (group A) and other 12 creole dogs from the same race and weight were operated by the modified technique (Group B). Both groups were compared in relation to operating time, difficulties in technique, cost, intestinal lengthening and anastomoses diameter. There were no statistical difference in the anastomoses diameter (A = 9.0 mm vs. B = 8.5 mm, p = 0.3846). Operating time (142 min vs. 63 min) cost and technique difficulties were lower in group B (p anastomoses (of Group B) and intestinal segments had good blood supply and were patent along their full length. Bianchi technique and the modified technique offer two good reliable alternatives for the treatment of short bowel syndrome. The modified technique improved operating time, cost and technical issues.
Herzog, R; Hefti, F
Since 1971, we have performed 189 leg lengthening procedures using the Wagner method at our institution. The results obtained in the first 26 cases (1971-1973) showed a high complication rate, which led us to reconsider the indications for this procedure. In the present paper, we analyze the results of 37 leg lengthening procedures carried out in 32 patients during the last 10 years (1981-1990) in the children's unit of the orthopedic department of the University of Basle. We found a complication rate of 78%, and in 46% of cases there was more than one major complication. We did not distinguish between "complications" and "problems", because such distinctions are of little importance to the patient. The average age at the time of surgery was 14.8 years, and the average increase in length was 4.3 (2.2-9.2) cm. For each 1 cm of lengthening, an average of 21 days in hospital and 64 days of reduced weight-bearing were needed. Our conclusion is that the Wagner method makes it possible to attain the goal of leg lengthening, but the second step cannot reduce the length of stay in hospital or the length of time the patient needs the help of crutches. Bone remodeling is disturbed. Our preliminary experience with the Ilizarov method is more encouraging.
Sullins, Veronica F; Wagner, Justin P; Walthers, Christopher M; Chiang, Elvin K; Lee, Steven L; Wu, Benjamin M; Dunn, James C Y
Distraction enterogenesis is a potential treatment for patients with short bowel syndrome. We previously demonstrated successful lengthening of jejunum using a degradable spring device in rats. Absorptive function of the lengthened jejunum after restoration into intestinal continuity needs to be determined. Encapsulated polycaprolactone springs were placed into isolated jejunal segments in rats for four weeks. Lengthened segments of jejunum were subsequently restored into intestinal continuity. Absorption studies were performed by placing a mixture of a non-absorbable substrate and glucose into the lumen of the restored jejunum. Restored jejunal segments demonstrated visible peristalsis at specimen retrieval. Compared to normal jejunal controls, restored segments demonstrated equal water absorption and greater glucose absorption. Restored segments had thicker smooth muscle, increased villus height, increased crypt depth, and decreased sucrase activity compared to normal jejunum. The density of enteric ganglia increased after restoration to near normal levels in the submucosa and to normal levels in the myenteric plexus. Jejunum lengthened with a degradable device demonstrates peristaltic and enzymatic activity as well as glucose and water absorption after restoration into intestinal continuity. Our findings further demonstrate the therapeutic potential of a degradable device. Copyright © 2014 Elsevier Inc. All rights reserved.
Tuzuner-Oncul, Aysegul Mine; Kisnisci, Reha S
Vertical lengthening of the mandibular ramus is considered to be one of the least stable surgical procedures in the management of musculoskeletal maxillofacial deformities. The aim of this study was to evaluate the response of the mandibular ramus following vertical lengthening by means of distraction osteogenesis. This study included eight non-syndromic adult patients with temporomandibular joint ankylosis. The vertical height deficiency of the mandibular ramus and the ramus/condyle unit on the affected side were simultaneously reconstructed by transportation of a bone segment using distraction osteogenesis following gap arthroplasty. Lateral and posteroanterior (PA) cephalograms taken postoperatively before active distraction, at the completion of distraction and 6, 12, 24 months after distraction, were compared to evaluate the changes of the ramus height. In all cases the vertical ramus and ramus/condyle unit height loss were successfully reconstructed by distraction osteogenesis. There was no relapse in the amount of height gained by distraction osteogenesis at the 24 months follow-up review (p>0.05). Acute one stage vertical lengthening of the mandibular ramus is considered to be one of the least stable musculoskeletal procedures with relapse being a significant adverse outcome. In this clinical study gradual vertical lengthening of the ramus through ramus/condyle unit distraction osteogenesis has maintained the initial vertical ramus height gained for 24 months. Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Tonogai, Ichiro; Takahashi, Mitsuhiko; Tsutsui, Takahiko; Goto, Tomohiro; Hamada, Daisuke; Suzue, Naoto; Matsuura, Tetsuya; Yasui, Natsuo; Sairyo, Koichi
Radioulnar length discrepancy causes pain and decreases function of the wrist, forearm, and elbow. Limb lengthening, which has been used in the treatment of various deformities of the forearm, is necessary to restore balance between the ulna and radius. We treated 5 limbs in 3 patients (2 boys, 1 girl; mean age 9.3 years old) with radioulnar length discrepancy by distraction osteogenesis of either the ulna or radius using external fixators. We dissected the interosseous membrane between the ulna and radius in 3 limbs in 2 cases and did not do so in 2 limbs of 1 case. These cases include 2 cases with hereditary multiple exostoses, and 1 case with multiple epiphyseal dysplasia. The results were investigated and evaluated in this study, using appropriate clinical and radiographic parameters, noting the state of the interosseous membrane, which has an important role in forearm stability. The mean fixation period was 113 days. The mean distraction distance was 22.8 mm. The mean follow-up period was 637.7 days. The mean ulnar shortening and radial articular angle respectively improved from 7.4 mm and 30.2° preoperatively to -0.1 mm and 34.8° postoperatively. Balance between the ulna and radius was restored, and the results showed significant improvements in range of motion of the joints. However, 2 unintended radial head subluxations occurred in 2 limbs without dissection of the interosseous membrane. In addition, a keloid remained in 1 limb due to pin site infection. Forearm lengthening by distraction osteogenesis was useful in our cases. It is important to recognize the function of the interosseous membrane when lengthening is performed by osteotomy of the proximal ulna by gradual distraction with an external fixator.
Kong, Chang-Bae; Lee, Soo-Yong; Jeon, Dae-Geun
Orthopaedic oncologists often must address leg-length discrepancy after resection of tumors in growing patients with osteosarcoma. There are various alternatives to address this problem. We describe a three-stage procedure: (1) temporary arthrodesis, (2) lengthening by Ilizarov apparatus, and (3) tumor prosthesis. We asked (1) to what extent are affected limbs actually lengthened; (2) how many of the patients who undergo a lengthening procedure eventually achieve joint arthroplasty; and (3) can the three-stage procedure give patients a functioning joint with equalization of limb length? We reviewed 56 patients (younger than 14 years) with osteosarcoma who had staged lengthening arthroplasty between 1991 and 2004. Thirty-five of the 56 patients (63%) underwent soft tissue lengthening, and of these 35, 28 (50% of the original group of 56) had implantation of a mobile joint. Three of the 28 prostheses were later removed owing to infection after arthroplasty. The overall average length gained was 7.8 cm (range, 4-14 cm), and 25 (71%) of the 35 patients had a mobile joint at final followup. The average Musculoskeletal Tumor Society functional score was 23.2 (range, 15-28) and limb-length discrepancy at final followup was 2.6 cm (range, 0-6.5 cm). Although most mobile joints had an acceptable ROM (average, 74.2 degrees ; range, 35 degrees -110 degrees ), extension lag was frequent. Our approach is one option for skeletally immature patients, especially in situations where an expandable prosthesis is not available. However, this technique requires multiple stages and would be inappropriate for patients who cannot accept prolonged functional deficit owing to a limited lifespan or other reasons. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Weaver, D.R.; Reppert, S.M.
The development of circadian rhythms was examined in a precocious rodent species, the spiny mouse. Spiny mouse pups born and reared in constant darkness expressed robust circadian rhythms in locomotor activity as early as day 5 of live. Free-running activity rhythms of pups born and reared in constant darkness were coordinated with the dam on the day of birth. Postnatal maternal influences on pup rhythmicity are minimal in this species, as pups fostered on the day of birth to dams whose circadian phases were opposite to the pups' original dams were coordinated with their original dams on the day of birth. Studies using 2-deoxy-D-[1- 14 C]-glucose authoradiography showed that there were synchronous (coordinated) rhythms in metabolic activity in the maternal and fetal suprachiasmatic nuclei, directly demonstrating prenatal coordination of maternal and fetal rhythmicity. Maternal-fetal coordination of circadian phase was not the result of direct entrainment of the fetuses to the environmental light-dark cycle. These results demonstrate that there is prenatal communication of circadian phase in this precocious species, without demonstrable postnatal maternal influences on pup circadian rhythmicity. Spiny mice therefore represent an important animal model in which circadian rhythms in the postnatal period can be used to precisely assess prenatal influences on circadian phase
Catharine E Boothroyd
Full Text Available Circadian clocks are aligned to the environment via synchronizing signals, or Zeitgebers, such as daily light and temperature cycles, food availability, and social behavior. In this study, we found that genome-wide expression profiles from temperature-entrained flies show a dramatic difference in the presence or absence of a thermocycle. Whereas transcript levels appear to be modified broadly by changes in temperature, there is a specific set of temperature-entrained circadian mRNA profiles that continue to oscillate in constant conditions. There are marked differences in the biological functions represented by temperature-driven or circadian regulation. The set of temperature-entrained circadian transcripts overlaps significantly with a previously defined set of transcripts oscillating in response to a photocycle. In follow-up studies, all thermocycle-entrained circadian transcript rhythms also responded to light/dark entrainment, whereas some photocycle-entrained rhythms did not respond to temperature entrainment. Transcripts encoding the clock components Period, Timeless, Clock, Vrille, PAR-domain protein 1, and Cryptochrome were all confirmed to be rhythmic after entrainment to a daily thermocycle, although the presence of a thermocycle resulted in an unexpected phase difference between period and timeless expression rhythms at the transcript but not the protein level. Generally, transcripts that exhibit circadian rhythms both in response to thermocycles and photocycles maintained the same mutual phase relationships after entrainment by temperature or light. Comparison of the collective temperature- and light-entrained circadian phases of these transcripts indicates that natural environmental light and temperature cycles cooperatively entrain the circadian clock. This interpretation is further supported by comparative analysis of the circadian phases observed for temperature-entrained and light-entrained circadian locomotor behavior. Taken
Rakshit, Kuntol; Wambua, Rebecca; Giebultowicz, Tomasz M; Giebultowicz, Jadwiga M
Daily life functions such as sleep and feeding oscillate with circa 24 h period due to endogenous circadian rhythms generated by circadian clocks. Genetic or environmental disruption of circadian rhythms is associated with various aging-related phenotypes. Circadian rhythms decay during normal aging, and there is a need to explore strategies that could avert age-related changes in the circadian system. Exercise was reported to delay aging in mammals. Here, we investigated whether daily exercise via stimulation of upward climbing movement could improve circadian rest/activity rhythms in aging Drosophila melanogaster. We found that repeated exercise regimen did not strengthen circadian locomotor activity rhythms in aging flies and had no effect on their lifespan. We also tested the effects of exercise on mobility and determined that regular exercise lowered age-specific climbing ability in both wild type and clock mutant flies. Interestingly, the climbing ability was most significantly reduced in flies carrying a null mutation in the core clock gene period, while rescue of this gene significantly improved climbing to wild type levels. Our work highlights the importance of period in sustaining endurance in aging flies exposed to physical challenge. © 2013.
Heller, H. C; Smith, Mark
.... Exposure of humans to bright light for an hour or more at the right phase of the circadian cycle produces significant phase shifts of circadian rhythms speeding recovery from jet-lag, and optimizing...
Nitschke, Silvia; Cortleven, Anne; Iven, Tim; Havaux, Michel; Schmülling, Thomas
The circadian clock helps plants measure daylength and adapt to changes in the day-night rhythm. We found that changes in the light-dark regime triggered stress responses, eventually leading to cell death, in leaves of Arabidopsis thaliana plants with reduced cytokinin levels or defective cytokinin signaling. Prolonged light treatment followed by a dark period induced stress and cell death marker genes while reducing photosynthetic efficiency. This response, called circadian stress, is also characterized by altered expression of clock and clock output genes. In particular, this treatment strongly reduced the expression of CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Intriguingly, similar changes in gene expression and cell death were observed in clock mutants lacking proper CCA1 and LHY function. Circadian stress caused strong changes in reactive oxygen species- and jasmonic acid (JA)-related gene expression. The activation of the JA pathway, involving the accumulation of JA metabolites, was crucial for the induction of cell death, since the cell death phenotype was strongly reduced in the jasmonate resistant1 mutant background. We propose that adaptation to circadian stress regimes requires a normal cytokinin status which, acting primarily through the AHK3 receptor, supports circadian clock function to guard against the detrimental effects of circadian stress. PMID:27354555
Alexander M Zöllner
Full Text Available Skeletal muscle responds to passive overstretch through sarcomerogenesis, the creation and serial deposition of new sarcomere units. Sarcomerogenesis is critical to muscle function: It gradually re-positions the muscle back into its optimal operating regime. Animal models of immobilization, limb lengthening, and tendon transfer have provided significant insight into muscle adaptation in vivo. Yet, to date, there is no mathematical model that allows us to predict how skeletal muscle adapts to mechanical stretch in silico. Here we propose a novel mechanistic model for chronic longitudinal muscle growth in response to passive mechanical stretch. We characterize growth through a single scalar-valued internal variable, the serial sarcomere number. Sarcomerogenesis, the evolution of this variable, is driven by the elastic mechanical stretch. To analyze realistic three-dimensional muscle geometries, we embed our model into a nonlinear finite element framework. In a chronic limb lengthening study with a muscle stretch of 1.14, the model predicts an acute sarcomere lengthening from 3.09[Formula: see text]m to 3.51[Formula: see text]m, and a chronic gradual return to the initial sarcomere length within two weeks. Compared to the experiment, the acute model error was 0.00% by design of the model; the chronic model error was 2.13%, which lies within the rage of the experimental standard deviation. Our model explains, from a mechanistic point of view, why gradual multi-step muscle lengthening is less invasive than single-step lengthening. It also explains regional variations in sarcomere length, shorter close to and longer away from the muscle-tendon interface. Once calibrated with a richer data set, our model may help surgeons to prevent muscle overstretch and make informed decisions about optimal stretch increments, stretch timing, and stretch amplitudes. We anticipate our study to open new avenues in orthopedic and reconstructive surgery and enhance
Oji, Tomito; Hayashi, Akiteru; Ogino, Akihiro; Onishi, Kiyoshi
Lengthening temporalis myoplasty is a faster and less invasive alternative to free muscle transfer for smile reconstruction. However, it requires a nasolabial fold incision, which leaves a midfacial scar. Based on esthetic considerations, a modified approach, involving an extended lazy-S (parotidectomy) incision instead of a nasolabial fold incision, was developed. A cadaveric study involving 10 hemifaces was conducted. From February 2013 to March 2016, the modified lengthening temporalis myoplasty procedure was employed in 10 patients. The results were graded from 1 (poor) to 5 (excellent) according to the Terzis grading system. The excursion of the oral commissure was also measured. The extended lazy-S incision provides easy and safe access to the coronoid process and good visibility. The patients' mean age was 56.5 years, and the mean duration of the postoperative follow-up period was 22.2 months. The patients' underlying conditions included acoustic neuroma (n = 2), Bell palsy (n = 3), congenital conditions (n = 2), brain infarction (n = 1), Ramsay Hunt syndrome (n = 1), and malignant parotid lymphoma (n = 1). One patient suffered a surgical site infection, which was successfully treated with irrigation. All the patients achieved improvements in smile symmetry: 2, 5, and 3 patients obtained excellent, good, and moderate results, respectively. The excursion of the oral commissure ranged from 5 to 10 mm. The modified lengthening temporalis myoplasty procedure provides satisfactory functional outcomes without causing significant complications. It does not leave a facial scar and is a preferable option, especially for young and female patients, and patients who have undergone ablative surgery involving the parotid region.
Full Text Available Abstract Background Prediabetes (PreDM in asymptomatic adults is associated with abnormal circadian blood pressure variability (abnormal CBPV. Hypothesis Systemic inflammation and glycemia influence circadian blood pressure variability. Methods Dahl salt-sensitive (S rats (n = 19 after weaning were fed either an American (AD or a standard (SD diet. The AD (high-glycemic-index, high-fat simulated customary human diet, provided daily overabundant calories which over time lead to body weight gain. The SD (low-glycemic-index, low-fat mirrored desirable balanced human diet for maintaining body weight. Body weight and serum concentrations for fasting glucose (FG, adipokines (leptin and adiponectin, and proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1 and tumor necrosis factor-α (TNF-α] were measured. Rats were surgically implanted with C40 transmitters and blood pressure (BP-both systolic; SBP and diastolic; DBP and heart rate (HR were recorded by telemetry every 5 minutes during both sleep (day and active (night periods. Pulse pressure (PP was calculated (PP = SBP-DBP. Results [mean(SEM]: The AD fed group displayed significant increase in body weight (after 90 days; p Conclusion These data validate our stated hypothesis that systemic inflammation and glycemia influence circadian blood pressure variability. This study, for the first time, demonstrates a cause and effect relationship between caloric excess, enhanced systemic inflammation, dysglycemia, loss of blood pressure control and abnormal CBPV. Our results provide the fundamental basis for examining the relationship between dysglycemia and perturbation of the underlying mechanisms (adipose tissue dysfunction induced local and systemic inflammation, insulin resistance and alteration of adipose tissue precursors for the renin-aldosterone-angiotensin system which generate abnormal CBPV.
Hadidi, Ahmed T; Hosie, Stuart; Waag, Karl-Ludwig
The treatment of long gap esophageal atresia remains a major surgical challenge. The authors describe a modification of a lengthening technique based on tissue expansion to avoid sutures cutting through the esophagus. Between January 2004 and August 2006, 4 patients did not respond to stretching, and underwent this modified esophageal lengthening technique using silastic tubes. RESULTS AND FOLLOW-UP: All infants recovered and have an intact esophagus. All infants developed gastroesophageal reflux. Thal antireflux procedure was performed in the first infant. The other 3 patients were managed conservatively. Follow-up ranged between 6 and 34 months. The tissue expansion principle can be successfully applied in the esophagus through external traction. Silastic tube fixation at esophageal ends may help to apply even traction and avoid sutures cutting through the esophageal tissue.
Blane, C.E.; DiPietro, M.A.; Herzenberg, J.E.
The Ilizarov method for limb lengthening is rapidly gaining popularity in North America. Use of this new technique has necessitated modifications in radiographic protocol. Initial imaging problems gained from our experience with twenty children are detailed including accurate centering for the plain films, correcting for magnification to accurately measure the distraction gap and the expected radiographic appearance of the regenerate bone. Ultrasonography has potential value in accurately measuring the distraction gap and in imaging the new bone prior to radiographic appearance. Since overly fast distraction inhibits bone formation and overly slow distraction leads to premature consolidation, ultrasound may serve a useful role in the qualitative evaluation of new bone formation in Ilizarov limb lengthening, enabling the orthopedic surgeon to tailor the distraction rate to the particular child. (orig.)
Karapetyan, K.V.; Khrennikov, S.B.; Voyevoda, A.N.
In order to prevent dragging of the block and tackle under the ground block, each drilling rig is equipped with block and tackle lift limiter. However these devices reduce the useful height of the derricks. Studies were carried out to achieve safe conditions for lengthening drillpipe strings with stands and advance of the borehole with a set of drilling stands. The basic precepts of this research were used to design the new drilling rig Uralmash-3000 EUK. In addition an increase of derrick height by 2.5 m was recommended for effective use of production drilling rigs BU-80. In order to lengthen the derrick a special support under the crown block articulated to the upper sections of the feet of the derrick with a frame under the crown block should be used.
organic carbon sediments demonstrate that chitin enhances and lengthens power production. Keywords—chitin; MFC; microbiology ; iron-reducing bacteria...levels of organic content available as a food source for bacteria in the sediment. Dependent upon applications, there are scenarios where a SMFC...as ethanol, molasses, or vegetable oils. In the case of underwater marine sediment, options for carbon amendment are limited to solid carbon
Perretta, Silvana; Wall, James K; Dallemagne, Bernard; Harrison, Michael; Becmeur, François; Marescaux, Jacques
Esophageal reconstruction presents a significant clinical challenge in patients ranging from neonates with long-gap esophageal atresia to adults after esophageal resection. Both gastric and colonic replacement conduits carry significant morbidity. As emerging organ-sparring techniques become established for early stage esophageal tumors, less morbid reconstruction techniques are warranted. We present two novel endoscopic approaches for esophageal lengthening and reconstruction in a porcine model. Two models of esophageal defects were created in pigs (30-35 kg) under general anesthesia and subsequently reconstructed with the novel techniques. The first model was a segmental defect of the esophagus created by thoracoscopically transecting the esophagus above the gastroesophageal (GE) junction. The first reconstruction technique involved bilateral submucosal endoscopic lengthening myotomies (BSELM) with a magnetic compression anastomosis (MAGNAMOSIS™). The second model was a wedge defect in the anterior esophagus created above the GE junction through a laparotomy. The second reconstruction technique involved an inverted mucosal-submucosal sleeve transposition graft (IMSTG) that crossed the esophageal gap and was secured in place with a self-expandable covered esophageal stent. Both techniques were feasible in the pig model. The BSELM approach lengthened the esophagus 1 cm for every 2 cm length of myotomy. The myotomy targeted only the inner circular fibers of the esophagus, with preservation of the longitudinal layer to protect against long-term dilation and pouching. The IMSTG approach generated a vascularized mucosal graft almost as long as the esophagus itself. Emerging endoscopic capabilities are enabling complex endoluminal esophageal procedures. BSELM and IMSTG are two novel and technically feasible approaches to esophageal lengthening and reconstruction. Further survival studies are needed to establish the safety and efficacy of these techniques.
Gögenur, Ismail; Bisgaard, Thue; Burgdorf, Stefan
BACKGROUND: Studies on the circadian variation in bodily functions and sleep are important for understanding the pathophysiological processes in the postoperative period. We aimed to investigate changes in the circadian variation in activity after minimally invasive surgery (laparoscopic...... scale (sleep quality, general well-being and pain) and fatigue was measured by a ten-point fatigue scale. The activity levels of the patients were monitored by actigraphy (a wrist-worn device measuring patient activity). Measures of circadian activity level [interday stability (IS), intraday variability...
Full Text Available Humans exhibit behaviour and physiology controlled by a circadian clock. The circadian period is genetically determined and administered by a series of interlocked autoregulatory feedback loops largely in the suprachiasmatic nuclei of the hypothalamus. The phase of the clock is, however, synchronised by a number of external environmental cues such as light. A failure or change in any one of the requisite clock components may result in the onset of a long-term sleep disorder. This review discusses the mechanism regulating circadian physiology in humans and explores how disturbances of this mechanism may result in sleep pathologies.
Zhang, Gong-Lin; Guo, Ao; Zhang, Ming; Xu, Zhao-Yao; Zhang, Ling-Zhi; Wang, Shun-Bing; Li, Jun; Wu, Fa-Lin; Yu, Hui
To summarize clinical application of one-stage toenail lengthening in free second toe transfer for reconstruction of the thumb (finger). Nine patients (male 7, female 2) underwent thumb (finger) reconstruction with second toe transfer were treated by one-stage toenail lengthening technique. Eight were the thumb and 1 was the index finger. Patients aged from 18 to 46 years,with an average of 25 years. A rectangle skin was resected at 0.5 cm away from the eponychium, which was 0.2 cm high and as wide as the toenail. Then stripped U shape flap gently towards proximal end and sutured it. During the operation, the injury of the subcutaneous vascular network should be avoided. Superficial infection at donor area happened in 1 case and was healed by changing dressings. All the reconstruction thumbs (fingers) had survived completely. 2 to 3 mm extending of toenail length was obtained and the appearance of thumb (finger) was improved. There was no growth deformation of toenail. After 7 to 24 months follow up (the average time 13 months), the appearance of the nail was good. One-stage toenail lengthening in free second toe transfer for reconstruction of the thumb (finger), which can obtain a satisfactory appearance of the nail and have no influence on the motion of the reconstruction thumb (finger), is a simple and an effective operative procedure.
A high level of current dependent bunch lengthening has been observed on the North damping ring of the Stanford Linear Collider (SLC). At currents of 3 x 10 10 this behavior does not appear to degrade the machine's performance significantly. However, at the higher currents that are envisioned for the future one fears that its performance could be greatly degraded due to the phenomenon of bunch lengthening. This was the motivation for the work described in this paper. In this paper we calculate the longitudinal impedance of the damping ring vacuum chamber. More specifically, in this paper we find the response function of the ring to a short Gaussian bunch, which we call the Green function wake. In addition, we try to estimate the relative importance of the different vacuum chamber objects, in order to see how we might reduce the ring impedance. This paper also describes bunch length measurements performed on the North damping ring. We use the Green function wake, discussed above, to compute the bunch lengthening. Then we compare these results with those obtained from the measurements. In addition, we calculate the current dependence of the tune distribution
Full Text Available Abstract Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.
Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabolism. Moreover, disruption of circadian rhythms leads to obesity and metabolic disorders. Therefore, it is plausible that resetting of the circadian clock can be used as a new approach to attenuate obesity. Feeding regimens, such as restricted feeding (RF), calorie restriction (CR), and intermittent fasting (IF), provide a time cue and reset the circadian clock and lead to better health. In contrast, high-fat (HF) diet leads to disrupted circadian expression of metabolic factors and obesity. This paper focuses on circadian rhythms and their link to obesity.
Thomas, Karen A; Burr, Robert L; Spieker, Susan
The study of infant and mother circadian rhythm entails choice of instruments appropriate for use in the home environment as well as selection of analytic approach that characterizes circadian rhythm. While actigraphy monitoring suits the needs of home study, limited studies have examined mother and infant rhythm derived from actigraphy. Among this existing research a variety of analyses have been employed to characterize 24-h rhythm, reducing ability to evaluate and synthesize findings. Few studies have examined the correspondence of mother and infant circadian parameters for the most frequently cited approaches: cosinor, non-parametric circadian rhythm analysis (NPCRA), and autocorrelation function (ACF). The purpose of this research was to examine analytic approaches in the study of mother and infant circadian activity rhythm. Forty-three healthy mother and infant pairs were studied in the home environment over a 72h period at infant age 4, 8, and 12 weeks. Activity was recorded continuously using actigraphy monitors and mothers completed a diary. Parameters of circadian rhythm were generated from cosinor analysis, NPCRA, and ACF. The correlation among measures of rhythm center (cosinor mesor, NPCRA mid level), strength or fit of 24-h period (cosinor magnitude and R(2), NPCRA amplitude and relative amplitude (RA)), phase (cosinor acrophase, NPCRA M10 and L5 midpoint), and rhythm stability and variability (NPCRA interdaily stability (IS) and intradaily variability (IV), ACF) was assessed, and additionally the effect size (eta(2)) for change over time evaluated. Results suggest that cosinor analysis, NPCRA, and autocorrelation provide several comparable parameters of infant and maternal circadian rhythm center, fit, and phase. IS and IV were strongly correlated with the 24-h cycle fit. The circadian parameters analyzed offer separate insight into rhythm and differing effect size for the detection of change over time. Findings inform selection of analysis and
Son, Gi Hoon; Cha, Hyo Kyeong; Chung, Sooyoung; Kim, Kyungjin
Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases.
Walker, Janet L; Knapp, Dwana; Minter, Christin; Boakes, Jennette L; Salazar, Juan Carlos; Sanders, James O; Lubicky, John P; Drvaric, David M; Davids, Jon R
Fibular deficiency results in a small, unstable foot and ankle as well as a limb-length discrepancy. The purpose of this study was to assess outcomes in adults who, as children, had had amputation or limb-lengthening, commonly used treatments for fibular deficiency. Retrospective review of existing data collected since 1950 at six pediatric orthopaedic centers identified 248 patients with fibular deficiency who were twenty-one years of age or older at the time of the review. Excluding patients with other anomalies and other treatments (with the excluded group including six who had had lengthening and then amputation), we identified ninety-eight patients who had had amputation or limb-lengthening for the treatment of isolated unilateral fibular deficiency. Sixty-two patients (with thirty-six amputations and twenty-six lengthening procedures) completed several questionnaires, including one asking general demographic questions, the Beck Depression Inventory-II, the Quality of Life Questionnaire, and the American Academy of Orthopaedic Surgeons Lower Limb Questionnaire including the Short Form-36. A group of twenty-eight control subjects completed the Beck Depression Inventory-II and the Quality of Life Questionnaire. There were forty men and twenty-two women. The average age at the time of the interview was thirty-three years. There were more amputations in those with fewer rays and less fibular preservation. Lengthening resulted in more surgical procedures (6.3 compared with 2.4 in patients treated with amputation) and more days in the hospital (184 compared with sixty-three) (both pemployment, income, public assistance or disability payments, pain or use of pain medicine, sports participation, activity restriction, comfort wearing shorts, dislike of limb appearance, or satisfaction with treatment. No patient who had been treated for fibular deficiency reported signs of depression. The only significant difference between treatment groups shown by the Quality of Life
Kim, Soon Ho; Goh, Segun; Han, Kyungreem; Kim, Jong Won; Choi, MooYoung
While the effects of light as a zeitgeber are well known, the way the effects are modulated by features of the sleep-wake system still remains to be studied in detail. A mathematical model for disturbance and recovery of the human circadian system is presented. The model combines a circadian oscillator and a sleep-wake switch that includes the effects of orexin. By means of simulations, we characterize the period-locking zone of the model, where a stable 24-hour circadian rhythm exists, and the occurrence of circadian disruption due to both insufficient light and imbalance in orexin. We also investigate how daily bright light treatments of short duration can recover the normal circadian rhythm. It is found that the system exhibits continuous phase advance/delay at lower/higher orexin levels. Bright light treatment simulations disclose two optimal time windows, corresponding to morning and evening light treatments. Among the two, the morning light treatment is found effective in a wider range of parameter values, with shorter recovery time. This approach offers a systematic way to determine the conditions under which circadian disruption occurs, and to evaluate the effects of light treatment. In particular, it could potentially offer a way to optimize light treatments for patients with circadian disruption, e.g., sleep and mood disorders, in clinical settings.
Caroline H Ko
Full Text Available Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.
Muthusamy, Saravanaraja; Rozbruch, S Robert; Fragomen, Austin T
Internal lengthening nail (ILN) is a recent development in limb lengthening and deformity correction specialty. The ILN has the distinct advantage of combining acute deformity correction with gradual lengthening of bone. While using ILN, the short metaphyseal bone fragment may develop a deformity at the time of osteotomy and nail insertion or during bone lengthening because of the wide medullary canal. These deformities are typically predictable, and blocking screws (Poller screws) are helpful in these situations. This manuscript describes the common deformities that occur in femur and tibia with osteotomies at different locations while using ILN in antegrade and retrograde nailing technique. Also, a systematic approach to the appropriate use of blocking screws in these deformities is described. In addition, the "reverse rule of thumb" is introduced as a quick reference to determine the ideal location(s) and number of blocking screws. These principles are applicable to limb lengthening and deformity correction as well as fracture fixation using intramedullary nails.
Two fungi growth chambers containing six growth tubes each are used in this experiment. One chamber is for the space experiment; the other is for the simultaneous ground control experiment. The hyphae of Neurospora crassa band A mutant are inoculated at one end of each tube. Both the chambers are kept at 3 C plus or minus 1.5 C to stop hyphae growth until the Spacelab is activated. After the activation, each chamber is transferred simultaneously to the Spacelab and a phytotron in KSC and kept in continuous light at the same temperature. After about 24 hours of light exposure, each chamber is inserted into a growth chamber bag to keep it in constant darkness. The circadian rhythm of conidiation is initiated by this light to dark transition. After the dark incubation for 5 days at room temperature, both the growth chambers are kept at 3 C plus or minus 1.5 C to stop growth of the hyphae. After the space shuttle lands, both conidiation patterns are compared and analyzed. It has been known that numerous physiological phenomena show circadian rhythms. They are characterized by the fact that the oscillation can persist under constant conditions of light and temperature. Therefore, it has been accepted by most investigators that the generation mechanism of the circadian rhythm is endogeneous. However, one cannot reject the possibility that these rhythms are caused by some geophysical exogeneous factor having a 24-hour period, such as atmospheric pressure, gravity, or electromagnetic radiation. We use Neurospora crassa band A mutual which shows an obvious circadian rhythm in its spore-forming (conidiation) on the ground, and we intend to attempt the conidation of this mutant in the Spacelab where 24-hour periodicity is severely attenuated and to elucidate the effect of the geophysical exogeneous factor in the generation mechanism of the circadian rhythm.
Frenkel, Lia; Muraro, Nara I; Beltrán González, Andrea N; Marcora, María S; Bernabó, Guillermo; Hermann-Luibl, Christiane; Romero, Juan I; Helfrich-Förster, Charlotte; Castaño, Eduardo M; Marino-Busjle, Cristina; Calvo, Daniel J; Ceriani, M Fernanda
The small ventral lateral neurons (sLNvs) constitute a central circadian pacemaker in the Drosophila brain. They organize daily locomotor activity, partly through the release of the neuropeptide pigment-dispersing factor (PDF), coordinating the action of the remaining clusters required for network synchronization. Despite extensive efforts, the basic principles underlying communication among circadian clusters remain obscure. We identified classical neurotransmitters released by sLNvs through disruption of specific transporters. Adult-specific RNAi-mediated downregulation of the glycine transporter or impairment of glycine synthesis in LNv neurons increased period length by nearly an hour without affecting rhythmicity of locomotor activity. Electrophysiological recordings showed that glycine reduces spiking frequency in circadian neurons. Interestingly, downregulation of glycine receptor subunits in specific sLNv targets impaired rhythmicity, revealing involvement of glycine in information processing within the network. These data identify glycinergic inhibition of specific targets as a cue that contributes to the synchronization of the circadian network. Copyright © 2017 Elsevier Inc. All rights reserved.
Irina V Zhdanova
Full Text Available In view of the inverse temporal relationship of central clock activity to physiological or behavioral outputs in diurnal and nocturnal species, understanding the mechanisms and physiological consequences of circadian disorders in humans would benefit from studies in a diurnal animal model, phylogenetically close to humans. Here we report the discovery of the first intrinsic circadian disorder in a family of diurnal non-human primates, the rhesus monkey. The disorder is characterized by a combination of delayed sleep phase, relative to light-dark cycle, mutual desynchrony of intrinsic rhythms of activity, food intake and cognitive performance, enhanced nighttime feeding or, in the extreme case, intrinsic asynchrony. The phenotype is associated with normal length of intrinsic circadian period and requires an intact central clock, as demonstrated by an SCN lesion. Entrainment to different photoperiods or melatonin administration does not eliminate internal desynchrony, though melatonin can temporarily reinstate intrinsic activity rhythms in the animal with intrinsic asynchrony. Entrainment to restricted feeding is highly effective in animals with intrinsic or SCN lesion-induced asynchrony. The large isolated family of rhesus macaques harboring the disorder provides a powerful new tool for translational research of regulatory circuits underlying circadian disorders and their effective treatment.
Full Text Available Blue light, a key abiotic signal, regulates a wide variety of physiological processes in many organisms. One of these phenomena is the circadian rhythm presents in organisms sensitive to the phase-setting effects of blue light and under control of the daily alternation of light and dark. Circadian clocks consist of autoregulatory alternating negative and positive feedback loops intimately connected with the cellular metabolism and biochemical processes. Neurospora crassa provides an excellent model for studying the molecular mechanisms involved in these phenomena. The White Collar Complex (WCC, a blue-light receptor and transcription factor of the circadian oscillator, and Frequency (FRQ, the circadian clock pacemaker, are at the core of the Neurospora circadian system. The eukaryotic circadian clock relies on transcriptional/translational feedback loops: some proteins rhythmically repress their own synthesis by inhibiting the activity of their transcriptional factors, generating self-sustained oscillations over a period of about 24 h. One of the basic mechanisms that perpetuate self-sustained oscillations is post translation modification (PTM. The acronym PTM generically indicates the addition of acetyl, methyl, sumoyl, or phosphoric groups to various types of proteins. The protein can be regulatory or enzymatic or a component of the chromatin. PTMs influence protein stability, interaction, localization, activity, and chromatin packaging. Chromatin modification and PTMs have been implicated in regulating circadian clock function in Neurospora. Research into the epigenetic control of transcription factors such as WCC has yielded new insights into the temporal modulation of light-dependent gene transcription. Here we report on epigenetic and protein PTMs in the regulation of the Neurospora crassa circadian clock. We also present a model that illustrates the molecular mechanisms at the basis of the blue light control of the circadian clock.
Full Text Available Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock
Fang, Mingzhu; Kang, Hwan-Goo; Park, Youngil; Estrella, Brian; Zarbl, Helmut
The circadian rhythm is a fundamental physiological process present in all organisms that regulates biological processes ranging from gene expression to sleep behavior. In vertebrates, circadian rhythm is controlled by a molecular oscillator that functions in both the suprachiasmatic nucleus (SCN; central pacemaker) and individual cells comprising most peripheral tissues. More importantly, disruption of circadian rhythm by exposure to light-at-night, environmental stressors and/or toxicants is associated with increased risk of chronic diseases and aging. The ability to identify agents that can disrupt central and/or peripheral biological clocks, and agents that can prevent or mitigate the effects of circadian disruption, has significant implications for prevention of chronic diseases. Although rodent models can be used to identify exposures and agents that induce or prevent/mitigate circadian disruption, these experiments require large numbers of animals. In vivo studies also require significant resources and infrastructure, and require researchers to work all night. Thus, there is an urgent need for a cell-type appropriate in vitro system to screen for environmental circadian disruptors and enhancers in cell types from different organs and disease states. We constructed a vector that drives transcription of the destabilized luciferase in eukaryotic cells under the control of the human PERIOD 2 gene promoter. This circadian reporter construct was stably transfected into human mammary epithelial cells, and circadian responsive reporter cells were selected to develop the in vitro bioluminescence assay. Here, we present a detailed protocol to establish and validate the assay. We further provide details for proof of concept experiments demonstrating the ability of our in vitro assay to recapitulate the in vivo effects of various chemicals on the cellular biological clock. The results indicate that the assay can be adapted to a variety of cell types to screen for both
Philbin, Terrence M; Pokabla, Christopher; Berlet, Gregory C
Lateral column lengthening has been used successfully in the treatment of stage II adult-acquired pes planovalgus deformity. The purpose of this study is to review the union rate when allograft material is used and the osteotomy stabilized with a cervical plate. A retrospective review was performed on 28 feet in 26 patients who underwent correction of stage II pes planovalgus deformity using a lateral column lengthening with allograft tricortical iliac crest stabilized with a cervical plate. Patients were evaluated preoperatively and postoperatively using a modified American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale and the Short Form-12 health survey, as well as radiographically by assessing the talonavicular coverage angle. At a mean follow-up of 9 months, the mean total modified AOFAS score and pain subscore were significantly higher (45.6 and 25.0, respectively) versus preoperatively (27.3 and 11.2, respectively). Graft incorporation occurred in all but one case, and the average length of time to union was 10.06 weeks. Complications included 4 hardware removals, 1 nonunion, 1 graft penetration of the calcaneocuboid joint, and 2 cases of calcaneocuboid joint arthritis. Lateral column lengthening using allograft tricortical iliac crest bone graft with cervical plate fixation is a viable option for the correction of acquired pes planovalgus deformity. Allograft bone avoids donor site morbidity of autogenous iliac crest grafts and was not shown to increase rates of nonunion. Cervical plate fixation avoids the necessity of penetrating the graft with a screw and is associated with high patient satisfaction and radiographic union.
Zhang, Wen-Xiang; Chen, Si-Yu; Liu, Chang
Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. Circadian rhythm is controlled by the central clock in the hypothalamic suprachiasmatic nucleus (SCN) and the peripheral clocks in various tissues. More importantly, the central clock can integrate photic/nonphotic signals to generate rhythmic outputs, and then drive the slave oscillators in peripheral tissues through neuroendocrine and behavioral signals. Human reproductive activities, as some other physiological functions, are controlled by the biological clocks. Accumulating lines of epidemiological and genetic evidence indicate that disruption of circadian clock can be directly involved in multiple pathological processes, including infertility. In this review, we mainly discuss the presence of a circadian clock in reproductive tissues and its roles in follicles development, ovulation, spermatogenesis, fertilization and embryo implantation, etc. As the increased shift work and assisted reproductive technologies possibly disrupt circadian rhythmicity to impact reproduction, the importance of circadian rhythms should be highlighted in the regulation of reproductive process.
Dannon, P N; Iancu, I; Hirschmann, S; Ross, P; Dolberg, O T; Grunhaus, L
Labetalol, a combined alpha- and beta-adrenergic blocker is often used to attenuate the transient increases in heart rate and blood pressure that accompany electroconvulsive therapy (ECT). It has been suggested that labetalol should not be administered during ECT without the protection provided by anticholinergic medications, because of its potential severe bradycardic effects. We present our experience with 32 patients from all age groups who received labetalol without anticholinergic treatment during ECT. None of the patients demonstrated adverse bradycardic effects. We conclude that administration of labetalol during ECT does not routinely require premedication with anticholinergic drugs and does not lengthen asystole.
Suzuki, T.; Chin, Y.; Satoh, K.
A mode-coupling theory of bunched-beam instabilities is developed for a Gaussian bunch. The theory converts Sacherer's integral equation with mode coupling into a matrix eigenvalue problem. The present theory assumes well-defined azimuthal modes and takes into account radial modes which are expressed as superpositions of orthogonal functions. The theory is applied to bunch lengthening observed at SPEAR II. The theory explains qualitative features of the experimental results fairly well, but quantitative agreement is not too good. This is ascribed to insufficient knowledge of the coupling impedance of SPEAR II or to the possibility that such effects as radiation damping and quantum excitation should be included. (author)
Full Text Available In quantity estimation, people often perceive that the whole is less than the sum of its parts. The current study investigated such an unpacking effect in temporal distance judgment. Our results showed that participants in the unpacked condition judged a given time interval longer than those in the packed condition, even the time interval was kept constant between the two conditions. Furthermore, this unpacking effect persists regardless of the unpacking ways we employed. Results suggest that unpacking a time interval may be a good strategy for lengthening its perceived temporal distance.
Bonde, Alexander; Wolthers, Mette Stueland
Introducing the lengthening temporalis myoplasty (LTM), a newly implemented surgical treatment of chronic facial paralysis. LTM is a single-stage operation where the temporalis muscle is transposed for dynamic smile reconstruction, hereby serving as an alternative to the more complex two-stage microvascular functional muscle transplantation. This case report demonstrates how LTM can be used to treat patients, who are not motivated or suitable for extensive surgery. The introduction of this technique aims to help a larger number of patients with chronic facial paralysis.
Richard D. Weiner
Full Text Available Foot and ankle surgeons are frequently challenged by the devastating systemic consequences of diabetes mellitus manifested through neuropathy, integumentary and joint breakdown, delayed healing, decreased ability to fight infection, and fragile tendon/ligaments. Diabetic neuropathic pedal ulcerations lead to amputations at an alarming rate and also carry a high mortality rate. This article will discuss causes of diabetic pedal ulcerations that persist or recur after tendo-Achilles lengthening and will highlight areas that need to be addressed by the practitioner such as infection, vascular and nutritional status, glucose control, off-loading, biomechanics, and patient compliance.
Maffulli, N.; Cheng, J. C.; Sher, A.; Lam, T. P.
The rate of regenerate bone mineral content (BMC) acceleration was studied using dual-energy X-ray absorptiometry (DEXA) in callotasis lengthening of the lower limb. Eleven youngsters (age range 5-17 years) undergoing callotasis lengthening for congenital, post-traumatic or post-infective conditions were studied longitudinally. Patients were initially scanned once a week until completion of the lengthening phase, and at 2-week intervals thereafter until removal of the fixator. They were subse...
Henderson, Eric R; Pepper, Andrew M; Letson, G Douglas
Growing prostheses accommodate skeletally immature patients with bone tumors undergoing limb-preserving surgery. Early devices required surgical procedures for lengthening; recent devices lengthen without surgery. Expenses for newer expandable devices that lengthen without surgery are more than for their predecessors but overall reimbursement amounts are not known. We sought to determine reimbursement amounts associated with lengthening of growing prostheses requiring surgical and nonsurgical lengthening. We retrospectively reviewed 17 patients with growing prostheses requiring surgical expansion and eight patients with prostheses capable of nonsurgical expansion. Insurance documents were reviewed to determine the reimbursement for implantation, lengthening, and complications. Growth data were obtained from the literature. Mean reimbursement amounts of surgical and nonsurgical lengthenings were $9950 and $272, respectively. Estimated reimbursements associated with implantation of a growing prosthesis varied depending on age, sex, and location. The largest difference was found for 4-year-old boys with distal femoral replacement where reimbursement for expansion to maturity for surgical and nonsurgical lengthening prostheses would be $379,000 and $208,000, respectively. For children requiring more than one surgical expansion, net reimbursements were lower when a noninvasive lengthening device was used. Annual per-prosthesis maintenance reimbursements to address complications for surgical and nonsurgical lengthening prostheses were $3386 and $1856, respectively. This study showed that reimbursements for lengthening of growing endoprostheses capable of nonsurgical expansion may be less expensive in younger patients, particularly male patients undergoing distal femur replacement, than endoprostheses requiring surgical lengthening. Longer outcomes studies are required to see if reimbursements for complications differ between devices. Level III, economic and decision
Tareen, Samar Hayat Khan; Ahmad, Jamil
Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system. PMID:25789928
Samar Hayat Khan Tareen
Full Text Available Circadian rhythms are certain periodic behaviours exhibited by living organism at different levels, including cellular and system-wide scales. Recent studies have found that the circadian rhythms of several peripheral organs in mammals, such as the liver, are able to entrain their clocks to received signals independent of other system level clocks, in particular when responding to signals generated during feeding. These studies have found SIRT1, PARP1, and HSF1 proteins to be the major influencers of the core CLOCKBMAL1:PER-CRY circadian clock. These entities, along with abstracted feeding induced signals were modelled collectively in this study using Petri Nets. The properties of the model show that the circadian system itself is strongly robust, and is able to continually evolve. The modelled feeding regimens suggest that the usual 3 meals/day and 2 meals/day feeding regimens are beneficial with any more or less meals/day negatively affecting the system.
Glotzbach, S. F.
The suprachiasmatic nucleus (SCN) was implicated as a primary component in central nervous system mechanisms governing circadian rhythms. Disruption of the normal synchronization of temperature, activity, and other rhythms is detrimental to health. Sleep wake disorders, decreases in vigilance and performance, and certain affective disorders may result from or be exacerbated by such desynchronization. To study the basic neurophysiological mechanisms involved in entrainment of circadian systems by the environment, Parylene-coated, etched microwire electrode bundles were used to record extracellular action potentials from the small somata of the SCN and neighboring hypothalamic nuclei in unanesthetized, behaving animals. Male Wistar rats were anesthetized and chronically prepared with EEG ane EMG electrodes in addition to a moveable microdrive assembly. The majority of cells had firing rates 10 Hz and distinct populations of cells which had either the highest firing rate or lowest firing rate during sleep were seen.
Full Text Available A 16-year-old girl presented with left fourth metatarsal shortening causing significant psychological distress. She underwent lengthening scarf osteotomy held with an Omnitech® screw (Biotech International, France with the addition of two 1 cm cancellous cubes (RTI Biologics, United States. A lengthening z-plasty of the extensor tendons and skin were also performed. At 6 weeks the patient was fully weight bearing and at one-year follow up, the patient was satisfied and discharged. A modified technique of lengthening scarf osteotomy is described for congenital brachymatatarsia. This technique allows one stage lengthening through a single incision with graft incorporation by 6 weeks.
Desai, Ankit; Lidder, Surjit; R Armitage, Andrew; S Rajaratnam, Samuel; D Skyrme, Andrew
A 16-year-old girl presented with left fourth metatarsal shortening causing significant psychological distress. She underwent lengthening scarf osteotomy held with an Omnitech(®) screw (Biotech International, France) with the addition of two 1 cm cancellous cubes (RTI Biologics, United States). A lengthening zplasty of the extensor tendons and skin were also performed. At 6 weeks the patient was fully weight bearing and at one-year follow up, the patient was satisfied and discharged. A modified technique of lengthening scarf osteotomy is described for congenital brachymatatarsia. This technique allows one stage lengthening through a single incision with graft incorporation by 6 weeks.
Abbott, Sabra M; Reid, Kathryn J; Zee, Phyllis C
The circadian system regulates the timing and expression of nearly all biological processes, most notably, the sleep-wake cycle, and disruption of this system can result in adverse effects on both physical and mental health. The circadian rhythm sleep-wake disorders (CRSWDs) consist of 5 disorders that are due primarily to pathology of the circadian clock or to a misalignment of the timing of the endogenous circadian rhythm with the environment. This article outlines the nature of these disorders, the association of many of these disorders with psychiatric illness, and available treatment options. Copyright © 2015 Elsevier Inc. All rights reserved.
Tomioka, Kenji; Abdelsalam, Salaheldin
The circadian system of hemimetabolous insects is reviewed in respect to the locus of the circadian clock and multioscillatory organization. Because of relatively easy access to the nervous system, the neuronal organization of the clock system in hemimetabolous insects has been studied, yielding identification of the compound eye as the major photoreceptor for entrainment and the optic lobe for the circadian clock locus. The clock site within the optic lobe is inconsistent among reported species; in cockroaches the lobula was previously thought to be a most likely clock locus but accessory medulla is recently stressed to be a clock center, while more distal part of the optic lobe including the lamina and the outer medulla area for the cricket. Identification of the clock cells needs further critical studies. Although each optic lobe clock seems functionally identical, in respect to photic entrainment and generation of the rhythm, the bilaterally paired clocks form a functional unit. They interact to produce a stable time structure within individual insects by exchanging photic and temporal information through neural pathways, in which serotonin and pigment-dispersing factor (PDF) are involved as chemical messengers. The mutual interaction also plays an important role in seasonal adaptation of the rhythm.
Agostinelli, Forest; Ceglia, Nicholas; Shahbaba, Babak; Sassone-Corsi, Paolo; Baldi, Pierre
Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/ email@example.com or firstname.lastname@example.org Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.
Zanello, S. B.; Boyle, R.
The physiology of both vertebrates and invertebrates follows internal rhythms coordinated in phase with the 24-hour daily light cycle. This circadian clock is governed by a central pacemaker, the suprachiasmatic nucleus (SCN) in the brain. However, peripheral circadian clocks or oscillators have been identified in most tissues. How the central and peripheral oscillators are synchronized is still being elucidated. Light is the main environmental cue that entrains the circadian clock. Under the absence of a light stimulus, the clock continues its oscillation in a free-running condition. In general, three functional compartments of the circadian clock are defined. The vertebrate retina contains endogenous clocks that control many aspects of retinal physiology, including retinal sensitivity to light, neurohormone synthesis (melatonin and dopamine), rod disk shedding, signalling pathways and gene expression. Neurons with putative local circadian rhythm generation are found among all the major neuron populations in the mammalian retina. In the mouse, clock genes and function are more localized to the inner retinal and ganglion cell layers. The photoreceptor, however, secrete melatonin which may still serve a an important circadian signal. The reception and transmission of the non-visual photic stimulus resides in a small subpopulation (1-3%) or retinal ganglion cells (RGC) that express the pigment melanopsin (Opn4) and are called intrisically photoreceptive RGC (ipRGC). Melanopsin peak absorption is at 420 nm and all the axons of the ipRGC reach the SCN. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate the risk of fatigue and health and performance decrement due to circadian rhythm disruption. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. We hypothesize that spaceflight may affect ip
Sulzman, F. M.; Ellman, D.; Wassmer, G.; Fuller, C. A.; Moore-Ede, M.
To test the functioning of circadian rhythms removed from periodicities of the earth's 24-hour rotation, the conidiation rhythm of the fungus Neurospora crassa was monitored in constant darkness during spaceflight. The free-running period of the rhythm was the same in space as on the earth, but there was a marked reduction in the clarity of the rhythm, and apparent arrhythmicity in some tubes. At the current stage of analysis of the results there is insufficient evidence to determine whether the effect seen in space was related to removal from 24-hour periodicities and whether the circadian timekeeping mechanism, or merely its expression, was affected.
Klevecz, R R; Li, C M
Analysis of genome-wide oscillations in transcription reveals that the cell is an oscillator and an attractor and that the maintenance of a stable phenotype requires that maximums in expression in clusters of transcripts must be poised at antipodal phases around the steady state-this is the dynamic architecture of phenotype. Plots of the path through concentration phase space taken by all of the transcripts of Saccharomyces cerevisiae yield a simple three-dimensional surface. How this surface might change as period lengthens or as a cell differentiates is at the center of current work. We have shown that changes in gene expression in response to mutation or perturbation by drugs occur through a folding or unfolding of the surface described by this circle of transcripts and we suggest that the path from this 40-minute oscillation to the cell cycle and circadian rhythms takes place through a series of period-two or period-three bifurcations. These foldings in the surface of the putative attractor result in an increasingly dense set of nested trajectories in the concentrations of message and protein. Evolutionary advantage might accrue to an organism that could change period by changes in just one or a few genes as day length increased from 4 hours in the prebiotic Earth, through 8 hours during the expansion of photoautotrophs, to the present 24 hours.
Casey J Guenthner
Full Text Available BACKGROUND: Hepatocytes, the parenchymal cells of the liver, express core clock genes, such as Period2 and Cryptochrome2, which are involved in the transcriptional/translational feedback loop of the circadian clock. Whether or not the liver is capable of sustaining rhythms independent of a central pacemaker is controversial. Whether and how circadian information may be shared among cells in the liver in order to sustain oscillations is currently unknown. RESULTS: In this study we isolated primary hepatocytes from transgenic Per2(Luc mice and used bioluminescence as a read-out of the state of the circadian clock. Hepatocytes cultured in a collagen gel sandwich configuration exhibited persistent circadian rhythms for several weeks. The amplitude of the rhythms damped, but medium changes consistently reset the phase and amplitude of the cultures. Cry2(-/- Per2(Luc cells oscillated robustly and expressed a longer period. Co-culturing with wildtype cells did not significantly shorten the period, indicating that coupling among hepatocytes is insufficient to synchronize cells with significantly differing periods. However, spatial patterns revealed by cellular imaging of wildtype cultures provided evidence of weak local coupling among the hepatocytes. CONCLUSIONS: Our results with primary hepatocyte cultures demonstrate that cultured hepatocytes are weakly coupled. While this coupling is not sufficient to sustain global synchrony, it does increase local synchrony, which may stabilize the circadian rhythms of peripheral oscillators, such as the liver, against noise in the entraining signals.
Aug 26, 2016 ... Keywords. circadian rhythm; neuronal network; ion channel; behaviour; neurotransmitter; electrophysiology; Drosophila. Abstract. As an experimental model system, the fruit fly Drosophila melanogaster has been seminal in shaping our understanding of the circadian clockwork. The wealth of genetic tools ...
Steensel, Mariska van
In order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in the suprachiasmatic nucleus at the base of the hypothalamus in the brain. Over the years, it has become
Weerth, C. de; Zijl, R.H.
BACKGROUND AND AIMS: Cortisol is the final product of the hypothalamus-pituitary-adrenal (HPA) axis. It is secreted in a pulsatile fashion that displays a circadian rhythm. Infants are born without a circadian rhythm in cortisol and they acquire it during their first year of life. Studies do not
Heath-Heckman, Elizabeth A C
The entrainment of circadian rhythms, physiological cycles with a period of about 24 h, is regulated by a variety of mechanisms, including nonvisual photoreception. While circadian rhythms have been shown to be integral to many processes in multicellular organisms, including immune regulation, the effect of circadian rhythms on symbiosis, or host-microbe interactions, has only recently begun to be studied. This review summarizes recent work in the interactions of both pathogenic and mutualistic associations with host and symbiont circadian rhythms, focusing specifically on three mutualistic systems in which this phenomenon has been best studied. One important theme taken from these studies is the fact that mutualisms are profoundly affected by the circadian rhythms of the host, but that the microbial symbionts in these associations can, in turn, manipulate host rhythms. The interplay between circadian rhythms and symbiosis is a promising new field with effects that should be kept in mind when designing future studies across biology. © The Author 2016. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: email@example.com.
Nishio, Koichi; Pornpitra, Tunanunkul; Izawa, Seiichiro; Nishiwaki-Ohkawa, Taeko; Kato, Souichiro; Hashimoto, Kazuhito; Nakanishi, Shuji
Recent research on cellular circadian rhythms suggests that the coupling of transcription-translation feedback loops and intracellular redox oscillations is essential for robust circadian timekeeping. For clarification of the molecular mechanism underlying the circadian rhythm, methods that allow for the dynamic and simultaneous detection of transcription/translation and redox oscillations in living cells are needed. Herein, we report that the cyanobacterial circadian redox rhythm can be electrochemically detected based on extracellular electron transfer (EET), a process in which intracellular electrons are exchanged with an extracellular electrode. As the EET-based method is non-destructive, concurrent detection with transcription/translation rhythm using bioluminescent reporter strains becomes possible. An EET pathway that electrochemically connected the intracellular region of cyanobacterial cells with an extracellular electrode was constructed via a newly synthesized electron mediator with cell membrane permeability. In the presence of the mediator, the open circuit potential of the culture medium exhibited temperature-compensated rhythm with approximately 24 h periodicity. Importantly, such circadian rhythm of the open circuit potential was not observed in the absence of the electron mediator, indicating that the EET process conveys the dynamic information regarding the intracellular redox state to the extracellular electrode. These findings represent the first direct demonstration of the intracellular circadian redox rhythm of cyanobacterial cells. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: firstname.lastname@example.org.
Shirai, Hidenori; Oishi, Katsutaka; Kudo, Takashi; Shibata, Shigenobu; Ishida, Norio
Recent progress at the molecular level has revealed that nuclear receptors play an important role in the generation of mammalian circadian rhythms. To examine whether peroxisome proliferator-activated receptor alpha (PPARα) is involved in the regulation of circadian behavioral rhythms in mammals, we evaluated the locomotor activity of mice administered with the hypolipidemic PPARα ligand, bezafibrate. Circadian locomotor activity was phase-advanced about 3 h in mice given bezafibrate under light-dark (LD) conditions. Transfer from LD to constant darkness did not change the onset of activity in these mice, suggesting that bezafibrate advanced the phase of the endogenous clock. Surprisingly, bezafibrate also advanced the phase in mice with lesions of the suprachiasmatic nucleus (SCN; the central clock in mammals). The circadian expression of clock genes such as period2, BMAL1, and Rev-erbα was also phase-advanced in various tissues (cortex, liver, and fat) without affecting the SCN. Bezafibrate also phase-advanced the activity phase that is delayed in model mice with delayed sleep phase syndrome (DSPS) due to a Clock gene mutation. Our results indicated that PPARα is involved in circadian clock control independently of the SCN and that PPARα could be a potent target of drugs to treat circadian rhythm sleep disorders including DSPS
Full Text Available The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER
Conclusions: Tibial lengthening may effectively correct gait and satisfactorily improve body image in young patients with unilateral Crowe type-IV DDH. Mono-lateral external fixator allows for accelerated postoperative rehabilitation and optimal preservation of ankle movements. Lengthening along with intramedullary nails may significantly reduce the external fixation time and the risk of fixator-related complications.
Kwon, S T; Chung, C Y
Distraction osteogenesis is a well-accepted method of bone lengthening. Its disadvantages, however, are that it requires an external fixator and takes a long time. One-stage lengthening therefore offers certain advantages. A first point of reference for the safe limits of this procedure might be the changes of blood flow, and this is also the crucial factor in deciding on the appropriate method of lengthening, particularly where the hand or foot is involved. Using a laser Doppler flowmeter we measured blood flow in the dorsum of the foot after using bilateral minimonofixators to lengthen the tibias of 15 Sprague-Dawley rats. They were lengthened in four stages: stage 0 (before lengthening); stage I--12.5%; stage II--25%; and stage III--31.25% of lengthening. The blood flow during stage I decreased to 79% compared to that of stage 0; 16% during stage II; and 1% during stage III. This study suggests that the maximal permissible extent of lengthening might be less than a quarter according to the blood flow as suggested by this animal model.
Minguella, J; Cabrera, M; Escolá, J
The purpose of this study is to analyse three different lengthening techniques used in 31 small bones for congenital malformations of the hand and foot: 15 metacarpals, 12 metatarsals, 1 foot stump and 3 spaces between a previously transplanted phalanx end of the carpus or the metacarpal. Progressive lengthening with an external fixator device was performed in 23 cases: the callus distraction (callotasis) technique was used in 15 cases, whereas in the other 8 cases the speed of lengthening was faster and the defect bridged with a bone graft as a second stage. In another eight cases, a one-stage lengthening was performed. In the callotasis group, the total length gained ranged from 9 mm to 30 mm and the percentage of lengthening obtained (compared with the initial bone length) averaged 53.4%; in the fast lengthening group, the length gained ranged from 8 mm to 15 mm, and the average percentage of lengthening was 53.1%; and in the one-stage group, the length gained ranged from 7 mm to 15 mm, and the average percentage of lengthening was 43%. The overall complication rate was 22.5%.
Andrey A Ptitsyn
Full Text Available In mammals, circadian periodicity has been described for gene expression in the hypothalamus and multiple peripheral tissues. It is accepted that 10%-15% of all genes oscillate in a daily rhythm, regulated by an intrinsic molecular clock. Statistical analyses of periodicity are limited by the small size of datasets and high levels of stochastic noise. Here, we propose a new approach applying digital signal processing algorithms separately to each group of genes oscillating in the same phase. Combined with the statistical tests for periodicity, this method identifies circadian baseline oscillation in almost 100% of all expressed genes. Consequently, circadian oscillation in gene expression should be evaluated in any study related to biological pathways. Changes in gene expression caused by mutations or regulation of environmental factors (such as photic stimuli or feeding should be considered in the context of changes in the amplitude and phase of genetic oscillations.
Boeckx, Willy; Misani, Marta; Vandermeeren, Liesbeth; Franck, Diane; Zirak, Christophe; Demey, Albert
Microsurgical nerve lengthening was performed in two siblings presenting a popliteal pterigium syndrome with a knee flexion contracture of 80 degrees. After the first attempt for nerve lengthening and knee extension elsewhere, a repeated lengthening was required due to continuing tip-toe walking and recurrent knee contracture at the age of 3 years. An extensive external and internal interfascicular microsurgical neurolysis resulted in a lengthening of the nerves. A full length of leg procedure had to be performed, inclusive of Achilles tendon lengthening to obtain a complete extension of the knee and a 90-degree ankle flexion. Maintaining the leg in a fully extended position was obtained with a dynamic splinting in the first month after the operation. When timing the operation we have to consider the importance of adequate precision of the microsurgical neurolysis, down to the identification of the Fontana bands, and the adequate postoperative splinting. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Wilson, P.B.; Servranckx, R.; Sabersky, A.P.; Gareyte, J.; Fischer, G.E.; Chao, A.W.; Donald, M.H.R.
In recent years, electron storage ring designers have become aware of the problems caused by the interaction of short, high current bunches with their environment. Important effects are: (1) energy loss can cause local overheating of chamber components; (2) additional rf power is required due to overall energy loss; (3) the increased energy spread requires increased aperture; (4) destructive instabilities could occur. Anomalous bunch lengthening and energy spread, the spectroscopy of longitudinal modes and the shift of synchronous phase were simultaneously measured in order to study the dynamics of the interaction. From the data obtained at SPEAR II one is led to a model of coupling impedance which should be useful in the design of any electron ring
Bok, H.E.; Holzapfel, W.H.
Radurization is a particularly suitable method to lengthen the shelf life of chicken carcasses. A study was undertaken to determine the influence of four different dose rates and three storage temperatures, namely 3, 4, 5 and 7 kGy and 2, 4 and 8 degrees Celsius respectively. A total bacteria population of 10 6 per gramme was used as cut-off point for shelf life. Accordingly the untreated samples had a shelf life of 3 days at 4 degrees Celsius in comparison with 13 and 29 days for 3 and 5 kGy respectively. This study showed that low gamma radiation doses is not only an economical preservation method for chicken carcasses, but also destroys typical food pathogens such as Salmonella spp. The method also produces an organoleptic acceptable product
Iriarte Locarno, Raymundo; Garcia Herrera, Alvaro; Bocanegra Navia, Sergio; Suarez Romero, Fabio
The thumb amputation represents one of the most anti functional, unsightly and psychological disabilities of the hand. We describe the surgical technique, the bone distraction phases, additional surgeries and external fixation. We review prospectively our experience in the Military Hospital in Bogota, Colombia, from 1996 until 2003: 9 patients, men, amputation level: 1C to 4, we used a monolateral external fixator; Distraction speed: 0,75 mm/d, mean lengthening 3,9 cms, mean time with de fixation: 6 months. Bone consolidation: 100%, mild functional activity according to the disabilities of the arm, shoulder and arm score (DASH). We recommended this surgical technique, because it is easy, reproducible, and allows a functional recuperation of the thumb
The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronizes these with daily cycles, feeding patterns also regulates circadian clocks. The clock genes and adipocytokines show circadian rhythmicity. Dysfunction of these genes are involved in the alteration of these adipokines during the development of obesity. Food availability promotes the stimuli associated with food intake which is a circadian oscillator outside of the suprachiasmatic nucleus (SCN). Its circadian rhythm is arranged with the predictable daily mealtimes. Food anticipatory activity is mediated by a self-sustained circadian timing and its principal component is food entrained oscillator. However, the hypothalamus has a crucial role in the regulation of energy balance rather than food intake. Fatty acids or their metabolites can modulate neuronal activity by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. The timing of three-meal schedules indicates close association with the plasma levels of insulin and preceding food availability. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition can lead to uncoupling of peripheral clocks from the central pacemaker and to the development of metabolic disorders. Metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, eventual disruption of circadian clock functioning can lead to obesity. While CLOCK expression levels are increased with high fat diet-induced obesity, peroxisome proliferator-activated receptor (PPAR) alpha increases the transcriptional level of brain and muscle ARNT-like 1 (BMAL1) in obese subjects. Consequently, disruption of clock genes results in dyslipidemia, insulin resistance and obesity. Modifying the time of feeding alone can greatly affect body weight. Changes in the circadian clock are associated with temporal alterations in
Full Text Available Introduction: Superior oblique split lengthening (SOSL is done for weakening of superior oblique. It corrects the superior oblique overaction (SOOA and A pattern. Its effect on the torsion of the eye is not known. We present our data on the effect of this particular procedure on torsion. Materials and Methods: We did a study of 16 patients (32 eyes who underwent bilateral SOSL and compared the disc foveal angle (DFA preoperatively and postoperatively. The split lengthening was done from 4 mm to 7 mm depending upon the overaction of superior oblique. Results: The mean age was 15.3 ± 8.4 years. Mean preoperative DFA in the right eye (RE was −3.9° and in the left eye (LE was −2.9°. Mean postoperative DFA in RE was 0.2° and in LE was 0.9°. The mean change in the DFA for RE was 4.1° ± 1.3° and for LE was 3.8° ± 1.2°. All the patients were aligned horizontally within 6 prism diopter and no pattern and no diplopia postoperatively. The A pattern was corrected in all the patient postsurgery. For each mm of surgery, an improvement of 0.8° was seen in the DFA. Conclusion: We report the effect of SOSL on torsion. The SOSL reduces intorsion postsurgery and is, therefore, a valuable procedure in SOOA where both pattern and in torsion needs to be corrected.
Rietveld, W J; van Schravendijk, K
Long-term application of sodium-valproate was studied while recording food intake of rats. It was found that sodium valproate was able to decrease the period length of free-running circadian rhythmicity. After withdrawal of the drug, the period length returned to the predrug values.
Full Text Available Abstract Background Insulin resistance (IR has been associated with cardiovascular diseases (CVD. Heart rate variability (HRV, an index of cardiac autonomic modulation (CAM, is also associated with CVD mortality and CVD morbidity. Currently, there are limited data about the impairment of IR on the circadian pattern of CAM. Therefore, we conducted this investigation to exam the association between IR and the circadian oscillations of CAM in a community-dwelling middle-aged sample. Method Homeostasis models of IR (HOMA-IR, insulin, and glucose were used to assess IR. CAM was measured by HRV analysis from a 24-hour electrocardiogram. Two stage modeling was used in the analysis. In stage one, for each individual we fit a cosine periodic model based on the 48 segments of HRV data. We obtained three individual-level cosine parameters that quantity the circadian pattern: mean (M, measures the overall average of a HRV index; amplitude (Â, measures the amplitude of the oscillation of a HRV index; and acrophase time (θ, measures the timing of the highest oscillation. At the second stage, we used a random-effects-meta-analysis to summarize the effects of IR variables on the three circadian parameters of HRV indices obtained in stage one of the analysis. Results In persons without type diabetes, the multivariate adjusted β (SE of log HOMA-IR and M variable for HRV were -0.251 (0.093, -0.245 (0.078, -0.19 (0.06, -4.89 (1.76, -3.35 (1.31, and 2.14 (0.995, for log HF, log LF, log VLF, SDNN, RMSSD and HR, respectively (all P Conclusion Elevated IR, among non-diabetics significantly impairs the overall mean levels of CAM. However, the Â or θ of CAM were not significantly affected by IR, suggesting that the circadian mechanisms of CAM are not impaired. However, among persons with type 2 diabetes, a group clinically has more severe form of IR, the adverse effects of increased IR on all three HRV circadian parameters are much larger.
Song, Sang-Heon; Agashe, Mandar Vikas; Huh, Young-Jae; Hwang, Soon-Young; Song, Hae-Ryong
Bilateral tibial lengthening has become one of the standard treatments for upper segment-lower segment disproportion and to improve quality of life in achondroplasia. We determined the effect of tibial lengthening on the tibial physis and compared tibial growth that occurred at the physis with that in non-operated patients with achondroplasia. We performed a retrospective analysis of serial radiographs until skeletal maturity in 23 achondroplasia patients who underwent bilateral tibial lengthening before skeletal maturity (lengthening group L) and 12 achondroplasia patients of similar height and age who did not undergo tibial lengthening (control group C). The mean amount of lengthening of tibia in group L was 9.2 cm (lengthening percentage: 60%) and the mean age at the time of lengthening was 8.2 years. The mean duration of follow-up was 9.8 years. Skeletal maturity (fusion of physis) occurred at 15.2 years in group L and at 16.0 years in group C. The actual length of tibia (without distraction) at skeletal maturity was 238 mm in group L and 277 mm in group C (p = 0.03). The mean growth rates showed a decrease in group L relative to group C from about 2 years after surgery. Physeal closure was most pronounced on the anterolateral proximal tibial physis, with relative preservation of the distal physis. Our findings indicate that physeal growth rate can be disturbed after tibial lengthening in achondroplasia, and a close watch should be kept for such an occurrence-especially when lengthening of more than 50% is attempted.
Foucher, G; Pajardi, G; Lamas, C; Medina, J; Navarro, R
We retrospectively reviewed the experience of two Hand Units with progressive bone distraction lengthening, collecting 41 cases of hand skeleton lengthening for congenital malformations. The Ilizarov callostasis method was used in 31 cases and in 10 cases bone union was reestablished at a second stage with an iliac graft (2 cases), vascularized metacarpal bone graft (one case), and vascularized (one case) or nonvascularized (3 cases) toe epiphysis. In the last three cases of index lengthening, the distal part was translocated to the tip of the third, deepening at the same stage the first web. The most frequently treated malformation was symbrachydactyly (22 cases). Mean lengthening was 2.3 cm (0.9 to 3.5) with a mean treatment duration of 3.8 months (1.5 - 8.2). The "lengthening index" was 0.59. There was a significant difference between phalanx and metacarpal lengthening, but the amount of lengthening or treatment duration were not affected by technique (Ilizarov vs bone grafting) or age. The complication rate was 32%. There were two complete failures, one extensor tendon tear, 3 pin tract infections (one requiring interruption of the lengthening), 2 cases of relevant pain, 2 delayed unions, 2 angulations and 1 callus fracture, 1 metacarpophalangeal dislocation and 1 joint stiffness. Despite advances in micorsurgical toe transfer, there are still indications for bone lengthening in congenital malformations. The apparent simplicity of the technique can mask a certain number of complications, emphasizing the need for surgical experience. Progressive bone lengthening in congenital deformity has the advantage of preserving sensitivity and avoiding bone resorption. Callostasis does not increase the duration of treatment compared to bone graft.
El-Mofty, S.K.; Hovenga, T.L.; Russell, J.E.; Simmons, D.J.
The radiosensitivity of the rat parotid gland to X-radiation increased considerably towards the end of the daily light span (0800-2000 hours) and to a lesser extent before the onset of that period. The major sensitivity peak occurred at 1600 hours and coincides with a diurnal nadir in the rates of protein and RNA synthesis. The minor peak occurred at 0400 hours and was temporally related to a daily period of maximal secretory activity. It is suggested that suboptimal repair and secretion-linked cellular perturbations might contribute to the pathogenesis of the circadian increases in radiosensitivity of parotid cells. (author)
Full Text Available L-glutamate is the major excitatory amino acid in the mammalian central nervous system (CNS. This neurotransmitter is essential for higher brain functions such as learning, cognition and memory. A tight regulation of extra-synaptic glutamate levels is needed to prevent a neurotoxic insult. Glutamate removal from the synaptic cleft is carried out by a family of sodium-dependent high-affinity transporters, collectively known as excitatory amino acid transporters. Dysfunction of glutamate transporters is generally involved in acute neuronal injury and neurodegenerative diseases, so characterizing and understanding the mechanisms that lead to the development of these disorders is an important goal in the design of novel treatments for the neurodegenerative diseases. Increasing evidence indicates glutamate transporters are controlled by the circadian system in direct and indirect manners, so in this contribution we focus on the mechanisms of circadian regulation (transcriptional, translational, post-translational and post-transcriptional regulation of glutamate transport in neuronal and glial cells, and their consequence in brain function.
Kristin Lynn Eckel-Mahan
Full Text Available The ability to sustain memories over long periods of time, sometimes even a lifetime, is one of the most remarkable properties of the brain. Much knowledge has been gained over the past few decades regarding the molecular correlates of memory formation. Once a memory is forged, however, the molecular events that provide permanence are as of yet unclear. Studies in multiple organisms have revealed that circadian rhythmicity is important for the formation, stability, and recall of memories . The neuronal events that provide this link need to be explored further. This article will discuss the findings related to the circadian regulation of memory-dependent processes in the hippocampus. Specifically, the circadian-controlled MAP kinase and cAMP signal transduction pathway plays critical roles in the consolidation of hippocampus-dependent memory. A series of studies have revealed the circadian oscillation of this pathway within the hippocampus, an activity that is absent in memory-deficient, transgenic mice lacking Ca2+-stimulated adenylyl cyclases. Interference with these oscillations proceeding the cellular memory consolidation period impairs the persistence of hippocampus-dependent memory. These data suggest that the persistence of long-term memories may depend upon reactivation of this signal transduction pathway in the hippocampus during the circadian cycle. New data reveals the dependence of hippocampal oscillation in MAPK activity on the SCN, again underscoring the importance of this region in maintaining the circadian physiology of memory. Finally, the downstream ramification of these oscillations in terms of gene expression and epigenetics should be considered, as emerging evidence is pointing strongly to a circadian link between epigenetics and long term synaptic plasticity.
Leloup, Jean-Christophe; Goldbeter, Albert
We present a computational model for the mammalian circadian clock based on the intertwined positive and negative regulatory loops involving the Per, Cry, Bmal1, Clock, and Rev-Erb genes. In agreement with experimental observations, the model can give rise to sustained circadian oscillations in continuous darkness, characterized by an antiphase relationship between Per/Cry/Rev-Erb and Bmal1 mRNAs. Sustained oscillations correspond to the rhythms autonomously generated by suprachiasmatic nuclei. For other parameter values, damped oscillations can also be obtained in the model. These oscillations, which transform into sustained oscillations when coupled to a periodic signal, correspond to rhythms produced by peripheral tissues. When incorporating the light-induced expression of the Per gene, the model accounts for entrainment of the oscillations by light-dark cycles. Simulations show that the phase of the oscillations can then vary by several hours with relatively minor changes in parameter values. Such a lability of the phase could account for physiological disorders related to circadian rhythms in humans, such as advanced or delayed sleep phase syndrome, whereas the lack of entrainment by light-dark cycles can be related to the non-24h sleep-wake syndrome. The model uncovers the possible existence of multiple sources of oscillatory behavior. Thus, in conditions where the indirect negative autoregulation of Per and Cry expression is inoperative, the model indicates the possibility that sustained oscillations might still arise from the negative autoregulation of Bmal1 expression.
Gupta, Hem Prabha; Singh, R K; Singh, Urmila; Mehrotra, Seema; Verma, N S; Baranwal, Neelam
AIMS #ENTITYSTARTX00026; To find out the circadian pattern of blood pressure in normotensive pregnant women and in women with preeclampsia. A cross-sectional prospective observational case control study. Blood pressure was sampled in thirty-five normotensive pregnant women (control) and thirty five preeclamptic women (study group) by using non-invasive automatic ambulatory blood pressure monitoring machine for 72 h. Blood pressure (BP) was not constant over 24 h period and it oscillated from time to time in control group. BP was maximum during early part of afternoon. However, in preeclampsia besides quantitative increase in BP, circadian BP oscillations were less pronounced and in around 50% subjects BP was maximum during evening and night hours. Both systolic and diastolic BP showed definite reproducible circadian pattern in both preeclamptic and normotensive pregnant women. This pattern both quantitatively and qualitatively was different in preeclamptic women. Standardized 24 h BP monitoring allows quantitative and qualitative evaluation of hypertensive status and is important for timing and dosing of antihypertensive medications.
Fogg, Paul C M; O'Neill, John S; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C; McIntosh, Rebecca L L; Elliott, Christopher J H; Sweeney, Sean T; Hastings, Michael H; Chawla, Sangeeta
Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
Dijk, D. J.
In humans, EEG power spectra in REM and NREM sleep, as well as characteristics of sleep spindles such as their duration, amplitude, frequency and incidence, vary with circadian phase. Recently it has been hypothesized that circadian variations in EEG spectra in humans are caused by variations in brain or body temperature and may not represent phenomena relevant to sleep regulatory processes. To test this directly, a further analysis of EEG power spectra - collected in a forced desynchrony protocol in which sleep episodes were scheduled to a 28-h period while the rhythms of body temperature and plasma melatonin were oscillating at their near 24-h period - was carried out. EEG power spectra were computed for NREM and REM sleep occurring between 90-120 and 270-300 degrees of the circadian melatonin rhythm, i.e. just after the clearance of melatonin from plasma in the 'morning' and just after the 'evening' increase in melatonin secretion. Average body temperatures during scheduled sleep at these two circadian phases were identical (36.72 degrees C). Despite identical body temperatures, the power spectra in NREM sleep were very different at these two circadian phases. EEG activity in the low frequency spindle range was significantly and markedly enhanced after the evening increase in plasma melatonin as compared to the morning phase. For REM sleep, significant differences in power spectra during these two circadian phases, in particular in the alpha range, were also observed. The results confirm that EEG power spectra in NREM and REM sleep vary with circadian phase, suggesting that the direct contribution of temperature to the circadian variation in EEG power spectra is absent or only minor, and are at variance with the hypothesis that circadian variations in EEG power spectra are caused by variations in temperature.
Papagiannakopoulos, Thales; Bauer, Matthew R; Davidson, Shawn M; Heimann, Megan; Subbaraj, Lakshmipriya; Bhutkar, Arjun; Bartlebaugh, Jordan; Vander Heiden, Matthew G; Jacks, Tyler
Circadian rhythms are 24-hr oscillations that control a variety of biological processes in living systems, including two hallmarks of cancer, cell division and metabolism. Circadian rhythm disruption by shift work is associated with greater risk for cancer development and poor prognosis, suggesting a putative tumor-suppressive role for circadian rhythm homeostasis. Using a genetically engineered mouse model of lung adenocarcinoma, we have characterized the effects of circadian rhythm disruption on lung tumorigenesis. We demonstrate that both physiologic perturbation (jet lag) and genetic mutation of the central circadian clock components decreased survival and promoted lung tumor growth and progression. The core circadian genes Per2 and Bmal1 were shown to have cell-autonomous tumor-suppressive roles in transformation and lung tumor progression. Loss of the central clock components led to increased c-Myc expression, enhanced proliferation, and metabolic dysregulation. Our findings demonstrate that both systemic and somatic disruption of circadian rhythms contribute to cancer progression. Copyright © 2016 Elsevier Inc. All rights reserved.
Goel, Namni; Basner, Mathias; Rao, Hengyi; Dinges, David F.
Much of the current science on, and mathematical modeling of, dynamic changes in human performance within and between days is dominated by the two-process model of sleep–wake regulation, which posits a neurobiological drive for sleep that varies homeostatically (increasing as a saturating exponential during wakefulness and decreasing in a like manner during sleep), and a circadian process that neurobiologically modulates both the homeostatic drive for sleep and waking alertness and performance. Endogenous circadian rhythms in neurobehavioral functions, including physiological alertness and cognitive performance, have been demonstrated using special laboratory protocols that reveal the interaction of the biological clock with the sleep homeostatic drive. Individual differences in circadian rhythms and genetic and other components underlying such differences also influence waking neurobehavioral functions. Both acute total sleep deprivation and chronic sleep restriction increase homeostatic sleep drive and degrade waking neurobehavioral functions as reflected in sleepiness, attention, cognitive speed, and memory. Recent evidence indicating a high degree of stability in neurobehavioral responses to sleep loss suggests that these trait-like individual differences are phenotypic and likely involve genetic components, including circadian genes. Recent experiments have revealed both sleep homeostatic and circadian effects on brain metabolism and neural activation. Investigation of the neural and genetic mechanisms underlying the dynamically complex interaction between sleep homeostasis and circadian systems is beginning. A key goal of this work is to identify biomarkers that accurately predict human performance in situations in which the circadian and sleep homeostatic systems are perturbed. PMID:23899598
Aisling K Brady
Full Text Available Circadian rhythms regulate many physiological, behavioral and reproductive processes. These rhythms are often controlled by light, and daily cycles of solar illumination entrain many clock regulated processes. In scleractinian corals a number of different processes and behaviors are associated with specific periods of solar illumination or non-illumination--for example, skeletal deposition, feeding and both brooding and broadcast spawning.We have undertaken an analysis of diurnal expression of the whole transcriptome and more focused studies on a number of candidate circadian genes in the coral Acropora millepora using deep RNA sequencing and quantitative PCR. Many examples of diurnal cycles of RNA abundance were identified, some of which are light responsive and damped quickly under constant darkness, for example, cryptochrome 1 and timeless, but others that continue to cycle in a robust manner when kept in constant darkness, for example, clock, cryptochrome 2, cycle and eyes absent, indicating that their transcription is regulated by an endogenous clock entrained to the light-dark cycle. Many other biological processes that varied between day and night were also identified by a clustering analysis of gene ontology annotations.Corals exhibit diurnal patterns of gene expression that may participate in the regulation of circadian biological processes. Rhythmic cycles of gene expression occur under constant darkness in both populations of coral larvae that lack zooxanthellae and in individual adult tissue containing zooxanthellae, indicating that transcription is under the control of a biological clock. In addition to genes potentially involved in regulating circadian processes, many other pathways were found to display diel cycles of transcription.
Klerman, E. B.; Goldenberg, D. L.; Brown, E. N.; Maliszewski, A. M.; Adler, G. K.
Fibromyalgia syndrome is a chronic and debilitating disorder characterized by widespread nonarticular musculoskeletal pain whose etiology is unknown. Many of the symptoms of this syndrome, including difficulty sleeping, fatigue, malaise, myalgias, gastrointestinal complaints, and decreased cognitive function, are similar to those observed in individuals whose circadian pacemaker is abnormally aligned with their sleep-wake schedule or with local environmental time. Abnormalities in melatonin and cortisol, two hormones whose secretion is strongly influenced by the circadian pacemaker, have been reported in women with fibromyalgia. We studied the circadian rhythms of 10 women with fibromyalgia and 12 control healthy women. The protocol controlled factors known to affect markers of the circadian system, including light levels, posture, sleep-wake state, meals, and activity. The timing of the events in the protocol were calculated relative to the habitual sleep-wake schedule of each individual subject. Under these conditions, we found no significant difference between the women with fibromyalgia and control women in the circadian amplitude or phase of rhythms of melatonin, cortisol, and core body temperature. The average circadian phases expressed in hours posthabitual bedtime for women with and without fibromyalgia were 3:43 +/- 0:19 and 3:46 +/- 0:13, respectively, for melatonin; 10:13 +/- 0:23 and 10:32 +/- 0:20, respectively for cortisol; and 5:19 +/- 0:19 and 4:57 +/- 0:33, respectively, for core body temperature phases. Both groups of women had similar circadian rhythms in self-reported alertness. Although pain and stiffness were significantly increased in women with fibromyalgia compared with healthy women, there were no circadian rhythms in either parameter. We suggest that abnormalities in circadian rhythmicity are not a primary cause of fibromyalgia or its symptoms.
Free muscle transfer for dynamic smile reanimation in facial paralysis is not always predictable with regard to cosmesis. Hospital stays range from 5 to 7 days. Prolonged operative times, longer hospital stays, and excessive cheek bulk are associated with free flap options. Lengthening temporalis myoplasty offers single-stage smile reanimation with theoretical advantages over free tissue transfer. From 2012 to 2014, 18 lengthening temporalis myoplasties were performed in 14 children for smile reconstruction. A retrospective chart review was completed for demographics, operative times, length of hospital stay, and perioperative complications. Fourteen consecutive patients with complete facial paralysis were included. Four patients underwent single-stage bilateral reconstruction, and 10 underwent unilateral procedures. Diagnoses included Möbius syndrome (n = 5), posterior cranial fossa tumors (n = 4), posttraumatic (n = 2), hemifacial microsomia (n = 1), and idiopathic (n = 2). Average patient age was 10.1 years. Average operative time was 410 minutes (499 minutes for bilateral lengthening temporalis myoplasty and 373 for unilateral lengthening temporalis myoplasty). Average length of stay was 3.3 days (4.75 days for bilateral lengthening temporalis myoplasty and 2.8 for unilateral lengthening temporalis myoplasty). Nine patients required minor revisions. Lengthening temporalis myoplasty is a safe alternative to free tissue transfer for dynamic smile reconstruction in children with facial paralysis. Limited donor-site morbidity, shorter operative times, and shorter hospital stays are some benefits over free flap options. However, revisions are required frequently secondary to tendon avulsions and adhesions. Therapeutic, IV.
Full Text Available Circadian rhythms, endogenous cycles of about 24 h in physiology, are generated by a master clock located in the suprachiasmatic nucleus of the hypothalamus and other clocks located in the brain and peripheral tissues. Circadian disruption is known to increase the incidence of various illnesses, such as mental disorders, metabolic syndrome and cancer. At the molecular level, periodicity is established by a set of clock genes via autoregulatory translation-transcription feedback loops. This clock mechanism is regulated by post-translational modifications such as phosphorylation and ubiquitination, which set the pace of the clock. Ubiquitination in particular has been found to regulate the stability of core clock components, but also other clock protein functions. Mutation of genes encoding ubiquitin ligases can cause either elongation or shortening of the endogenous circadian period. Recent research has also started to uncover roles for deubiquitination in the molecular clockwork. Here we review the role of the ubiquitin pathway in regulating the circadian clock and we propose that ubiquitination is a key element in a clock protein modification code that orchestrates clock mechanisms and circadian behavior over the daily cycle.
Ma, Peijun; Woelfle, Mark A.; Johnson, Carl Hirschie
Circadian clocks are found in a wide variety of organisms from cyanobacteria to mammals. Many believe that the circadian clock system evolved as an adaption to the daily cycles in light and temperature driven by the rotation of the earth. Studies on the cyanobacterium, Synechococcus elongatus PCC 7942, have confirmed that the circadian clock in resonance with environmental cycles confers an adaptive advantage to cyanobacterial strains with different clock properties when grown in competition under light–dark cycles. The results thus far suggest that in a cyclic environment, the cyanobacterial strains whose free running periods are closest to the environmental period are the most fit and the strains lacking a functional circadian clock are at a competitive disadvantage relative to strains with a functional clock. In contrast, the circadian system provides little or no advantage to cyanobacteria grown in competition in constant light. To explain the potential mechanism of this clock-mediated enhancement in fitness in cyanobacteria, several models have been proposed; these include the limiting resource model, the diffusible inhibitor model and the cell-to-cell communication model. None of these models have been excluded by the currently available experimental data and the mechanistic basis of clock-mediated fitness enhancement remains elusive
Full Text Available Hypercholesterolemia is a well-known risk factor for a wide range of diseases in developed countries. Here, we report that mice lacking functional LDLR (low density lipoprotein receptor, an animal model of human familial hypercholesterolemia, show circadian abnormalities. In free running behavioral experiments in constant darkness, these mice showed a prolonged active phase and distinctly bimodal rhythms. Even when the circadian rhythms were entrained by light and dark cycles, these mice showed a significant attenuation of behavioral onset intensity at the start of the dark period. Further, we hypothesized that the combination of hypercholesterolemia and circadian abnormalities may affect cardiovascular disease progression. To examine this possibility, we generated LDLR-deficient mice with impaired circadian rhythms by simultaneously introducing a mutation into Period2, a core clock gene, and found that these mice showed a significant enlargement of artery plaque area with an increase in inflammatory cytokine IL-6 levels. These results suggest that circadian dysfunction may be associated with the development or progression of cardiovascular diseases.
Abraham, Ute; Schlichting, Julia Katharina; Kramer, Achim; Herzel, Hanspeter
Body temperature rhythms synchronize circadian oscillations in different tissues, depending on the degree of cellular coupling: the responsiveness to temperature is higher when single circadian oscillators are uncoupled. So far, the role of coupling in temperature responsiveness has only been studied in organotypic tissue slices of the central circadian pacemaker, because it has been assumed that peripheral target organs behave like uncoupled multicellular oscillators. Since recent studies indicate that some peripheral tissues may exhibit cellular coupling as well, we asked whether peripheral network dynamics also influence temperature responsiveness. Using a novel technique for long-term, high-resolution bioluminescence imaging of primary cultured cells, exposed to repeated temperature cycles, we were able to quantitatively measure period, phase, and amplitude of central (suprachiasmatic nuclei neuron dispersals) and peripheral (mouse ear fibroblasts) single cell oscillations in response to temperature. Employing temperature cycles of different lengths, and different cell densities, we found that some circadian characteristics appear cell-autonomous, e.g. period responses, while others seem to depend on the quality/degree of cellular communication, e.g. phase relationships, robustness of the oscillation, and amplitude. Overall, our findings indicate a strong dependence on the cell's ability for intercellular communication, which is not only true for neuronal pacemakers, but, importantly, also for cells in peripheral tissues. Hence, they stress the importance of comparative studies that evaluate the degree of coupling in a given tissue, before it may be used effectively as a target for meaningful circadian manipulation.
Full Text Available Abstract Background The Magel2 gene is most highly expressed in the suprachiasmatic nucleus of the hypothalamus, where its expression cycles in a circadian pattern comparable to that of clock-controlled genes. Mice lacking the Magel2 gene have hypothalamic dysfunction, including circadian defects that include reduced and fragmented total activity, excessive activity during the subjective day, but they have a normal circadian period. Magel2 is a member of the MAGE family of proteins that have various roles in cellular function, but the specific function of Magel2 is unknown. Methods We used a variety of cell-based assays to determine whether Magel2 modifies the properties of core circadian rhythm proteins. Results Magel2 represses the activity of the Clock:Bmal1 heterodimer in a Per2-luciferase assay. Magel2 interacts with Bmal1 and with Per2 as measured by co-immunoprecipitation in co-transfected cells, and exhibits a subcellular distribution consistent with these interactions when visualized by immunofluorescence. As well, Magel2 induces the redistribution of the subcellular localization of Clock towards the cytoplasm, in contrast to the nucleus-directed effect of Bmal1 on Clock subcellular localization. Conclusion Consistent with the blunted circadian rhythm observed in Magel2-null mice, these data suggest that Magel2 normally promotes negative feedback regulation of the cellular circadian cycle, through interactions with key core circadian rhythm proteins.
Wulund, Lisa; Reddy, Akhilesh B.
Circadian rhythms are present in all living organisms. They organise processes such as gene transcription, mitosis, feeding, and rest at different times of day and night. These rhythms are orchestrated by a network of core ‘clock genes’ that are organised into transcription–translation feedback loops (TTFLs), producing oscillations with a period of approximately 24 h. The modern understanding of circadian timekeeping has revolved around the TTFL paradigm. Recently, however, this has been chal...
Jasiewicz, Barbara; Kacki, Wojciech; Tesiorowski, Maciej; Potaczek, Tomasz
Current techniques of operative limb lengthening usually are based on distraction osteogenesis. One of the techniques is limb lengthening over an intramedullary nail. The goal of this study is to evaluate the results of femoral lengthening over an intramedullary nail. Between 1999 and 200619 femoral "over nail" lengthenings were performed. There were 7 males and 12 females. Mean patients' age at surgery was 15.8 years, and mean initial femoral shortening was 5.1 cm. Operative technique consisted of one-stage implantation of intramedullary nail and external fixator. Ilizarov apparatus was used in 9 patients, monolateral fixator in 10 cases--ORTHOFIX in 9 patients, Wagner fixator--in 1 patient. Intramedullary nail was locked proximally with screws or Schanz pins from external fixator. After distraction phase, external fixator was removed and distal locking screws were applied. Evaluation criteria: obtained lengthening, time of external fixator, treatment time, healing index, external fixation index, range of motion in hip and knee joints and complications according to Paley. The mean lengthening was 4.6 cm, and mean distraction time was 66.6 days. Mean time of external fixation was 115.5 days, and external fixation index was 26.2 days for centimeter. Healing index was 36.9 days for centimeter. In cases with monolateral fixator, healing index did not differ with the whole group. During treatment 18 complications occurred, for a rate of 0.9 complication per segment. Lengthening over an intramedullary nail reduces the time of external fixator. Over nail femoral lengthening can prevent axis deviation following regenerate bending. Complication rate is similar to lengthenings with the classic Ilizarov technique. There are no differences in the treatment time in relation to the type of external fixator.
Hastings, M H; Brancaccio, M; Maywood, E S
The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker of the brain. It co-ordinates the daily rhythms of sleep and wakefulness, as well as physiology and behaviour, that set the tempo to our lives. Disturbance of this daily pattern, most acutely with jet-lag but more insidiously with rotational shift-work, can have severely deleterious effects for mental function and long-term health. The present review considers recent developments in our understanding of the properties of the SCN that make it a robust circadian time-keeper. It first focuses on the intracellular transcriptional/ translational feedback loops (TTFL) that constitute the cellular clockwork of the SCN neurone. Daily timing by these loops pivots around the negative regulation of the Period (Per) and Cryptochrome (Cry) genes by their protein products. The period of the circadian cycle is set by the relative stability of Per and Cry proteins, and this can be controlled by both genetic and pharmacological interventions. It then considers the function of these feedback loops in the context of cytosolic signalling by cAMP and intracellular calcium ([Ca(2+) ]i ), which are both outputs from, and inputs to, the TTFL, as well as the critical role of vasoactive intestinal peptide (VIP) signalling in synchronising cellular clocks across the SCN. Synchronisation by VIP in the SCN is paracrine, operating over an unconventionally long time frame (i.e. 24 h) and wide spatial domain, mediated via the cytosolic pathways upstream of the TTFL. Finally, we show how intersectional pharmacogenetics can be used to control G-protein-coupled signalling in individual SCN neurones, and how manipulation of Gq/[Ca(2+) ]i -signalling in VIP neurones can re-programme the circuit-level encoding of circadian time. Circadian pacemaking in the SCN therefore provides an unrivalled context in which to understand how a complex, adaptive behaviour can be organised by the dynamic activity of a relatively
Full Text Available Abstract Internal lengthening nail (ILN is a recent development in limb lengthening and deformity correction specialty. The ILN has the distinct advantage of combining acute deformity correction with gradual lengthening of bone. While using ILN, the short metaphyseal bone fragment may develop a deformity at the time of osteotomy and nail insertion or during bone lengthening because of the wide medullary canal. These deformities are typically predictable, and blocking screws (Poller screws are helpful in these situations. This manuscript describes the common deformities that occur in femur and tibia with osteotomies at different locations while using ILN in antegrade and retrograde nailing technique. Also, a systematic approach to the appropriate use of blocking screws in these deformities is described. In addition, the “reverse rule of thumb” is introduced as a quick reference to determine the ideal location(s and number of blocking screws. These principles are applicable to limb lengthening and deformity correction as well as fracture fixation using intramedullary nails.
José A. Berenguer-Sánchez
Full Text Available Against the traditional explanation of the initial vowel’s lengthening in second member of compound, the so called «Wackernagel’s Law of lengthening», it is possible a different proposal, already suggested in some places to try to explain the law. According to this analysis, a process of elision or glide formation and compensatory lengthening, instead of, or alongside, the primitive vowel contraction and subsequent analogical extension of its result proposed by Wackernagel should be recognized. This process of vowel hiatus resolution has parallels in other languages, and allows a more suitable study of the available examples.
van Doorn, R; Leemans, R; Stapert, J W
To study the results of a one-stage lengthening and derotational osteotomy stabilised with a Gamma nail. Retrospective study. 2 hospitals, The Netherlands. 5 patients after failed osteosynthesis of femoral fractures. Mean lengthening of 3 cm and derotation of 30 degrees. Complications and functional results, after a mean follow-up of 43 months (range 30-57). Two patients required dynamisation and a cancellous bone graft to achieve union, which resulted in 1 and 1.5 cm loss of length. One patient had a temporary peroneal neurapraxy. No infections were observed. Our method is not an ultimate solution, but is suitable for one-stage lengthening and derotation osteotomies.
Bamne, Mikhil N; Ponder, Christine A; Wood, Joel A; Mansour, Hader; Frank, Ellen; Kupfer, David J; Young, Michael W; Nimgaonkar, Vishwajit L
Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Katsanos, Evangelos; Sextos, A.G.
Period lengthening, exhibited by structures when subjected to strong ground motions, constitutes an implicit proxy of structural inelasticity and associated damage. However, the reliable prediction of the inelastic period is tedious and a multi-parametric task, which is related to both epistemic ...... for period lengthening as a function of Ry and Tel. These equations may be used in the framework of the earthquake record selection and scaling....
Mattis, Joanna; Sehgal, Amita
Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.
.... These 'biological clocks' are important to human physiology. For example, psychiatric and medical studies have shown that circadian rhythmicity is involved in some forms of depressive illness, 'jet lag', drug tolerance/efficacy, memory, and insomnia...
National Aeronautics and Space Administration — The value of measuring sleep-wake cycles is significantly enhanced by measuring other physiological signals that depend on circadian rhythms (such as heart rate and...
National Aeronautics and Space Administration — We developed and refined our current mathematical model of circadian rhythms to incorporate melatonin as a marker rhythm. We used an existing physiologically based...
Fang, Ming Zhu; Ohman-Strickland, Pamela; Kelly-McNeil, Kathie; Kipen, Howard; Crabtree, Benjamin F; Lew, Jenny Pan; Zarbl, Helmut
Epidemiological studies indicate that disruption of circadian rhythm by shift work increases the risk of breast and prostate cancer. Our studies demonstrated that carcinogens disrupt the circadian expression of circadian genes (CGs) and circadian-controlled genes (CCGs) during the early stages of rat mammary carcinogenesis. A chemopreventive regimen of methylselenocysteine (MSC) restored the circadian expression of CGs and CCGs, including PERIOD 2 (PER2) and estrogen receptor β (ERS2), to normal. The present study evaluated whether changes in CG and CCG expression in whole blood can serve as indicators of circadian disruption in shift workers. Fifteen shift workers were recruited to a crossover study. Blood samples were drawn before (6 PM) and after (8 AM) completing a night shift after at least seven days on floating night-shift rotation, and before (8 AM), during (1 PM), and after (6 PM) completing seven days on day shift. The plasma melatonin level and messenger RNA (mRNA) expression of PER2, nuclear receptor subfamily 1, group d, member 1 (NR1D1), and ERS2 were measured, and the changes in levels of melatonin and gene expression were evaluated with statistical analyses. The mRNA expression of PER2 was affected by shift (p = 0.0079); the levels were higher in the evening for the night shift, but higher in the morning for the day shift. Increased PER2 expression (p = 0.034) was observed in the evening on the night versus day shifts. The melatonin level was higher in the morning for both day shifts (p = 0.013) and night shifts (p <0.0001). Changes in the level of PER2 gene expression can serve as a biomarker of disrupted circadian rhythm in blood cells. Therefore, they can be a useful intermediate indicator of efficacy in future MSC-mediated chemoprevention studies. Copyright © 2015 Elsevier B.V. All rights reserved.
Cui, Peng; Zhong, Tingyan; Wang, Zhuo; Wang, Tao; Zhao, Hongyu; Liu, Chenglin; Lu, Hui
Circadian genes express periodically in an approximate 24-h period and the identification and study of these genes can provide deep understanding of the circadian control which plays significant roles in human health. Although many circadian gene identification algorithms have been developed, large numbers of false positives and low coverage are still major problems in this field. In this study we constructed a novel computational framework for circadian gene identification using deep neural networks (DNN) - a deep learning algorithm which can represent the raw form of data patterns without imposing assumptions on the expression distribution. Firstly, we transformed time-course gene expression data into categorical-state data to denote the changing trend of gene expression. Two distinct expression patterns emerged after clustering of the state data for circadian genes from our manually created learning dataset. DNN was then applied to discriminate the aperiodic genes and the two subtypes of periodic genes. In order to assess the performance of DNN, four commonly used machine learning methods including k-nearest neighbors, logistic regression, naïve Bayes, and support vector machines were used for comparison. The results show that the DNN model achieves the best balanced precision and recall. Next, we conducted large scale circadian gene detection using the trained DNN model for the remaining transcription profiles. Comparing with JTK_CYCLE and a study performed by Möller-Levet et al. (doi: https://doi.org/10.1073/pnas.1217154110), we identified 1132 novel periodic genes. Through the functional analysis of these novel circadian genes, we found that the GTPase superfamily exhibits distinct circadian expression patterns and may provide a molecular switch of circadian control of the functioning of the immune system in human blood. Our study provides novel insights into both the circadian gene identification field and the study of complex circadian-driven biological
Lunsford-Avery, Jessica R; Gonçalves, Bruno da Silva Brandão; Brietzke, Elisa; Bressan, Rodrigo A; Gadelha, Ary; Auerbach, Randy P; Mittal, Vijay A
Individuals with psychotic disorders experience disruptions to both the sleep and circadian components of the sleep/wake cycle. Recent evidence has supported a role of sleep disturbances in emerging psychosis. However, less is known about how circadian rhythm disruptions may relate to psychosis symptoms and prognosis for adolescents with clinical high-risk (CHR) syndromes. The present study examines circadian rest/activity rhythms in CHR and healthy control (HC) youth to clarify the relationships among circadian rhythm disturbance, psychosis symptoms, psychosocial functioning, and the longitudinal course of illness. Thirty-four CHR and 32 HC participants were administered a baseline evaluation, which included clinical interviews, 5days of actigraphy, and a sleep/activity diary. CHR (n=29) participants were re-administered clinical interviews at a 1-year follow-up assessment. Relative to HC, CHR youth exhibited more fragmented circadian rhythms and later onset of nocturnal rest. Circadian disturbances (fragmented rhythms, low daily activity) were associated with increased psychotic symptom severity among CHR participants at baseline. Circadian disruptions (lower daily activity, rhythms that were more fragmented and/or desynchronized with the light/dark cycle) also predicted severity of psychosis symptoms and psychosocial impairment at 1-year follow-up among CHR youth. Circadian rhythm disturbances may represent a potential vulnerability marker for emergence of psychosis, and thus, rest/activity rhythm stabilization has promise to inform early-identification and prevention/intervention strategies for CHR youth. Future studies with longer study designs are necessary to further examine circadian rhythms in the prodromal period and rates of conversion to psychosis among CHR teens. Copyright © 2017. Published by Elsevier B.V.
Obesity has become a serious public health problem and a major risk factor for the development of illnesses, such as insulin resistance and hypertension. Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating the circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabol...
Full Text Available Circadian organization means the way in which the entire circadian system above the cellular level is put together physically and the principles and rules that determine the interactions among its component parts which produce overt rhythms of physiology and behavior. Understanding this organization and its evolution is of practical importance as well as of basic interest. The first major problem that we face is the difficulty of making sense of the apparently great diversity that we observe in circadian organization of diverse vertebrates. Some of this diversity falls neatly into place along phylogenetic lines leading to firm generalizations: i in all vertebrates there is a "circadian axis" consisting of the retinas, the pineal gland and the suprachiasmatic nucleus (SCN, ii in many non-mammalian vertebrates of all classes (but not in any mammals the pineal gland is both a photoreceptor and a circadian oscillator, and iii in all non-mammalian vertebrates (but not in any mammals there are extraretinal (and extrapineal circadian photoreceptors. An interesting explanation of some of these facts, especially the differences between mammals and other vertebrates, can be constructed on the assumption that early in their evolution mammals passed through a "nocturnal bottleneck". On the other hand, a good deal of the diversity among the circadian systems of vertebrates does not fall neatly into place along phylogenetic lines. In the present review we will consider how we might better understand such "phylogenetically incoherent" diversity and what sorts of new information may help to further our understanding of the evolution of circadian organization in vertebrates
Pål O Westermark
Full Text Available Circadian rhythms in transcription are generated by rhythmic abundances and DNA binding activities of transcription factors. Propagation of rhythms to transcriptional initiation involves the core promoter, its chromatin state, and the basal transcription machinery. Here, I characterize core promoters and chromatin states of genes transcribed in a circadian manner in mouse liver and in Drosophila. It is shown that the core promoter is a critical determinant of circadian mRNA expression in both species. A distinct core promoter class, strong circadian promoters (SCPs, is identified in mouse liver but not Drosophila. SCPs are defined by specific core promoter features, and are shown to drive circadian transcriptional activities with both high averages and high amplitudes. Data analysis and mathematical modeling further provided evidence for rhythmic regulation of both polymerase II recruitment and pause release at SCPs. The analysis provides a comprehensive and systematic view of core promoters and their link to circadian mRNA expression in mouse and Drosophila, and thus reveals a crucial role for the core promoter in regulated, dynamic transcription.
Kenneth A. Dyar
Full Text Available Circadian rhythms are widely known to govern human health and disease, but specific pathogenic mechanisms linking circadian disruption to metabolic diseases are just beginning to come to light. This is thanks in part to the development and application of various “omics”-based tools in biology and medicine. Current high-throughput technologies allow for the simultaneous monitoring of multiple dynamic cellular events over time, ranging from gene expression to metabolite abundance and sub-cellular localization. These fundamental temporal and spatial perspectives have allowed for a more comprehensive understanding of how various dynamic cellular events and biochemical processes are related in health and disease. With advances in technology, metabolomics has become a more routine “omics” approach for studying metabolism, and “circadian metabolomics” (i.e., studying the 24-h metabolome has recently been undertaken by several groups. To date, circadian metabolomes have been reported for human serum, saliva, breath, and urine, as well as tissues from several species under specific disease or mutagenesis conditions. Importantly, these studies have consistently revealed that 24-h rhythms are prevalent in almost every tissue and metabolic pathway. Furthermore, these circadian rhythms in tissue metabolism are ultimately linked to and directed by internal 24-h biological clocks. In this review, we will attempt to put these data-rich circadian metabolomics experiments into perspective to find out what they can tell us about metabolic health and disease, and what additional biomarker potential they may reveal.
Andrey A Ptitsyn
Full Text Available Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.
Sabado, Virginie; Vienne, Ludovic; Nagoshi, Emi
Circadian behavioral rhythms offer an excellent model to study intricate interactions between the molecular and neuronal mechanisms of behavior. In mammals, pacemaker neurons in the suprachiasmatic nucleus (SCN) generate rhythms cell-autonomously, which are synchronized by the network interactions within the circadian circuit to drive behavioral rhythms. However, whether this principle is universal to circadian systems in animals remains unanswered. Here, we examined the autonomy of the Drosophila circadian clock by monitoring transcriptional and post-transcriptional rhythms of individual clock neurons in dispersed culture with time-lapse microscopy. Expression patterns of the transcriptional reporter show that CLOCK/CYCLE (CLK/CYC)-mediated transcription is constantly active in dissociated clock neurons. In contrast, the expression profile of the post-transcriptional reporter indicates that PERIOD (PER) protein levels fluctuate and ~10% of cells display rhythms in PER levels with periods in the circadian range. Nevertheless, PER and TIM are enriched in the cytoplasm and no periodic PER nuclear accumulation was observed. These results suggest that repression of CLK/CYC-mediated transcription by nuclear PER is impaired, and thus the negative feedback loop of the molecular clock is incomplete in isolated clock neurons. We further demonstrate that, by pharmacological assays using the non-amidated form of neuropeptide pigment-dispersing factor (PDF), which could be specifically secreted from larval LNvs and adult s-LNvs, downstream events of the PDF signaling are partly impaired in dissociated larval clock neurons. Although non-amidated PDF is likely to be less active than the amidated one, these results point out the possibility that alteration in PDF downstream signaling may play a role in dampening of molecular rhythms in isolated clock neurons. Taken together, our results suggest that Drosophila clocks are weak oscillators that need to be in the intact circadian
Full Text Available Circadian behavioral rhythms offer an excellent model to study intricate interactions between the molecular and neuronal mechanisms of behavior. In mammals, pacemaker neurons in the suprachiasmatic nucleus (SCN generate rhythms cell-autonomously, which are synchronized by the network interactions within the circadian circuit to drive behavioral rhythms. However, whether this principle is universal to circadian systems in animals remains unanswered. Here, we examined the autonomy of the Drosophila circadian clock by monitoring transcriptional and post-transcriptional rhythms of individual clock neurons in dispersed culture with time-lapse microscopy. Expression patterns of the transcriptional reporter show that CLOCK/CYCLE (CLK/CYC-mediated transcription is constantly active in dissociated clock neurons. In contrast, the expression profile of the post-transcriptional reporter indicates that PERIOD (PER protein levels fluctuate and ~10% of cells display rhythms in PER levels with periods in the circadian range. Nevertheless, PER and TIM are enriched in the cytoplasm and no periodic PER nuclear accumulation was observed. These results suggest that repression of CLK/CYC-mediated transcription by nuclear PER is impaired, and thus the negative feedback loop of the molecular clock is incomplete in isolated clock neurons. We further demonstrate that, by pharmacological assays using the non-amidated form of neuropeptide pigment-dispersing factor (PDF, which could be specifically secreted from larval LNvs and adult s-LNvs, downstream events of the PDF signaling are partly impaired in dissociated larval clock neurons. Although non-amidated PDF is likely to be less active than the amidated one, these results point out the possibility that alteration in PDF downstream signaling may play a role in dampening of molecular rhythms in isolated clock neurons. Taken together, our results suggest that Drosophila clocks are weak oscillators that need to be in the
Altenburg, T.M.; de Ruiter, C.J.; Verdijk, P.W.L.; van Mechelen, W.; de Haan, A.
A single shortening contraction reduces the force capacity of muscle fibers, whereas force capacity is enhanced following lengthening. However, how motor unit recruitment and discharge rate (muscle activation) are adapted to such changes in force capacity during submaximal contractions remains
Bane, K.L.F.; Ruth, R.D.
The problem of bunch lengthening in electron storage rings has been treated by many people, and there have been many experiments. In the typical experiment, the theory is used to determine the impedance of the ring. What has been lacking thus far, however, is a calculation of bunch lengthening that uses a carefully calculated ring impedance (or wakefield). In this paper we begin by finding the potential well distortion due to some very simple impedance models, in order to illustrate different types of bunch lengthening behavior. We then give a prescription for extending potential well calculations into the turbulent regime once the threshold is known. Then finally, using the wakefield calculated for the SLC damping rings, combined with the measured value of the threshold, we calculate bunch lengthening for the damping rings, and compare the results with the measurements. 9 refs., 6 figs
Anglès, F G; Manubens, X B; Anglès, F C
An original technique for lengthening primary tight semitendinosus and semimembranosus muscles in their proximal portion is presented. The authors consider that primary shortening of these muscles rebounds on hip biomechanics and on the spine kinematics chain.
Singh, D; Dudkiewicz, I
Metatarsalgia is a recognised complication following iatrogenic shortening of the first metatarsal in the management of hallux valgus. The traditional surgical treatment is by shortening osteotomies of the lesser metatarsals. We describe the results of lengthening of iatrogenic first brachymetatarsia in 16 females. A Scarf-type osteotomy was used in the first four cases and a step-cut of equal thicknesses along the axis of the first metatarsal was performed in the others. The mean follow-up was 21 months (19 to 26). Relief of metatarsalgia was obtained in the six patients in whom 10 mm of lengthening had been achieved, compared to only 50% relief in those where less than 8 mm of lengthening had been gained. One-stage step-cut lengthening osteotomy of the first metatarsal may be preferable to shortening osteotomies of the lesser metatarsals in the treatment of metatarsalgia following surgical shortening of the first metatarsal.
Mantovani, Matheus Bortoluzzi; Souza, Eduardo Clemente; Marson, Fabiano Carlos; Corrêa, Giovani Oliveira; Progiante, Patrícia Saram; Silva, Cléverson Oliveira
Excessive gingival display during smile can result in compromised esthetics. This study aims to report a case of excessive gingival display with multiple etiologies treated by means of modified lip repositioning technique associated with esthetic crown lengthening. A 23-year-old female patient, with 5-mm gingival display during smile caused by altered passive eruption and hypermobility of the upper lip, underwent the modified lip repositioning technique associated with gingivectomy followed by flap elevation and ostectomy/osteoplasty. Seven months after the second procedure, the patient had her esthetic complaint solved appearing stable in the observation period. The modified lip repositioning technique is an effective procedure employed to reduce gingival display and when associated with esthetic clinical crown lengthening, can appropriately treat cases of gummy smile. PMID:27041845
Fuller, Charles A.; Murakami, Dean M.; Hoban-Higgins, Tana M.; Fuller, Patrick M.; Robinson, Edward L.; Tang, I.-Hsiung
Two fundamental environmental influences that have shaped the evolution of life on Earth are gravity and the cyclic changes occurring over the 24-hour day. Light levels, temperature, and humidity fluctuate over the course of a day, and organisms have adapted to cope with these variations. The primary adaptation has been the evolution of a biological timing system. Previous studies have suggested that this system, named the circadian (circa - about; dies - a day) timing system (CTS), may be sensitive to changes in gravity. The NASA Neurolab spaceflight provided a unique opportunity to evaluate the effects of microgravity on the mammalian CTS. Our experiment tested the hypotheses that microgravity would affect the period, phasing, and light sensitivity of the CTS. Twenty-four Fisher 344 rats were exposed to 16 days of microgravity on the Neurolab STS-90 mission, and 24 Fisher 344 rats were also studied on Earth as one-G controls. Rats were equipped with biotelemetry transmitters to record body temperature (T(sub b)) and heart rate (HR) continuously while the rats moved freely. In each group, 18 rats were exposed to a 24-hour light-dark (LD 12:12) cycle, and six rats were exposed to constant dim red-light (LL). The ability of light to induce a neuronal activity marker (c-fos) in the circadian pacemaker of the brain, the suprachiasmatic nucleus (SCN), was examined in rats studied on flight days two (FD2) and 14 (FD14), and postflight days two (R+1) and 14 (R+13). The flight rats in LD remained synchronized with the LD cycle. However, their T(sub b), rhythm was markedly phase-delayed relative to the LD cycle. The LD flight rats also had a decreased T(sub b) and a change in the waveform of the T(sub b) rhythm compared to controls. Rats in LL exhibited free-running rhythms of T(sub b), and HR; however, the periods were longer in microgravity. Circadian period returned to preflight values after landing. The internal phase angle between rhythms was different in flight than
Launay, F; Younsi, R; Pithioux, M; Chabrand, P; Bollini, G; Jouve, J-L
Fracture is one of the main complications following external fixator removal used in cases of progressive lower limb lengthening; rates as high as 50% are found in the literature. The aim of this study was to determine the factors influencing this complication. One hundred and eleven cases of lower limb lengthening were performed in 58 patients (40 femurs and 71 tibias). The mean age at surgery was 10.1years old. Lengthening was performed in all cases with an external fixator alone, associated in 39.6% of cases with intramedullary nailing. The patients were divided into three groups according to disease etiology (congenital, achondroplasia and other). The fractures were classified according to the Simpson classification. Twenty fractures were recorded (18%). Sixteen fractures were found in patients with congenital disease, four with achondroplasia and none in the group of other etiologies. The fracture was more often in the femur (27.5%) than in the tibia (12.7%). The rate of fracture is influenced by different factors depending on the etiology of disease. In congenital diseases, the fracture rate is higher when there is lengthening of more than 15% of the initial length and a delay between surgery and the beginning of lengthening of less than 7days. In patients with achondroplasia, the influence of a relative percentage of lengthening is less important than in those with congenital disease. However, to avoid fractures, lengthening should not be started in children under the age of nine. Moreover, lengthening should begin at least 7days after the fixator has been placed. Retrospective. Level IV. Copyright © 2012 Elsevier Masson SAS. All rights reserved.
Desai, Ankit; Lidder, Surjit; R. Armitage, Andrew; S. Rajaratnam, Samuel; D. Skyrme, Andrew
A 16-year-old girl presented with left fourth metatarsal shortening causing significant psychological distress. She underwent lengthening scarf osteotomy held with an Omnitech® screw (Biotech International, France) with the addition of two 1 cm cancellous cubes (RTI Biologics, United States). A lengthening z-plasty of the extensor tendons and skin were also performed. At 6 weeks the patient was fully weight bearing and at one-year follow up, the patient was satisfied and discharged. A modifie...
HANS G RICHTER
Full Text Available The circadian time-keeping system ensures predictive adaptation of individuals to the reproducible 24-h day/night alternations of our planet by generating the 24-h (circadian rhythms found in hormone release and cardiovascular, biophysical and behavioral functions, and others. In mammals, the master clock resides in the suprachiasmatic nucleus (SCN of the hypothalamus. The molecular events determining the functional oscillation of the SCN neurons with a period of 24-h involve recurrent expression of several clock proteins that interact in complex transcription/translation feedback loops. In mammals, a glutamatergic monosynaptic pathway originating from the retina regulates the clock gene expression pattern in the SCN neurons, synchronizing them to the light:dark cycle. The emerging concept is that neural/humoral output signals from the SCN impinge upon peripheral clocks located in other areas of the brain, heart, lung, gastrointestinal tract, liver, kidney, fibroblasts, and most of the cell phenotypes, resulting in overt circadian rhythms in integrated physiological functions. Here we review the impact of day/night alternation on integrated physiology; the molecular mechanisms and input/output signaling pathways involved in SCN circadian function; the current concept of peripheral clocks; and the potential role of melatonin as a circadian neuroendocrine transducer
Preußner, Marco; Heyd, Florian
Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease.
Beer, Katharina; Kolbe, Esther; Kahana, Noa B.; Yayon, Nadav; Weiss, Ron; Menegazzi, Pamela; Bloch, Guy
Pigment-Dispersing Factor (PDF) is an important neuropeptide in the brain circadian network of Drosophila and other insects, but its role in bees in which the circadian clock influences complex behaviour is not well understood. We combined high-resolution neuroanatomical characterizations, quantification of PDF levels over the day and brain injections of synthetic PDF peptide to study the role of PDF in the honey bee Apis mellifera. We show that PDF co-localizes with the clock protein Period (PER) in a cluster of laterally located neurons and that the widespread arborizations of these PER/PDF neurons are in close vicinity to other PER-positive cells (neurons and glia). PDF-immunostaining intensity oscillates in a diurnal and circadian manner with possible influences for age or worker task on synchrony of oscillations in different brain areas. Finally, PDF injection into the area between optic lobes and the central brain at the end of the subjective day produced a consistent trend of phase-delayed circadian rhythms in locomotor activity. Altogether, these results are consistent with the hypothesis that PDF is a neuromodulator that conveys circadian information from pacemaker cells to brain centres involved in diverse functions including locomotion, time memory and sun-compass orientation. PMID:29321240
Le Glou, Eric; Seugnet, Laurent; Shaw, Paul J; Preat, Thomas; Goguel, Valérie
Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time.
Chapman, D. K.; Brown, A. H.; Dahl, A. O.
Plant circadian rhythms of leaf movement in seedlings of the pepper plant (Capsicum annuum L., var. Yolo Wonder) were observed at different g-levels by means of a centrifuge. Except for the chronically imposed g-force all environmental conditions to which the plants were exposed were held constant. The circadian period, rate of change of amplitude of successive oscillations, symmetry of the cycles, and phase of the rhythm all were found not to be significantly correlated with the magnitude of the sustained g-force.
Reijmers, L.G.J.E.; Leus, I.E.; Burbach, J.P.H.; Spruijt, B.M.; Ree, van J.M.
Disruption of circadian rhythm can impair long-term passive avoidance memory of rats and mice. The present study investigated whether disruption of circadian rhythm can also impair social memory of male rats. Social memory was assessed using the social discrimination test, in which a short-term
Full Text Available Clock gene oscillations are necessary for a successful pregnancy and parturition, but little is known about their function during lactation, a period demanding from the mother multiple physiological and behavioral adaptations to fulfill the requirements of the offspring. First, we will focus on circadian rhythms and clock genes in reproductive tissues mainly in rodents. Disruption of circadian rhythms or proper rhythmic oscillations of clock genes provoke reproductive problems, as found in clock gene knockout mice. Then, we will focus mainly on the rabbit doe as this mammal nurses the young just once a day with circadian periodicity. This daily event synchronizes the behavior and the activity of specific brain regions critical for reproductive neuroendocrinology and maternal behavior, like the preoptic area. This region shows strong rhythms of the PER1 protein (product of the Per1 clock gene associated with circadian nursing. Additionally, neuroendocrine cells related to milk production and ejections are also synchronized to daily nursing. A threshold of suckling is necessary to entrain once a day nursing; this process is independent of milk output as even virgin does (behaving maternally following anosmia can display circadian nursing behavior. A timing motivational mechanism may regulate such behavior as mesolimbic dopaminergic cells are entrained by daily nursing. Finally, we will explore about the clinical importance of circadian rhythms. Indeed, women in chronic shift-work schedules show problems in their menstrual cycles and pregnancies and also have a high risk of preterm delivery, making this an important field of translational research.
Luuk, Hendrik; Fahrenkrug, Jan; Hannibal, Jens
in significantly lower body weight and reduced wheel-running activity. Circadian rhythmicity of behavior was normal in Wfs1-deficient mice under ad libitum feeding apart from elongated free-running period in constant light. The amount of food anticipatory activity induced by restricted feeding...
Koorengevel, Kathelijne M.; Beersma, Domien G.M.; den Boer, Johan; Hoofdakker, Rutger H. van den
The circadian pacemaker is an endogenous clock that regulates oscillations in most physiological and psychological processes with a near 24-h period. In many species, this pacemaker triggers seasonal changes in behavior. The seasonality of symptoms and the efficacy of light therapy suggest
Pittendrigh, Colin S.; Daan, Serge
1. In the first part of the paper, the model of non-parametric entrainment of circadian pacemakers is tested for the case of nocturnal rodents. The model makes use of the available data on freerunning period (τ) in constant darkness and on phase response curves (PRC) for short light pulses. It is
Dana, C; Aurégan, J-C; Salon, A; Guéro, S; Glorion, C; Pannier, S
Metacarpal lengthening is a useful procedure to address hand deficiencies in children. In this study, we aimed to compare the results of three different techniques from one consecutive clinical series of hand deficiencies. A total of 15 metacarpal lengthenings have been performed in 12 children aged from 9 to 14 years. The callotasis technique was used in seven cases, the two-stage distraction-graft technique in four cases and the single-stage lengthening in four cases. All the metacarpals healed with bone. The lengthening obtained was a mean of 13 mm (range 8-21 mm), a mean of 22 mm (range 13-32 mm) and a mean of 12 mm (range 9-15 mm), respectively, in the three different techniques. The healing index was longer for callotasis (81 days/cm) compared with the other techniques (41 days/cm and 46 days/cm, respectively). We observed one case of fracture after callotasis and one after distraction-graft. One patient underwent tenolysis of the extensor mechanism after single-stage lengthening. In conclusion, distraction graft and single-stage lengthening may be valuable alternatives to callotasis. IV; therapeutic study; multi-case series. © The Author(s) 2016.
Tim, Tyler; McHugh, Malachy
Back ground and Purpose: Hamstring injury is a common occurrence in sport and there has been limited success in reducing this rate of recurrence to date. Description of Topic with Related Evidence: High speed running requires eccentric strength when the hamstring muscles are in a lengthened state. The lengthened state occurs when the hip is in flexion and the lower leg moves into extension, thus lengthening the two joint hamstring muscle over both articulations upon which they act. There is evidence to suggest that athletes who have sustained a hamstring strain lack strength when the muscle is utilized during performance in a lengthened state. Purpose: To examine the risk factors contributing to such a high recurrence rate and propose a unique rehabilitation strategy addressing these factors in order to decrease the rate of reinjury. Discussion/Relation to Clinical Practice: Failing to increase an athlete's eccentric strength in a lengthened position after a hamstring injury may predispose an athlete to subsequent reinjury. Incorporating lengthened state eccentric training may help reduce the rate of reinjury. Level of Evidence: Level 5 PMID:22666648
Baandrup, Lone; Fasmer, Ole Bernt; Glenthøj, Birte Yding
is associated with changes in circadian rhythm parameters. METHOD: Data were derived from a randomized, double-blinded clinical trial with 24 weeks follow-up. Participants were randomized to add-on treatment with prolonged-release melatonin (2 mg) or matching placebo, and usual benzodiazepine dosage...... significantly increased the interdaily stability and at a trend level decreased the intradaily variability compared with placebo. Benzodiazepine dose reduction was not associated with these circadian rhythm parameters. Activity counts were generally higher after benzodiazepine dose reduction compared with pre......BACKGROUND: Patients with severe mental illness often suffer from disruptions in circadian rest-activity cycles, which might partly be attributed to ongoing psychopharmacological medication. Benzodiazepines are frequently prescribed for prolonged periods despite recommendations of only short...
Full Text Available Antarctic krill, Euphausia superba, shapes the structure of the Southern Ocean ecosystem. Its central position in the food web, the ongoing environmental changes due to climatic warming, and increasing commercial interest on this species emphasize the urgency of understanding the adaptability of krill to its environment. Krill has evolved rhythmic physiological and behavioral functions which are synchronized with the daily and seasonal cycles of the complex Southern Ocean ecosystem. The mechanisms, however, leading to these rhythms are essentially unknown. Here, we show that krill possesses an endogenous circadian clock that governs metabolic and physiological output rhythms. We found that expression of the canonical clock gene cry2 was highly rhythmic both in a light-dark cycle and in constant darkness. We detected a remarkable short circadian period, which we interpret as a special feature of the krill's circadian clock that helps to entrain the circadian system to the extreme range of photoperiods krill is exposed to throughout the year. Furthermore, we found that important key metabolic enzymes of krill showed bimodal circadian oscillations (∼9-12 h period in transcript abundance and enzymatic activity. Oxygen consumption of krill showed ∼9-12 h oscillations that correlated with the temporal activity profile of key enzymes of aerobic energy metabolism. Our results demonstrate the first report of an endogenous circadian timing system in Antarctic krill and its likely link to metabolic key processes. Krill's circadian clock may not only be critical for synchronization to the solar day but also for the control of seasonal events. This study provides a powerful basis for the investigation into the mechanisms of temporal synchronization in this marine key species and will also lead to the first comprehensive analyses of the circadian clock of a polar marine organism through the entire photoperiodic cycle.
Full Text Available Breastfeeding improves maternal and child health. The American Academy of Pediatrics recommends exclusive breastfeeding for six months, with continued breastfeeding for at least one year. However, in the US, only 18.8% of infants are exclusively breastfed until six months of age. For mothers who initiate breastfeeding, the early postpartum period sets the stage for sustained breastfeeding. Mothers who experience breastfeeding problems in the early postpartum period are more likely to discontinue breastfeeding within two weeks. A major risk factor for shorter breastfeeding duration is delayed lactogenesis II (i.e. onset of milk coming in more than 72 h postpartum. Recent studies report a metabolic-hormonal link to delayed lactogenesis II. This is not surprising because around the time of birth the mother’s entire metabolism changes to direct nutrients to mammary glands. Circadian and metabolic systems are closely linked, and our rodent studies suggest circadian clocks coordinate hormonal and metabolic changes to support lactation. Molecular and environmental disruption of the circadian system decreases a dam’s ability to initiate lactation and negatively impacts milk production. Circadian and metabolic systems evolved to be functional and adaptive when lifestyles and environmental exposures were quite different from modern times. We now have artificial lights, longer work days, and increases in shift work. Disruption in the circadian system due to shift work, jet lag, sleep disorders and other modern life style choices are associated with metabolic disorders, obesity, and impaired reproduction. We hypothesize delayed lactogenesis II is related to disruption of the mother’s circadian system. Here we review literature that supports this hypothesis, and describe interventions that may help to increase breastfeeding success.
Akten, Bikem; Tangredi, Michelle M.; Jauch, Eike; Roberts, Mary A.; Ng, Fanny; Raabe, Thomas; Jackson, F. Rob
There is a universal requirement for post-translational regulatory mechanisms in circadian clock systems. Previous work in Drosophila has identified several kinases, phosphatases and an E3 ligase that are critical for determining the nuclear translocation and/or stability of clock proteins. The present study evaluated the function of p90 ribosomal S6 kinase (RSK) in the Drosophila circadian system. In mammals, RSK1 is a light- and clock-regulated kinase known to be activated by the MAPK pathway, but there is no direct evidence that it functions as a component of the circadian system. Here, we show that Drosophila S6KII RNA displays rhythms in abundance, indicative of circadian control. Importantly, an S6KII null mutant exhibits a short-period circadian phenotype that can be rescued by expression of the wild-type gene in clock neurons, indicating a role for S6KII in the molecular oscillator. Peak PER clock protein expression is elevated in the mutant, indicative of enhanced stability, whereas per mRNA level is decreased, consistent with enhanced feedback repression. Gene reporter assays show that decreased S6KII is associated with increased PER repression. Surprisingly, we demonstrate a physical interaction between S6KII and the Casein Kinase 2 regulatory subunit (CK2β), suggesting a functional relationship between the two kinases. In support of such a relationship, there are genetic interactions between S6KII and CK2 mutations, in vivo, which indicate that CK2 activity is required for S6KII action. We propose that the two kinases cooperate within clock neurons to fine-tune circadian period, improving the precision of the clock mechanism. PMID:19144847
Bessa, Zoélia Camila Moura; Melo, Paula Rocha De; Gonçalves, Bruno S B; Azevedo, Carolina V M De
In marmosets, social synchrony between circadian profiles of activity is stronger in animals that cohabit in a family. The activity of three breeding pairs was recorded by actiwatches to investigate the mechanisms involved in the synchrony between the circadian activity profiles during cohabitation in marmoset reproductive pairs. The dyads were submitted to LD 12:12 (21 days) and LL: 1) cohabitation (24 days), 2) removal of the cage mate (20 days), 3) reintroduction of the mate into the cage of the 1 st situation (30 days) and 4) removal of the cage mate (7 days). Next, they were rejoined and maintained in LD 12:12 (11 days). In conditions involving cohabitation of pair, the general and maximum correlation indexes between circadian profiles were higher in cage mates compared to animals of the same or different sex with which they maintain only acoustic and olfactive contact. This strong synchrony between rhythms was accompanied by a stable phase relationship at the activity onset and offset, with identical circadian periods between mates. When the pairs were separated, there was a break in stability in the phase relationships between activity profiles with different circadian periods and a greater phase angle difference between rhythms of cage mates. During separation, two females and one male progressively anticipated the activity onset and offset in a phase similar to that in previous conditions, expressing entrainment to the mate. During the first reintroduction, two pairs exhibited signs of masking in rhythm. Although modulation in the rhythm of some animals has been observed through acoustic cues from animals outside the colony, we suggest that cohabitation favors strong synchrony between the circadian activity profiles of marmoset reproductive pairs involving synchronization by entrainment and masking. Further studies in the absence of external social cues are necessary to clarify the role of these mechanisms on social synchronization in marmosets.
Zhao, Y; Zhang, S; Sun, T; Wang, D; Lian, W; Tan, J; Zou, D; Zhao, Y
To compare the stability of lengthened sacroiliac screw and standard sacroiliac screw for the treatment of unilateral vertical sacral fractures; to provide reference for clinical applications. A finite element model of Tile type C pelvic ring injury (unilateral Denis type II fracture of the sacrum) was produced. The unilateral sacral fractures were fixed with lengthened sacroiliac screw and sacroiliac screw in six different types of models respectively. The translation and angle displacement of the superior surface of the sacrum (in standing position on both feet) were measured and compared. The stability of one lengthened sacroiliac screw fixation in S1 or S2 segment is superior to that of one sacroiliac screw fixation in the same sacral segment. The stability of one lengthened sacroiliac screw fixation in S1 and S2 segments respectively is superior to that of one sacroiliac screw fixation in S1 and S2 segments respectively. The stability of one lengthened sacroiliac screw fixation in S1 and S2 segments respectively is superior to that of one lengthened sacroiliac screw fixation in S1 or S2 segment. The stability of one sacroiliac screw fixation in S1 and S2 segments respectively is markedly superior to that of one sacroiliac screw fixation in S1 or S2 segment. The vertical and rotational stability of lengthened sacroiliac screw fixation and sacroiliac screw fixation in S2 is superior to that of S1. In a finite element model of type C pelvic ring disruption, S1 and S2 lengthened sacroiliac screws should be utilized for the fixation as regularly as possible and the most stable fixation is the combination of the lengthened sacroiliac screws of S1 and S2 segments. Even if lengthened sacroiliac screws cannot be systematically used due to specific conditions, one sacroiliac screw fixation in S1 and S2 segments respectively is recommended. No matter which kind of sacroiliac screw is used, if only one screw can be implanted, the fixation in S2 segment is more recommended
For the Academy of Science St. Louis Science Fair, I tested how different photoperiods affect the morphology of Pyrocystis fusiformis with respect to the placement and formation of the chloroplasts. I set up four different rooms to observe the effect the different times in the photoperiod on location of chloroplasts in the cell. At 3:00pm, one room has been in the dark for 12 hours, one for 6 hours, one had been in the light phase for 12 hours and the fourth in the light phase for 6 hours. P fusiformis samples were obtained from each room, observed, photographed at X100 power, and categorized as being a 1, 2, 3, or 4 depending on the position of the chloroplasts. The samples in the different rooms were observed once a week for two weeks, then the samples were rotated to see if P. fusiformis would synchronize the same to the new photoperiod. It was observed that the cells changed morphological stages in the circadian cycle, the chloroplasts moved further away from the nucleus when exposed to light and moved closer to the nucleus when experiencing no light.
Okada, Masaaki; Muranaka, Tomoaki; Ito, Shogo; Oyama, Tokitaka
Individual cells in a plant can work independently as circadian clocks, and their properties are the basis of various circadian phenomena. The behaviour of individual cellular clocks in Lemna gibba was orderly under 24-h light/dark cycles despite their heterogeneous free-running periods (FRPs). Here, we reveal the entrainment habits of heterogeneous cellular clocks using non-24-h light/dark cycles (T-cycles). The cellular rhythms of AtCCA1::LUC under T = 16 h cycles showed heterogeneous entrainment that was associated with their heterogeneous FRPs. Under T = 12 h cycles, most cells showed rhythms having ~24-h periods. This suggested that the lower limit of entrainment to the light/dark cycles of heterogeneous cellular circadian clocks is set to a period longer than 12 h, which enables them to be synchronous under ~24-h daily cycles without being perturbed by short light/dark cycles. The entrainment habits of individual cellular clocks are likely to be the basis of the circadian behaviour of plant under the natural day-night cycle with noisy environmental fluctuations. We further suggest that modifications of EARLY FLOWERING3 (ELF3) in individual cells deviate the entrainability to shorter T-cycles possibly by altering both the FRPs and light responsiveness.
Chan, Webber; Lynch, Nicole; Bampton, Peter; Chang, Jeff; Chung, Alvin; Florin, Timothy; Hetzel, David J; Jakobovits, Simon; Moore, Gregory; Pavli, Paul; Radford-Smith, Graham; Thin, Lena; Baraty, Brandon; Haifer, Craig; Yau, Yunki; Leong, Rupert W L
Vedolizumab (VDZ), an α4β7 anti-integrin antibody, is efficacious in the induction and maintenance of remission in ulcerative colitis (UC) and Crohn's disease (CD). In the GEMINI long-term safety study, enrolled patients received 4-weekly VDZ. Upon completion, patients were switched to 8-weekly VDZ in Australia. The clinical success rate of treatment de-escalation for patients in remission on VDZ has not been described previously. To determine the proportion of patients who relapsed after switching from 4 to 8-weekly VDZ, the mean time to relapse, and the recapture rate when switching back to 8-weekly dosing. This was a retrospective, observational, multicenter study of patients previously recruited into GEMINI long-term safety in Australia. Data on the demographics and biochemical findings were collected. There were 34 patients [23 men, mean age 49.1 (±13.1) years] and their mean disease duration was 17.6 (±8.5) years. The mean 4-weekly VDZ infusion duration was 286.5 (±48.8) weeks. A total of five (15%) patients relapsed on dose-interval increase (4/17 UC, 1/17 CD) at a median duration from dose interval lengthening to flare of 14 weeks (interquartile range=6-25). Eighty percent (4/5) of patients re-entered remission following dose-interval decrease back to 4-weekly. No clinical predictors of relapse could be determined because of the small cohort size. The risk of patients relapsing when switching from 4 to 8-weekly VDZ ∼15% and is similar between CD and UC. Dose-interval decrease recaptures 80% of patients who relapsed. Therapeutic drug monitoring of VDZ may be of clinical relevance.
Researchers have provided evidence for a link between obesity and altered circadian rhythms (e.g., shift work, disrupted sleep), but the mechanism for this association is still unknown. Adipocytes possess an intrinsic circadian clock, and circadian rhythms in adipocytokines and adipose tissue metab...
Lucassen, Eliane Alinda
In modern society, circadian rhythms and sleep are often disturbed, which may negatively affect health. This thesis examines these associations and focuses on the basic functioning of sleep and the circadian system in mice and in humans. Circadian rhythms are orchestrated by ~20,000 neurons in the
Nigel I Wood
Full Text Available The R6/2 transgenic mouse model of Huntington's disease (HD shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks. R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.
Fenske, Myles P; Nguyen, LeAnn P; Horn, Erin K; Riffell, Jeffrey A; Imaizumi, Takato
Most plant-pollinator interactions occur during specific periods during the day. To facilitate these interactions, many flowers are known to display their attractive qualities, such as scent emission and petal opening, in a daily rhythmic fashion. However, less is known about how the internal timing mechanisms (the circadian clocks) of plants and animals influence their daily interactions. We examine the role of the circadian clock in modulating the interaction between Petunia and one of its pollinators, the hawkmoth Manduca sexta. We find that desynchronization of the Petunia circadian clock affects moth visitation preference for Petunia flowers. Similarly, moths with circadian time aligned to plants show stronger flower-foraging activities than moths that lack this alignment. Moth locomotor activity is circadian clock-regulated, although it is also strongly repressed by light. Moths show a time-dependent burst increase in flight activity during subjective night. In addition, moth antennal responsiveness to the floral scent compounds exhibits a 24-hour rhythm in both continuous light and dark conditions. This study highlights the importance of the circadian clocks in both plants and animals as a crucial factor in initiating specialized plant-pollinator relationships.
Cordes, Sara; Gallistel, C R
While progress has been made in determining the molecular basis for the circadian clock, the mechanism by which mammalian brains time intervals measured in seconds to minutes remains a mystery. An obvious question is whether the interval-timing mechanism shares molecular machinery with the circadian timing mechanism. In the current study, we trained circadian CLOCK +/- and -/- mutant male mice in a peak-interval procedure with 10 and 20-s criteria. The mutant mice were more active than their wild-type littermates, but there were no reliable deficits in the accuracy or precision of their timing as compared with wild-type littermates. This suggests that expression of the CLOCK protein is not necessary for normal interval timing.
Shirasu, Naoto; Shimohigashi, Yasuyuki; Tominaga, Yoshiya; Shimohigashi, Miki
During the last five years, enormous progress has been made in understanding the molecular basis of circadian systems, mainly by molecular genetic studies using the mouse and fly. Extensive evidence has revealed that the core clock machinery involves "clock genes" and "clock proteins" functioning as molecular cogs. These participate in transcriptional/translational feedback loops and many homologous clock-components in the fruit fly Drosophila are also expressed in mammalian clock tissues with circadian rhythms. Thus, the mechanisms of the central clock seem to be conserved across animal kingdom. However, some recent studies imply that the present widely accepted molecular models of circadian clocks may not always be supported by the experimental evidence.
Full Text Available Life on earth has adapted to the day-night cycle by evolution of internal, so-called circadian clocks that adjust behavior and physiology to the recurring changes in environmental conditions. In mammals, a master pacemaker located in the suprachiasmatic nucleus (SCN of the hypothalamus receives environmental light information and synchronizes peripheral tissues and central non-SCN clocks to geophysical time. Regulatory systems such as the hypothalamus-pituitary-adrenal (HPA axis and the autonomic nervous system (ANS, both being important for the regulation of stress responses, receive strong circadian input. In this review, we summarize the interaction of circadian and stress systems and the resulting physiological and pathophysiological consequences. Finally, we critically discuss the relevance of rodent stress studies for humans, addressing complications of translational approaches and offering strategies to optimize animal studies from a chronobiological perspective.
Kloehn, Ian; Pillai, Savin B; Officer, Laurel; Klement, Claire; Gasser, Paul J; Evans, Jennifer A
Sex differences in glucocorticoid production are associated with increased responsiveness of the adrenal gland in females. However, the adrenal-intrinsic mechanisms that establish sexual dimorphic function remain ill defined. Glucocorticoid production is gated at the molecular level by the circadian clock, which may contribute to sexual dimorphic adrenal function. Here we examine sex differences in the adrenal gland using an optical reporter of circadian clock function. Adrenal glands were cultured from male and female Period2::Luciferase (PER2::LUC) mice to assess clock function in vitro in real time. We confirm that there is a pronounced sex difference in the intrinsic capacity to sustain PER2::LUC rhythms in vitro, with higher amplitude rhythms in adrenal glands collected from males than from females. Changes in adrenal PER2::LUC rhythms over the reproductive life span implicate T as an important factor in driving sex differences in adrenal clock function. By directly manipulating hormone levels in adult mice in vivo, we demonstrate that T increases the amplitude of PER2::LUC rhythms in adrenal glands of both male and female mice. In contrast, we find little evidence that ovarian hormones modify adrenal clock function. Lastly, we find that T in vitro can increase the amplitude of PER2::LUC rhythms in male adrenals but not female adrenals, which suggests the existence of sex differences in the mechanisms of T action in vivo. Collectively these results reveal that activational effects of T alter circadian timekeeping in the adrenal gland, which may have implications for sex differences in stress reactivity and stress-related disorders.
Sellix, Michael T; Murphy, Zachary C; Menaker, Michael
Circadian clocks have been described in each tissue of the hypothalamo-pituitary-ovarian axis. Although a role for the clock in the timing of ovulation is indicated, the impact of diseases that disrupt fertility on clock function or the clocks' role in the etiology of these pathologies has yet to be fully appreciated. Polycystic ovary syndrome (PCOS) is a particularly devastating endocrinopathy, affecting approximately 10% of women at childbearing age. Common features of PCOS are a polycystic ovary, amenorrhea, and excess serum androgen. Approximately 40% of these women have metabolic syndrome, including hyperinsulinemia, dyslipidemia, and hyperleptinemia. It has been suggested that excess androgen is a critical factor in the etiology of PCOS. We have examined the effects of androgen excess during puberty on the phase of circadian clocks in tissues of the metabolic and hypothalamo-pituitary-ovarian axes. Female period1-luciferase (per1-luc) rats were exposed to androgen (5α-dihydrotestosterone [DHT]) or placebo for 4-6 weeks (short term) or 9-15 weeks (long term). As expected, DHT-treated animals gained more weight than controls and had disrupted estrous cycles. At the end of treatment, tissues, including the liver, lung, kidney, white adipose, cornea, pituitary, oviduct, and ovarian follicles, were cultured, and per1-luc expression in each was recorded. Analysis of per1-luc expression revealed that DHT exposure increased phase distribution of multiple oscillators, including ovarian follicles, liver, and adipose, and altered phase synchrony between animals. These data suggest that excess androgen during puberty, a common feature of PCOS, negatively affects internal circadian organization in both the reproductive and metabolic axes.
Full Text Available From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH in comparison to those of healthy controls (HC. Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG and Multiple Sleep Latency Test (MSLT. Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.
Lippert, Julian; Halfter, Hartmut; Heidbreder, Anna; Röhr, Dominik; Gess, Burkhard; Boentert, Mathias; Osada, Nani; Young, Peter
From single cell organisms to the most complex life forms, the 24-hour circadian rhythm is important for numerous aspects of physiology and behavior such as daily periodic fluctuations in body temperature and sleep-wake cycles. Influenced by environmental cues - mainly by light input -, the central pacemaker in the thalamic suprachiasmatic nuclei (SCN) controls and regulates the internal clock mechanisms which are present in peripheral tissues. In order to correlate modifications in the molecular mechanisms of circadian rhythm with the pathophysiology of idiopathic hypersomnia, this study aimed to investigate the dynamics of the expression of circadian clock genes in dermal fibroblasts of idiopathic hypersomniacs (IH) in comparison to those of healthy controls (HC). Ten clinically and polysomnographically proven IH patients were recruited from the department of sleep medicine of the University Hospital of Muenster. Clinical diagnosis was done by two consecutive polysomnographies (PSG) and Multiple Sleep Latency Test (MSLT). Fourteen clinical healthy volunteers served as control group. Dermal fibroblasts were obtained via punch biopsy and grown in cell culture. The expression of circadian clock genes was investigated by semiquantitative Reverse Transcriptase-PCR qRT-PCR analysis, confirming periodical oscillation of expression of the core circadian clock genes BMAL1, PER1/2 and CRY1/2. The amplitude of the rhythmically expressed BMAL1, PER1 and PER2 was significantly dampened in dermal fibroblasts of IH compared to HC over two circadian periods whereas the overall expression of only the key transcriptional factor BMAL1 was significantly reduced in IH. Our study suggests for the first time an aberrant dynamics in the circadian clock in IH. These findings may serve to better understand some clinical features of the pathophysiology in sleep - wake rhythms in IH.
Boumans, Iris J M M; de Boer, Imke J M; Hofstede, Gert Jan; la Fleur, Susanne E; Bokkers, Eddie A M
The interaction between hormonal circadian rhythms and feeding behaviour is not well understood. This study aimed to deepen our understanding of mechanisms underlying circadian feeding behaviour in animals, using pigs, Sus scrofa, as a case study. Pigs show an alternans feeding pattern, that is, a small peak of feed intake at the beginning of the day and a larger peak at the end of the day. We simulated the feeding behaviour of pigs over a 24h period. The simulation model contained mechanisms that regulate feeding behaviour of animals, including: processing of feed in the gastrointestinal tract, fluctuation in energy balance, circadian rhythms of melatonin and cortisol and motivational decision-making. From the interactions between these various processes, feeding patterns (e.g. feed intake, meal frequency, feeding rate) emerge. These feeding patterns, as well as patterns for the underlying mechanisms (e.g. energy expenditure), fitted empirical data well, indicating that our model contains relevant mechanisms. The circadian rhythms of cortisol and melatonin explained the alternans pattern of feeding in pigs. Additionally, the timing and amplitude of cortisol peaks affected the diurnal and nocturnal peaks in feed intake. Furthermore, our results suggest that circadian rhythms of other hormones, such as leptin and ghrelin, are less important in circadian regulation of feeding behaviour than previously thought. These results are relevant to animal species with a metabolic and endocrine system similar to that of pigs, such as humans. Moreover, the modelling approach to understand feeding behaviour can be applied to other animal species. Copyright © 2017 Elsevier Inc. All rights reserved.
Full Text Available Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods. Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.
Kuula, Liisa; Pesonen, Anu-Katriina; Heinonen, Kati; Kajantie, Eero; Eriksson, Johan Gunnar; Andersson, Sture; Lano, Aulikki; Lahti, Jari; Wolke, Dieter; Räikkönen, Katri
Experimental sleep deprivation studies suggest that insufficient sleep and circadian misalignment associates with poorer executive function. It is not known whether this association translates to naturally occurring sleep patterns. A total of 512 of full-term-born members of the Arvo Ylppö Longitudinal Study [mean age = 25.3, standard deviation (SD) = 0.65] (44.3% men) wore actigraphs to define sleep duration, its irregularity and circadian rhythm (sleep mid-point) during a 1-week period (mean 6.9 nights, SD = 1.7). Performance-based executive function was assessed with the Trail-Making Test, Conners' Continuous Performance Test and Stroop. The self-rated adult version of Behavior Rating Inventory of Executive Function was used to assess trait-like executive function. We found that performance-based and self-reported trait-like executive function correlated only modestly (all correlations ≤0.17). Shorter sleep duration associated with more commission errors. Later circadian rhythm associated with poorer trait-like executive function, as indicated by the Brief Metacognitive Index and the Behavior Regulation Index. Those belonging to the group with the most irregular sleep duration performed slower than others in the Trail-Making Test Part A. All associations were adjusted for sex, age, socioeconomic status and body mass index. In conclusion, naturally occurring insufficient sleep and later circadian rhythm showed modest associations with poorer executive function. Shorter habitual sleep duration was associated with lower scores of performance-based tests of executive function, and later circadian rhythm was associated mainly with poorer trait-like executive function characteristics. Our findings suggest additionally that sleep duration and circadian rhythm associate with different domains of executive function, and there are no additive effects between the two. © 2017 European Sleep Research Society.
Full Text Available The fan activity rhythm of Sabella spallanzanii (Gmelin, 1791 and its entrainment capability to light were studied. Animals were tested under constant darkness (DD followed by two consecutive 24 h light-darkness regimes: a first 11 h light period (LD and a second 9 h light period, with its phase inverted (DL. An infrared analogical video-camera took shots each 30 s. A number of pictures with open fan were counted every 15 min. In DD a weak free-running periodicity in the circadian range was found, thus reinforcing the matching of the 24 h period under study in both photoperiod regimes. A nocturnal activity was characterised with a consistent anticipation to lightOFF (i.e. entrainment. Moreover, this phase of entrainment differed between DL and LD. The presence of endogenous activity rhythm with a variable phase angle of entrainment is a distinctive feature of circadian pacemakers.
Märtson, Aare; Haviko, Tiit; Kirjanen, Kaur
A case of extensive lower limb lengthening (32 cm) in a 14-year-old male patient with Ollier's disease is reported. A varus deformity of the femur and a valgus deformity of the tibia were evident. The femur was successfully lengthened 22 cm by metaphyseal distraction, and the tibia was lengthened 10 cm by two-stage distraction-compression method with a cylindrical bone allograft. Ilizarov's distraction device was used. Radiologically, a good bone regenerate was formed. Host bone has incorporated (like sarcophagi) the allograft of tibia. No evidence of vascular or neural disturbances was found. The lengthening indices were counted for femur 22.5 days per centimeter and for tibia 21 days per centimeter, altogether 15.5 days per centimeter. Bone lengthening was performed through the Ollier's disease foci. Fine needle biopsy investigation showed that most embryonic cartilage cells had been replaced with bone tissue. After five years and a 25-year follow-up the patient was satisfied with the result. The function of the knee joint was limited, but the limb was fully weight-bearing. Signs of knee osteoarthritis were found.
Harmon Frank G
Full Text Available Abstract Background The plant circadian clock orchestrates 24-hour rhythms in internal physiological processes to coordinate these activities with daily and seasonal changes in the environment. The circadian clock has a profound impact on many aspects of plant growth and development, including biomass accumulation and flowering time. Despite recent advances in understanding the circadian system of the model plant Arabidopsis thaliana, the contribution of the circadian oscillator to important agronomic traits in Zea mays and other cereals remains poorly defined. To address this deficit, this study investigated the transcriptional landscape of the maize circadian system. Results Since transcriptional regulation is a fundamental aspect of circadian systems, genes exhibiting circadian expression were identified in the sequenced maize inbred B73. Of the over 13,000 transcripts examined, approximately 10 percent displayed circadian expression patterns. The majority of cycling genes had peak expression at subjective dawn and dusk, similar to other plant circadian systems. The maize circadian clock organized co-regulation of genes participating in fundamental physiological processes, including photosynthesis, carbohydrate metabolism, cell wall biogenesis, and phytohormone biosynthesis pathways. Conclusions Circadian regulation of the maize genome was widespread and key genes in several major metabolic pathways had circadian expression waveforms. The maize circadian clock coordinated transcription to be coincident with oncoming day or night, which was consistent with the circadian oscillator acting to prepare the plant for these major recurring environmental changes. These findings highlighted the multiple processes in maize plants under circadian regulation and, as a result, provided insight into the important contribution this regulatory system makes to agronomic traits in maize and potentially other C4 plant species.
Rath, Martin Fredensborg; Rohde, Kristian; Fahrenkrug, Jan
in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene...... expression in the neocortex is dependent on the SCN. In situ hybridization and immunohistochemistry showed that products of the canonical clock gene Per2 are located in perikarya throughout all areas of the neocortex. These findings show that local circadian oscillators driven by the SCN reside within...... neurons of the neocortex....
Duback, Victoria E; Sabrina Pankey, M; Thomas, Rachel I; Huyck, Taylor L; Mbarani, Izhar M; Bernier, Kyle R; Cook, Geoffrey M; O'Dowd, Colleen A; Newcomb, James M; Watson, Winsor H
The nudibranch, Melibe leonina, expresses a circadian rhythm of locomotion, and we recently determined the sequences of multiple circadian clock transcripts that may play a role in controlling these daily patterns of behavior. In this study, we used these genomic data to help us: 1) identify putative clock neurons using fluorescent in situ hybridization (FISH); and 2) determine if there is a daily rhythm of expression of clock transcripts in the M. leonina brain, using quantitative PCR. FISH indicated the presence of the clock-related transcripts clock, period, and photoreceptive and non-photoreceptive cryptochrome (pcry and npcry, respectively) in two bilateral neurons in each cerebropleural ganglion and a group of <10 neurons in the anterolateral region of each pedal ganglion. Double-label experiments confirmed colocalization of all four clock transcripts with each other. Quantitative PCR demonstrated that the genes clock, period, pcry and npcry exhibited significant differences in expression levels over 24 h. These data suggest that the putative circadian clock network in M. leonina consists of a small number of identifiable neurons that express circadian genes with a daily rhythm. Copyright © 2018 Elsevier Inc. All rights reserved.
Chagoya de Sánchez, V
The present review describes the biological implications of the periodic changes of adenosine concentrations in different tissues of the rat. Adenosine is a purine molecule that could have been formed in the prebiotic chemical evolution and has been preserved. The rhythmicity of this molecule, as well as its metabolism and even the presence of specific receptors, suggests a regulatory role in eukaryotic cells and in multicellular organisms. Adenosine may be considered a chemical messenger and its action could take place at the level of the same cell (autocrine), the same tissue (paracrine), or on separate organs (endocrine). Exploration of the circadian variations of adenosine was planned considering the liver as an important tissue for purine formation, the blood as a vehicle among tissues, and the brain as the possible acceptor for hepatic adenosine or its metabolites. The rats used in these studies were adapted to a dark-light cycle of 12 h with an unrestrained feeding and drinking schedule. The metabolic control of adenosine concentration in the different tissues studied through the 24-h cycle is related to the activity of adenosine-metabolizing enzyme: 5'-nucleotidase adenosine deaminase, adenosine kinase, and S-adenosylhomocysteine hydrolase. Some possibilities of the factors modulating the activity of these enzymes are commented upon. The multiphysiological action of adenosine could be mediated by several actions: (i) by interaction with extracellular and intracellular receptors and (ii) through its metabolism modulating the methylation pathway, possibly inducing physiological lipoperoxidation, or participating in the energetic homeostasis of the cell. The physiological meaning of the circadian variations of adenosine and its metabolism was focused on: maintenance of the energetic homeostasis of the tissues, modulation of membrane structure and function, regulation of fasting and feeding metabolic pattern, and its participation in the sleep-wake cycle. From
Bering, Tenna; Carstensen, Mikkel Bloss; Wörtwein, Gitta
for normal function of the cortical circadian oscillator. Daily rhythms in running activity and temperature were not influenced, whereas the resynchronization response to experimental jet-lag exhibited minor though significant differences between genotypes. The tail-suspension test revealed significantly...... prolonged immobility periods in the knockout mouse indicative of a depressive-like behavioral state. This phenotype was accompanied by reduced norepinephrine levels in the cerebral cortex. Our data show that Arntl is required for normal cortical clock function and further give reason to suspect...... that the circadian oscillator of the cerebral cortex is involved in regulating both circadian biology and mood-related behavior and biochemistry....
Full Text Available Ningbo Zhao,* Hong Tang,* Kai Yang, Dan Chen Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China*These authors contributed equally to this workBackground: Recent studies show that circadian rhythm changes are closely related to the occurrence and development of various tumors, such as breast, liver, and prostate. However, there are significant differences in circadian rhythm between different tumors. At present, the circadian rhythm characteristics of oral cancer remain unknown. The purpose of this study is to investigate the circadian rhythm characteristics of the in vivo growth of oral squamous cell carcinoma (OSCC.Materials and methods: Thirty-two nude mice were placed under 12-hour light/12-hour dark cycles. The human OSCC cell line BcaCD885 was inoculated in the cheek of nude mice. After 3 weeks, eight mice were sacrificed at four time points, including 4 hours after light onset (HALO, 10 HALO, 16 HALO, and 22 HALO, during a period of 24 hours. The volume of excised tumors was measured and the proliferative index (PI and apoptotic index (AI of tumor cells were determined by flow cytometry. A cosine analysis method was used to determine whether the tumor volume, PI, and AI obeyed a circadian rhythm.Results: There was a significant circadian rhythm in the tumor volume and PI of OSCC cells. For the tumor volume, there were significant differences between the four time points. The peak and trough values of the tumor volume appeared at 3.23 HALO and 15.23 HALO, whereas the peak and trough values of PI appeared at 6.60 HALO and 18.16 HALO, respectively. However, there was no circadian rhythm in the AI of tumor cells, despite significant differences between the four time points.Conclusion: This study demonstrates, for the first time, that the tumor volume and PI of in vivo growing OSCC undergo circadian rhythms. These results support the assertion that time factor should be
Full Text Available Abstract Background Fluorescent and bioluminescent time-lapse microscopy approaches have been successfully used to investigate molecular mechanisms underlying the mammalian circadian oscillator at the single cell level. However, most of the available software and common methods based on intensity-threshold segmentation and frame-to-frame tracking are not applicable in these experiments. This is due to cell movement and dramatic changes in the fluorescent/bioluminescent reporter protein during the circadian cycle, with the lowest expression level very close to the background intensity. At present, the standard approach to analyze data sets obtained from time lapse microscopy is either manual tracking or application of generic image-processing software/dedicated tracking software. To our knowledge, these existing software solutions for manual and automatic tracking have strong limitations in tracking individual cells if their plane shifts. Results In an attempt to improve existing methodology of time-lapse tracking of a large number of moving cells, we have developed a semi-automatic software package. It extracts the trajectory of the cells by tracking theirs displacements, makes the delineation of cell nucleus or whole cell, and finally yields measurements of various features, like reporter protein expression level or cell displacement. As an example, we present here single cell circadian pattern and motility analysis of NIH3T3 mouse fibroblasts expressing a fluorescent circadian reporter protein. Using Circadian Gene Express plugin, we performed fast and nonbiased analysis of large fluorescent time lapse microscopy datasets. Conclusions Our software solution, Circadian Gene Express (CGE, is easy to use and allows precise and semi-automatic tracking of moving cells over longer period of time. In spite of significant circadian variations in protein expression with extremely low expression levels at the valley phase, CGE allows accurate and
Sage, Daniel; Unser, Michael; Salmon, Patrick; Dibner, Charna
Fluorescent and bioluminescent time-lapse microscopy approaches have been successfully used to investigate molecular mechanisms underlying the mammalian circadian oscillator at the single cell level. However, most of the available software and common methods based on intensity-threshold segmentation and frame-to-frame tracking are not applicable in these experiments. This is due to cell movement and dramatic changes in the fluorescent/bioluminescent reporter protein during the circadian cycle, with the lowest expression level very close to the background intensity. At present, the standard approach to analyze data sets obtained from time lapse microscopy is either manual tracking or application of generic image-processing software/dedicated tracking software. To our knowledge, these existing software solutions for manual and automatic tracking have strong limitations in tracking individual cells if their plane shifts. In an attempt to improve existing methodology of time-lapse tracking of a large number of moving cells, we have developed a semi-automatic software package. It extracts the trajectory of the cells by tracking theirs displacements, makes the delineation of cell nucleus or whole cell, and finally yields measurements of various features, like reporter protein expression level or cell displacement. As an example, we present here single cell circadian pattern and motility analysis of NIH3T3 mouse fibroblasts expressing a fluorescent circadian reporter protein. Using Circadian Gene Express plugin, we performed fast and nonbiased analysis of large fluorescent time lapse microscopy datasets. Our software solution, Circadian Gene Express (CGE), is easy to use and allows precise and semi-automatic tracking of moving cells over longer period of time. In spite of significant circadian variations in protein expression with extremely low expression levels at the valley phase, CGE allows accurate and efficient recording of large number of cell parameters, including
Roberts, W. E.; Mozsary, P. G.; Klingler, E.
The differential of osteoblasts in response to orthodontic pressure in the periodontal ligament of the maxillary-first-molar periodontal ligaments of 12-h-light/dark-entrained 7-wk-old male Simonsen outbred rats is measured by (H-3)-Thymidine nuclear-volume morphometry (Roberts et al., 1983) at hourly intervals throughout the circadian cycle. The results are presented in graphs and discussed. Preosteoblast large nuclei (D-cells) are found to synthesize DNA mainly in light and to divide in the following dark period, while small-nucleus osteoprogenitors (A-cells) synthesize in darkness and divide in light. These findings are seen as consistent with a model in which the sequence of proliferation and differentiation requires at least 60 h (five 12-h periods) and the shift from A to D cells lasts about 19 h.
D'Eysmond, Thomas; De Simone, Alessandro; Naef, Felix
Biochemical reaction networks often exhibit spontaneous self-sustained oscillations. An example is the circadian oscillator that lies at the heart of daily rhythms in behavior and physiology in most organisms including humans. While the period of these oscillators evolved so that it resonates with the 24 h daily environmental cycles, the precision of the oscillator (quantified via the Q factor) is another relevant property of these cell-autonomous oscillators. Since this quantity can be measured in individual cells, it is of interest to better understand how this property behaves across mathematical models of these oscillators. Current theoretical schemes for computing the Q factors show limitations for both high-dimensional models and in the vicinity of Hopf bifurcations. Here, we derive low-noise approximations that lead to numerically stable schemes also in high-dimensional models. In addition, we generalize normal form reductions that are appropriate near Hopf bifurcations. Applying our approximations to two models of circadian clocks, we show that while the low-noise regime is faithfully recapitulated, increasing the level of noise leads to species-dependent precision. We emphasize that subcomponents of the oscillator gradually decouple from the core oscillator as noise increases, which allows us to identify the subnetworks responsible for robust rhythms. (paper)
Flannery, J.G.; Fisher, S.K.
To further examine the endogenous rhythm of disc shedding and phagocytosis observed in several species, adult Xenopus were entrained to a 12 hr light/12 hr dark cycle and then placed in constant darkness. At various times during a 3-day period of constant darkness, eyes were explanted and placed into culture medium, then processed for light and electron microscopy. A clear rhythmicity of disc shedding was observed, with pronounced peaks at the times light onset occurred in the original entrainment cycle. Modification of the HCO 3 - ion concentration in the medium was found to raise the amplitude of the peak of endogenous disc shedding. Explants maintained in culture medium containing deuterium oxide (a compound known to perturb circadian oscillators) were found to shed with a longer interval between peaks. The addition of the protein synthesis inhibitor, anisomycin, to this preparation suppressed the shedding rhythm. The action of anisomycin was investigated by autoradiographic examination of the pattern of 3 H-leucine uptake and protein synthesis by the explant. The findings suggest the presence of a circadian oscillator for rhythmic disc shedding within the amphibian eye
In this manuscript we review the combination of experimental methodologies, bioinformatics and theoretical models that have been essential to explore this remarkable timing-system. Such an integrative and interdisciplinary approach may provide new strategies with regard to chronotherapeutic treatment and new insights concerning the restoration of the circadian timing in clock-associated diseases.
Jasper, Isabelle; Gordijn, Marijke; Haeussler, Andreas; Hermsdoerfer, Joachim
The aim of the present study was to analyze the circadian rhythmicity in handwriting kinematics and legibility and to compare the performance between Dutch and German writers. Two subject groups underwent a 40 h sleep deprivation protocol under Constant Routine conditions either in Groningen (10
Full Text Available Introduction. The aim of the study was to examine the effect of circadian rhythm on dynamic balance performance and to determine the role of physical activity level, body temperature, chronotype, and gender in this possible effect. Material and
Jasper, Isabelle; Gordijn, Marijke; Häussler, Andreas; Hermsdörfer, Joachim
The aim of the present study was to analyze the circadian rhythmicity in handwriting kinematics and legibility and to compare the performance between Dutch and German writers. Two subject groups underwent a 40 h sleep deprivation protocol under Constant Routine conditions either in Groningen (10 Dutch subjects) or in Berlin (9 German subjects). Both groups wrote every 3h a test sentence of similar structure in their native language. Kinematic handwriting performance was assessed with a digitizing tablet and evaluated by writing speed, writing fluency, and script size. Writing speed (frequency of strokes and average velocity) revealed a clear circadian rhythm, with a parallel decline during night and a minimum around 3:00 h in the morning for both groups. Script size and movement fluency did not vary with time of day in neither group. Legibility of handwriting was evaluated by intra-individually ranking handwriting specimens of the 13 sessions by 10 German and 10 Dutch raters. Whereas legibility ratings of the German handwriting specimens deteriorated during night in parallel with slower writing speed, legibility of the Dutch handwriting deteriorated not until the next morning. In conclusion, the circadian rhythm of handwriting kinematics seems to be independent of script language at least among the two tested western countries. Moreover, handwriting legibility is also subject to a circadian rhythm which, however, seems to be influenced by variations in the assessment protocol. Copyright © 2010 Elsevier B.V. All rights reserved.
Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V
The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the
Gerhart-Hines, Zachary; Lazar, Mitchell A.
was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain const. ambient temp.; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes...
Koczewski, Paweł; Shadi, Milud; Napiontek, Marek; Dorman, T; Faflik, J; Grzegorzewski, A; Jasiewicz, B; Kacki, W; Kucharski, R; Niedzielski, K; Synder, M; Tesiorowski, M; Zarzycka, M; Zarek, S
26 patients (17 female, 9 male) from 5 centers were evaluated. The age at the beginning of treatment ranged from 6 to 29 years (mean 13.8). The cause of short stature in 19 patients was achondroplasia or pseudoachondroplasia, in next 2--other bone dysplasias. The other 5 patients had not bone pathology and were treated because of cosmetic indications. Preoperative body height ranged from 90 to 149 cm (mean 120). Axial deviations of the lower extremities were noted in 11 patients. Mean follow-up was 3.7 years. METHOD OF TREATMENT: Most of patients were treated with Ilizarov device using cross lengthening strategy (2 stages--opposite femur and tibia lengthening). Mean duration of treatment including interval between two stages (mean 12 months) was 29 months. Planned increase of body height ranged from 10 to 26 cm (mean 16.4). Planned or greater lengthening (mean 14.8 cm) was achieved in 14 patients. Partial planned lengthening (mean 65% of planned lengthening) was achieved in 8 patients (mean 11.8 cm) including two patients who resigned the second stage of treatment. In two patients lengthening was stopped during first month of treatment because of great complications. In 2 patients treatment was not completed (interval between first and second stage). Mean increase of body height of patients with complete treatment was 13.1 cm (from 2 to 28). Problems, obstacles and complications were analyzed according to Paley classification. There were 24 problems in 15 patient (inflammation process around K wires--15 patients, bone healing disturbances--3, regenerate fracture--2, transient foot equinus--2 and axial deviation of the lower extremity--1). There were 31 obstacles in 19 patients (regenerate's defect--7 patients, premature bone consolidation--6, foot equinus--4 and other--14). There were 26 complications in 18 patients (axial deviation of the lengthened segment--8, foot equinus--6, paresis of the peroneal nerve--3, fractures--2 and other--5). The most serious
Full Text Available Abstract Background Clinical symptoms of affective disorders, their response to light treatment, and sensitivity to other circadian interventions indicate that the circadian system has a role in mood disorders. Possibly the mechanisms involve circadian seasonal and photoperiodic mechanisms. Since genetic susceptibilities contribute a strong component to affective disorders, we explored whether circadian gene polymorphisms were associated with affective disorders in four complementary studies. Methods Four groups of subjects were recruited from several sources: 1 bipolar proband-parent trios or sib-pair-parent nuclear families, 2 unrelated bipolar participants who had completed the BALM morningness-eveningness questionnaire, 3 sib pairs from the GenRed Project having at least one sib with early-onset recurrent unipolar depression, and 4 a sleep clinic patient group who frequently suffered from depression. Working mainly with the SNPlex assay system, from 2 to 198 polymorphisms in genes related to circadian function were genotyped in the participant groups. Associations with affective disorders were examined with TDT statistics for within-family comparisons. Quantitative trait associations were examined within the unrelated samples. Results In NR1D1, rs2314339 was associated with bipolar disorder (P = 0.0005. Among the unrelated bipolar participants, 3 SNPs in PER3 and CSNK1E were associated with the BALM score. A PPARGC1B coding SNP, rs7732671, was associated with affective disorder with nominal significance in bipolar family groups and independently in unipolar sib pairs. In TEF, rs738499 was associated with unipolar depression; in a replication study, rs738499 was also associated with the QIDS-SR depression scale in the sleep clinic patient sample. Conclusion Along with anti-manic effects of lithium and the antidepressant effects of bright light, these findings suggest that perturbations of the circadian gene network at several levels may
of ischemia, 312 (76%) of which were silent; a circadian rhythm was noted for the occurrence of total and silent ischemia. Thirty-eight percent of the ischemic episodes occurred between 6 AM and 12 noon, and total and silent ischemia were significantly more frequent during this period compared with the other......The circadian variation of total ischemic activity was examined during 3289 hours of ambulatory ECG monitoring in 101 patients with stable angina pectoris and proved coronary artery disease, who were not receiving any prophylactic antianginal therapy. The 101 patients displayed 411 episodes...... three 6-hour periods (p less than 0.01); a lesser peak was noted in the evening. The effects of metoprolol and combined therapy with metoprolol and nifedipine on the circadian variation of ischemic activity were studied in two subgroups of patients in a random, double-blind study design (31 patients...
Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V
The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the field's pioneers, and the astonishing finding that circadian rhythms continue a self-sustained oscillation in constant conditions has become central to our understanding of entrainment.Here, we argue that we have to rethink these initial circadian dogmas to fully understand the circadian programme and how it entrains. Light is also the prominent zeitgeber for the human clock, as has been shown experimentally in the laboratory and in large-scale epidemiological studies in real life, and we hypothesise that social zeitgebers act through light entrainment via behavioural feedback loops (zeitnehmer). We show that human entrainment can be investigated in detail outside of the laboratory, by using the many 'experimental' conditions provided by the real world, such as daylight savings time, the 'forced synchrony' imposed by the introduction of time zones, or the fact that humans increasingly create their own light environment. The conditions of human entrainment have changed drastically over the past 100 years and have led to an increasing discrepancy between biological and social time (social jetlag). The increasing evidence that social jetlag has detrimental consequences for health suggests that shift-work is only an extreme form of circadian misalignment, and that the majority of the population in the industrialised world suffers from a similarly 'forced synchrony'.
Krishnan, Natraj; Rakshit, Kuntol; Chow, Eileen S; Wentzell, Jill S; Kretzschmar, Doris; Giebultowicz, Jadwiga M
Circadian clocks generate rhythms in molecular, cellular, physiological, and behavioral processes. Recent studies suggest that disruption of the clock mechanism accelerates organismal senescence and age-related pathologies in mammals. Impaired circadian rhythms are observed in many neurological diseases; however, it is not clear whether loss of rhythms is the cause or result of neurodegeneration, or both. To address this important question, we examined the effects of circadian disruption in Drosophila melanogaster mutants that display clock-unrelated neurodegenerative phenotypes. We combined a null mutation in the clock gene period (per(01)) that abolishes circadian rhythms, with a hypomorphic mutation in the carbonyl reductase gene sniffer (sni(1)), which displays oxidative stress induced neurodegeneration. We report that disruption of circadian rhythms in sni(1) mutants significantly reduces their lifespan compared to single mutants. Shortened lifespan in double mutants was coupled with accelerated neuronal degeneration evidenced by vacuolization in the adult brain. In addition, per(01)sni(1) flies showed drastically impaired vertical mobility and increased accumulation of carbonylated proteins compared to age-matched single mutant flies. Loss of per function does not affect sni mRNA expression, suggesting that these genes act via independent pathways producing additive effects. Finally, we show that per(01) mutation accelerates the onset of brain pathologies when combined with neurodegeneration-prone mutation in another gene, swiss cheese (sws(1)), which does not operate through the oxidative stress pathway. Taken together, our data suggest that the period gene may be causally involved in neuroprotective pathways in aging Drosophila. Copyright © 2011 Elsevier Inc. All rights reserved.
Full Text Available Diapause is an adaptive response triggered by seasonal photoperiodicity to overcome unfavorable seasons. The photoperiodic clock is a system that controls seasonal physiological processes, but our knowledge about its physiological mechanisms and genetic architecture remains incomplete. The circadian clock is another system that controls daily rhythmic physiological phenomena. It has been argued that there is a connection between the two clocks. To examine the genetic connection between them, we analyzed the associations of five circadian clock genes (period, timeless, Clock, cycle and cryptochrome with the occurrence of diapause in Drosophila triauraria, which shows a robust reproductive diapause with clear photoperiodicity. Non-diapause strains found in low latitudes were compared in genetic crosses with the diapause strain, in which the diapause trait is clearly dominant. Single nucleotide polymorphism and deletion analyses of the five circadian clock genes in backcross progeny revealed that allelic differences in timeless and cryptochrome between the strains were additively associated with the differences in the incidence of diapause. This suggests that there is a molecular link between certain circadian clock genes and the occurrence of diapause.
Reiter, Russel J; Tan, Dun Xian; Korkmaz, Ahmet; Rosales-Corral, Sergio A
circadian clock, either directly or indirectly via the melatonin rhythm, programs the developing master oscillator of the fetus. Experimental studies have shown that disturbed maternal circadian rhythms, referred to as chronodisruption, and perturbed melatonin cycles have negative consequences for the maturing fetal oscillators, which may lead to psychological and behavioral problems in the newborn. To optimize regular circadian rhythms and prevent disturbances of the melatonin cycle during pregnancy, shift work and bright light exposure at night should be avoided, especially during the last trimester of pregnancy. Finally, melatonin synergizes with oxytocin to promote delivery of the fetus. Since blood melatonin levels are normally highest during the dark period, the propensity of childbirth to occur at night may relate to the high levels of melatonin at this time which work in concert with oxytocin to enhance the strength of uterine contractions. A number of conclusions naturally evolve from the data summarized in this review: (i) melatonin, of both pineal and placental origin, has essential functions in fetal maturation and placenta/uterine homeostasis; (ii) circadian clock genes, which are components of all cells including those in the peripheral reproductive organs, have important roles in reproductive and organismal (fetal and maternal) physiology; (iii) due to the potent antioxidant actions of melatonin, coupled with its virtual absence of toxicity, this indoleamine may have utility in the treatment of pre-eclampsia, intrauterine growth restriction, placental and fetal ischemia/reperfusion, etc. (iv) the propensity for parturition to occur at night may relate to the synergism between the nocturnal increase in melatonin and oxytocin.
Kim, Jeongah; Jang, Sangwon; Choe, Han Kyoung; Chung, Sooyoung; Son, Gi Hoon; Kim, Kyungjin
Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-erbα induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.
Keith, Dove; Finlay, Liam; Butler, Judy; Gómez, Luis; Smith, Eric; Moreau, Régis; Hagen, Tory
Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks
Keith, Dove; Finlay, Liam; Butler, Judy [Linus Pauling Institute, Oregon State University (United States); Gómez, Luis; Smith, Eric [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States); Moreau, Régis [Linus Pauling Institute, Oregon State University (United States); Hagen, Tory [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States)
Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.
Ahmed Nageeb Mahmoud
Conclusion: Even though the classic complications of external lengthening are virtually diminished, alterations to the current design of the ISKD are needed to avoid the distraction- related complications. Risk of unplanned surgery could be minimized through proper patient selection and proper surgical techniques.
Bae, Yong-Chan; Choi, Soo-Jong; Lee, Jae-Woo; Seo, Hyoung-Joon
Operative techniques in performing cleft palate repair have gradually evolved to achieve better speech ability with its main focus on palatal lengthening and accurate approximation of the velar musculature. The authors doubted whether the extent of palatal lengthening would be directly proportional to the speech outcome. Patients with incomplete cleft palates who went into surgery before 18 months of age were intended for this study. Cases with associated syndromes, mental retardation, hearing loss, or presence of postoperative complications were excluded from the analysis. Palatal length was measured by the authors' devised method before and immediately after the cleft palate repair. Postoperative speech outcome was evaluated around 4 years by a definite pronunciation scoring system. Statistical analysis was carried out between the extent of palatal lengthening and the postoperative pronunciation score by Spearman correlation coefficient method. However, the authors could not find any significant correlation. Although the need for additional research on other variables affecting speech outcome is unequivocal, we carefully conclude that other intraoperative constituents such as accurate reapproximation of the velar musculature should be emphasized more in cleft palate repair rather than palatal lengthening itself.
Giannini, Sandro; Faldini, Cesare; Pagkrati, Stavroula; Miscione, Maria Teresa; Luciani, Deianira
Congenital brachymetatarsia, a shortened metatarsal bone, can be corrected surgically by callus distraction or one-stage lengthening using bone graft. We asked whether one-stage metatarsal lengthening using metatarsal homologous bone graft could improve forefoot function, lead to metatarsal healing, restore metatarsal parabola, and improve cosmetic appearance. We retrospectively reviewed 29 patients (41 feet) in whom we lengthened 50 metatarsals. Surgery consisted of a transverse proximal osteotomy of the metatarsal shaft and interposition of a metatarsal homologous bone graft (average, 13 mm long) fixed with an intramedullary Kirschner wire. Minimum followup was 3 years (mean, 5 years; range, 3-11 years). Bone union was achieved in all cases. The mean preoperative American Orthopaedic Foot and Ankle Society score was 37 points (range, 28-53 points) and the mean postoperative score was 88 points (range, 74-96 points), with an average improvement of 51 points. Radiographically, the mean gain in length was 13 mm (range, 10-15 mm), and the mean percentage increase was 23%. One-stage metatarsal lengthening using interposition of metatarsal homologous bone graft to correct congenital brachymetatarsia has low morbidity for the patient, limited complications, short recovery times, and restores forefoot anatomy. Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
Full Text Available Forest plantation may contribute economically and socially as a provider of wood raw materials for industry and providing jobs for local people. In addition, forest plantation may also contribute as watershed protection and carbon sequestration. Projects on carbon sequestration from plantation forest can be conducted in two types: (1 afforestation and (2 lengthening forest rotation. One of the potential carbon markets operationalized in the field is voluntary market with Verified Carbon Standard mechanism. This study aimed to analyze the optimal rotations of gmelina forests on two carbon projects: lengthening rotation and afforestation. The method used in this study was by using Hartman model ( i.e. Faustmann by maximizing profit with the revenue source from timber and carbon sequestration project. The results of this study showed that carbon price will affect the optimal rotation for lengthening forest rotation of VCS project. Meanwhile, for VCS afforestation project, carbon price had no effect on the optimal rotation on gmelina forest. The NPV value of afforestation project was relatively higher than that of NPV value of lengthening forest rotation project, since the amount of carbon that can be credited relatively higher in afforestation project.
Full Text Available Reconstructive surgery following an internal hemipelvectomy for a malignant pelvic tumor is difficult due to the structural complexity of the pelvis and the massive extension of the tumor. While high complication rates have been encountered in various types of reconstructive surgery, resection without reconstruction reportedly involved fewer complications. However, this method often results in limb shortening with resultant instability during walking. We reported herein leg lengthening performed to correct lower limb shortening after an internal hemipelvectomy, which improved ambulatory stability and overall QOL. An 18-year-old male patient came to our hospital to correct a lower limb discrepancy resulting from a left internal hemipelvectomy. His left pelvis and proximal femur had been resected, and the femur remained without an acetabular roof. His left lower limb was about 8 centimeters shorter. The left tibia was lengthened 8 centimeters with an external fixator. After the lengthening, the patient was able to walk without support and his gait remarkably improved. Additionally he no longer required placing a wallet in his back pocket as a pad as a means of raising the left side of his torso while sitting. Leg lengthening was a useful method of improving ambulation after an internal hemipelvectomy.
Villarreal, Seth A.; Pattanayek, Rekha; Williams, Dewight R.; Mori, Tetsuya; Qin, Ximing; Johnson, Carl H.; Egli, Martin; Stewart, Phoebe L. [Case Western; (Vanderbilt); (Vanderbilt-MED)
The circadian control of cellular processes in cyanobacteria is regulated by a posttranslational oscillator formed by three Kai proteins. During the oscillator cycle, KaiA serves to promote autophosphorylation of KaiC while KaiB counteracts this effect. Here, we present a crystallographic structure of the wild-type Synechococcus elongatus KaiB and a cryo-electron microscopy (cryoEM) structure of a KaiBC complex. The crystal structure shows the expected dimer core structure and significant conformational variations of the KaiB C-terminal region, which is functionally important in maintaining rhythmicity. The KaiBC sample was formed with a C-terminally truncated form of KaiC, KaiC-Δ489, which is persistently phosphorylated. The KaiB–KaiC-Δ489 structure reveals that the KaiC hexamer can bind six monomers of KaiB, which form a continuous ring of density in the KaiBC complex. We performed cryoEM-guided molecular dynamics flexible fitting simulations with crystal structures of KaiB and KaiC to probe the KaiBC protein–protein interface. This analysis indicated a favorable binding mode for the KaiB monomer on the CII end of KaiC, involving two adjacent KaiC subunits and spanning an ATP binding cleft. A KaiC mutation, R468C, which has been shown to affect the affinity of KaiB for KaiC and lengthen the period in a bioluminescence rhythm assay, is found within the middle of the predicted KaiBC interface. The proposed KaiB binding mode blocks access to the ATP binding cleft in the CII ring of KaiC, which provides insight into how KaiB might influence the phosphorylation status of KaiC.
Arendt, Josephine; Middleton, Benita
Living for extended periods in Antarctica exposes base personnel to extremes of daylength (photoperiod) and temperature. At the British Antarctic Survey base of Halley, 75°S, the sun does not rise for 110 d in the winter and does not set for 100 d in summer. Photoperiod is the major time cue governing the timing of seasonal events such as reproduction in many species. The neuroendocrine signal providing photoperiodic information to body physiology is the duration of melatonin secretion which reflects the length of the night: longer in the short days of winter and shorter in summer. Light of sufficient intensity and spectral composition serves to suppress production of melatonin and to set the circadian timing and the duration of the rhythm. In humans early observations suggested that bright (>2000 lux) white light was needed to suppress melatonin completely. Shortly thereafter winter depression (Seasonal Affective Disorder or SAD) was described, and its successful treatment by an artificial summer photoperiod of bright white light, sufficient to shorten melatonin production. At Halley dim artificial light intensity during winter was measured, until 2003, at a maximum of approximately 500 lux in winter. Thus a strong seasonal and circadian time cue was absent. It seemed likely that winter depression would be common in the extended period of winter darkness and could be treated with an artificial summer photoperiod. These observations, and predictions, inspired a long series of studies regarding human seasonal and circadian status, and the effects of light treatment, in a small overwintering, isolated community, living in the same conditions for many months at Halley. We found little evidence of SAD, or change in duration of melatonin production with season. However the timing of the melatonin rhythm itself, and/or that of its metabolite 6-sulphatoxymelatonin (aMT6s), was used as a primary marker of seasonal, circadian and treatment changes. A substantial phase
Devmurari, Kamlesh N.; Song, Hae Ryong; Modi, Hitesh N.; Venkatesh, K.P.; Ju, Kim Seung; Song, Sang Heon
We studied the callus features seen in cases of regenerate fracture in femoral lengthening using a monolateral fixator in achondroplasia to determine whether callus types and shapes can predict the probability of callus fracture. The radiographs of 28 cases of femoral lengthening in 14 patients, 14 cases of callus fracture, and 14 cases without callus fracture were retrospectively analyzed by four observers and classified into different shapes and types in concordance with the Ru Li classification. The average lengthening of 9.4 cm (range 7.5-11.8 cm) was achieved, which was 41% (range 30-55%) of the original length and the average timing of callus fracture was 470 days (range 440-545 days) after surgery in the callus fracture group. While the average lengthening of 9.1 cm (range 8-9.7 cm) was achieved, this was 30% (range 28-32%) of the original length in the group of patients without callus fracture. The callus was atypically shaped, there was a 48% average (range 30-72%) reduction of the callus width compared with the natural width of the femur, and a lucent pathway was present in all cases of regenerate fracture. A lucent pathway was seen in all fracture cases with concave, lateral, and atypical shapes, and there was more than 30% lengthening and 30% reduction of the callus width compared with the natural width of the femur, which are the warning signs for regenerate fractures. These signs help the surgeon to predict the outcome and guide him in planning for any additional interventions. The Ru Li classification is an effective method for the evaluation of the chance of callus fracture. (orig.)
Devmurari, Kamlesh N.; Song, Hae Ryong; Modi, Hitesh N.; Venkatesh, K.P.; Ju, Kim Seung; Song, Sang Heon [Korea University Medical College, Institute for Rare Diseases and Department of Orthopedic Surgery, Seoul (Korea)
We studied the callus features seen in cases of regenerate fracture in femoral lengthening using a monolateral fixator in achondroplasia to determine whether callus types and shapes can predict the probability of callus fracture. The radiographs of 28 cases of femoral lengthening in 14 patients, 14 cases of callus fracture, and 14 cases without callus fracture were retrospectively analyzed by four observers and classified into different shapes and types in concordance with the Ru Li classification. The average lengthening of 9.4 cm (range 7.5-11.8 cm) was achieved, which was 41% (range 30-55%) of the original length and the average timing of callus fracture was 470 days (range 440-545 days) after surgery in the callus fracture group. While the average lengthening of 9.1 cm (range 8-9.7 cm) was achieved, this was 30% (range 28-32%) of the original length in the group of patients without callus fracture. The callus was atypically shaped, there was a 48% average (range 30-72%) reduction of the callus width compared with the natural width of the femur, and a lucent pathway was present in all cases of regenerate fracture. A lucent pathway was seen in all fracture cases with concave, lateral, and atypical shapes, and there was more than 30% lengthening and 30% reduction of the callus width compared with the natural width of the femur, which are the warning signs for regenerate fractures. These signs help the surgeon to predict the outcome and guide him in planning for any additional interventions. The Ru Li classification is an effective method for the evaluation of the chance of callus fracture. (orig.)
Ruan, Hongjiang; Zhu, Yi; Liu, Shen; Kang, Qinglin
Several humeral lengthening or simultaneous deformity corrections through one osteotomy using various external fixators were reported, while literature regarding correction of shortening and proximal varus deformity is scarce. This retrospective clinical study evaluated the results of preforming an acute correction and delayed lengthening in young adults through two osteotomies using monorail external fixator. We report seven patients with various pathologies who underwent humeral proximal deformity correction and lengthening between 2009 and 2015. Pre-operative and post-operative clinical and radiographic data were collected. The mean follow-up time was 33.4 months (25-46 months). The humeral neck-shaft angle improved from 97.9° (85-110°) to 138.6° (135-145°). The magnitude of lengthening achieved was average 7.6 cm (range, 6-10 cm) at an average healing index of lengthening of 30.2 days/cm (range, 27.7-35.4 days/cm). There was a significant increase in range of shoulder abduction, and active abduction improved from pre-operative 136.4° (range, 95-160°) to post-operative 166.4° (range, 150-180°). The DASH score improved significance from 23.29 ± 8.36 to 6.57 ± 3.65 (t = 4.848; p monorail external fixator can be used for humeral shortening and proximal varus angular deformity. Functional improvement is expected after surgery and post-operative therapy.
Chalopin, A; Geffroy, L; Pesenti, S; Hamel, A; Launay, F
Childhood fibular hypoplasia is a rare pathology which may or may not involve limb-length discrepancy and axial deformity in one or more dimensions. The objective of the present study was to compare the quality of the axial correction achieved in lengthening procedures by hexapodal versus monorail external fixators. The hypothesis was that the hexapodal fixator provides more precise correction. A retrospective multicenter study included 52 children with fibular hypoplasia. Seventy-two tibias were analyzed, in 2 groups: 52 using a hexapodal fixator, and 20 using a monorail fixator. Mean age was 10.2 years. Mean lengthening was 5.7cm. Deformities were analyzed and measured in 3 dimensions and classified in 4 preoperative types and 4 post-lengthening types according to residual deformity. Complete correction was achieved in 26 tibias in the hexapodal group (50%) and 2 tibias in the monorail group (10%). Mean post-correction mechanical axis deviation was smaller in the hexapodal group: 12.83mm, versus 14.29mm in the monorail group. Mean post-correction mechanical lateral distal femoral angle was 87.5° in the hexapodal group, versus 84.3° in the monorail group (P=0.002), and mean mechanical medial proximal tibial angle 86.9° versus 89.5°, respectively (P=0.015). No previous studies focused on this congenital pathology in lengthening and axial correction programs for childhood lower-limb deformity. The present study found the hexapodal fixator to be more effective in conserving or restoring mechanical axes during progressive bone lengthening for fibular hypoplasia. The hexapodal fixator met the requirements of limb-length equalization in childhood congenital lower-limb hypoplasia, providing better axial correction than the monorail fixator. IV. Copyright © 2017 Elsevier Masson SAS. All rights reserved.
Orzechowski, Wiktor; Morasiewicz, Leszek; Krawczyk, Artur; Dragan, Szymon; Czapiński, Jacek
Background. Shortening and deformity of the forearm is most frequently caused by congenital disorders or posttraumatic injury. Given its complex anatomy and biomechanics, the forearm is clearly the most difficult segment for lengthening and deformity correction. Material and methods. We analyzed 16 patients with shortening and deformity of the forearm, treated surgically, using the Ilizarov method in our Department from 1989 to 2001. in 9 cases 1-stage surgery was sufficient, while the remaining 7 patients underwent 2-5 stages of treatment. At total of 31 surgical operations were performed. The extent of forearm shortening ranged from 1,5 to 14,5 cm (5-70%). We development a new fixator based on Schanz half-pins. Results. The length of forearm lengthening per operative stage averaged 2,35 cm. the proportion of lengthening ranged from 6% to 48% with an average of 18,3%. The mean lengthening index was 48,15 days/cm. the per-patient rate of complications was 88% compared 45% per stage of treatment, mostly limited rotational mobility and abnormal consolidation of regenerated bone. Conclusions. Despite the high complication rate, the Ilizarov method is the method of choice for patients with forearm shortenings and deformities. Treatment is particularly indicated in patients with shortening caused by disproportionate length of the ulnar and forearm bones. Treatment should be managed so as cause the least possible damage to arm function, even at the cost of limited lengthening. Our new stabilizer based on Schanz half-pins makes it possible to preserve forearm rotation.
This study aims at examining and accounting for the scope of the temporal effect of phrase boundaries. Previous research has indicated that there is an interaction between boundary-related lengthening and prominence such that the former extends towards the nearby prominent syllable. However, it is unclear whether this interaction is due to lexical stress and/or phrasal prominence (marked by pitch accent) and how far towards the prominent syllable the effect extends. Here, we use an electromagnetic articulography (EMA) study of Greek to examine the scope of boundary-related lengthening as a function of lexical stress and pitch accent separately. Boundaries are elicited by the means of a variety of syntactic constructions.. The results show an effect of lexical stress. Phrase-final lengthening affects the articulatory gestures of the phrase-final syllable that are immediately adjacent to the boundary in words with final stress, but is initiated earlier within phrase-final words with non-final stress. Similarly, the articulatory configurations during inter-phrasal pauses reach their point of achievement later in words with final stress than in words with non-final stress. These effects of stress hold regardless of whether the phrase-final word is accented or de-accented. Phrase-initial lengthening, on the other hand, is consistently detected on the phrase-initial constriction, independently of where the stress is within the preceding, phrase-final, word. These results indicate that the lexical aspect of prominence plays a role in determining the scope of boundary-related lengthening in Greek. Based on these results, a gestural account of prosodic boundaries in Greek is proposed in which lexical and phrasal prosody interact in a systematic and coordinated fashion. The cross-linguistic dimensions of this account and its implications for prosodic structure are discussed.
Peake, Jonathan M; Nosaka, Kazunori; Muthalib, Makii; Suzuki, Katsuhiko
We compared changes in markers of muscle damage and systemic inflammation after submaximal and maximal lengthening muscle contractions of the elbow flexors. Using a cross-over design, 10 healthy young men not involved in resistance training completed a submaximal trial (10 sets of 60 lengthening contractions at 10% maximum isometric strength, 1 min rest between sets), followed by a maximal trial (10 sets of three lengthening contractions at 100% maximum isometric strength, 3 min rest between sets). Lengthening contractions were performed on an isokinetic dynamometer. Opposite arms were used for the submaximal and maximal trials, and the trials were separated by a minimum of two weeks. Blood was sampled before, immediately after, 1 h, 3 h, and 1-4 d after each trial. Total leukocyte and neutrophil numbers, and the serum concentration of soluble tumor necrosis factor-alpha receptor 1 were elevated after both trials (P < 0.01), but there were no differences between the trials. Serum IL-6 concentration was elevated 3 h after the submaximal contractions (P < 0.01). The concentrations of serum tumor necrosis factor-alpha, IL-1 receptor antagonist, IL-10, granulocyte-colony stimulating factor and plasma C-reactive protein remained unchanged following both trials. Maximum isometric strength and range of motion decreased significantly (P < 0.001) after both trials, and were lower from 1-4 days after the maximal contractions compared to the submaximal contractions. Plasma myoglobin concentration and creatine kinase activity, muscle soreness and upper arm circumference all increased after both trials (P < 0.01), but were not significantly different between the trials. Therefore, there were no differences in markers of systemic inflammation, despite evidence of greater muscle damage following maximal versus submaximal lengthening contractions of the elbow flexors.
Full Text Available The loss of teeth and their replacement by artificial denture is associated with many problems. The denture needs a certain amount of ridge height to give it retention and a long-term function. Crest lengthening procedures are performed to provide a better anatomic environment and to create proper supporting structures for more stability and retention of the denture. The purpose of our study is to describe and evaluate the effectiveness of CO2 laser-assisted surgery in patients treated for crest lengthening (vestibular deepening. There have been various surgical techniques described in order to restore alveolar ridge height by pushing muscles attaching of the jaws. Most of these techniques cause postoperative complications such as edemas, hemorrhage, pain, infection, slow healing, and rebound to initial position. Our clinical study describes the treatment planning and clinical steps for the crest lengthening with the use of CO2 laser beam (6–15 Watts in noncontact, energy density range: 84.92–212.31 J/cm2, focus, and continuous mode with a focal point diameter of 0.3 mm. At the end of each surgery, dentures were temporarily relined with a soft material. Patients were asked to mandatorily wear their relined denture for a minimum of 4–6 weeks and to remove it for hygienic purposes. At the end of each surgery, the deepest length of the vestibule was measured by the operator. No sutures were made and bloodless wounds healed in second intention without grafts. Results pointed out the efficiency of the procedure using CO2 laser. At 8 weeks of post-op, the mean of crest lengthening was stable without rebound. Only a loss of 15% was noticed. To conclude, the use of CO2 laser is an effective option for crest lengthening.
Jørgensen, Anders Bech; Amirian, Ilda; Kehlet Watt, Sara
OBJECTIVE: To examine if there were circadian variations in surgeons' ability to diagnose acute appendicitis. DESIGN: Retrospective database study of all patients admitted to an acute surgical procedure under the potential diagnosis of acute appendicitis in a 4-year period. The day was divided...... patients were included. There were no age limitations or selection in sex. RESULTS: There was no significant difference in the ability to diagnose appendicitis in day-evening hours vs night hours (p = 0.391), nor was any significant difference found on weekdays (Monday-Thursday) vs weekends (Friday...... of imaging had no effect on the ability to diagnose appendicitis. Male sex showed a higher probability of the diagnosis being appendicitis compared with other or no pathology (odds ratio: 3.094; p
Figueiro, Mariana G
This study aims to discuss possible reasons why research to date has not forged direct links between light at night, acute melatonin suppression or circadian disruption, and risks for disease. Data suggest that irregular light-dark patterns or light exposures at the wrong circadian time can lead to circadian disruption and disease risks. However, there remains an urgent need to: (1) specify light stimulus in terms of circadian rather than visual response; (2) when translating research from animals to humans, consider species-specific spectral and absolute sensitivities to light; (3) relate the characteristics of photometric measurement of light at night to the operational characteristics of the circadian system; and (4) examine how humans may be experiencing too little daytime light, not just too much light at night. To understand the health effects of light-induced circadian disruption, we need to measure and control light stimulus during the day and at night.
Liu, Fang; Chang, Hung-Chun
Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.
Dani M Long
Full Text Available Circadian clocks coordinate physiological, neurological, and behavioral functions into circa 24 hour rhythms, and the molecular mechanisms underlying circadian clock oscillations are conserved from Drosophila to humans. Clock oscillations and clock-controlled rhythms are known to dampen during aging; additionally, genetic or environmental clock disruption leads to accelerated aging and increased susceptibility to age-related pathologies. Neurodegenerative diseases, such as Alzheimer's disease (AD, are associated with a decay of circadian rhythms, but it is not clear whether circadian disruption accelerates neuronal and motor decline associated with these diseases. To address this question, we utilized transgenic Drosophila expressing various Amyloid-β (Aβ peptides, which are prone to form aggregates characteristic of AD pathology in humans. We compared development of AD-like symptoms in adult flies expressing Aβ peptides in the wild type background and in flies with clocks disrupted via a null mutation in the clock gene period (per01. No significant differences were observed in longevity, climbing ability and brain neurodegeneration levels between control and clock-deficient flies, suggesting that loss of clock function does not exacerbate pathogenicity caused by human-derived Aβ peptides in flies. However, AD-like pathologies affected the circadian system in aging flies. We report that rest/activity rhythms were impaired in an age-dependent manner. Flies expressing the highly pathogenic arctic Aβ peptide showed a dramatic degradation of these rhythms in tune with their reduced longevity and impaired climbing ability. At the same time, the central pacemaker remained intact in these flies providing evidence that expression of Aβ peptides causes rhythm degradation downstream from the central clock mechanism.
Full Text Available Daily, circadian rhythms influence essentially all living organisms and affect many physiological processes from sleep and nutrition to immunity. This ability to respond to environmental daily rhythms has been conserved along evolution, and it is found among species from bacteria to mammals. The hematopoietic process of the crayfish Pacifastacus leniusculus is under circadian control and is tightly regulated by astakines, a new family of cytokines sharing a prokineticin (PROK domain. The expression of AST1 and AST2 are light-dependent, and this suggests an evolutionarily conserved function for PROK domain proteins in mediating circadian rhythms. Vertebrate PROKs are transmitters of circadian rhythms of the suprachiasmatic nucleus (SCN in the brain of mammals, but the mechanism by which they function is unknown. Here we demonstrate that high AST2 expression is induced by melatonin in the brain. We identify RACK1 as a binding protein of AST2 and further provide evidence that a complex between AST2 and RACK1 functions as a negative-feedback regulator of the circadian clock. By DNA mobility shift assay, we showed that the AST2-RACK1 complex will interfere with the binding between BMAL1 and CLK and inhibit the E-box binding activity of the complex BMAL1-CLK. Finally, we demonstrate by gene knockdown that AST2 is necessary for melatonin-induced inhibition of the complex formation between BMAL1 and CLK during the dark period. In summary, we provide evidence that melatonin regulates AST2 expression and thereby affects the core clock of the crustacean brain. This process may be very important in all animals that have AST2 molecules, i.e. spiders, ticks, crustaceans, scorpions, several insect groups such as Hymenoptera, Hemiptera, and Blattodea, but not Diptera and Coleoptera. Our findings further reveal an ancient evolutionary role for the prokineticin superfamily protein that links melatonin to direct regulation of the core clock gene feedback loops.
Full Text Available Regulators of G protein signaling (RGS are a multi-functional protein family, which functions in part as GTPase-activating proteins (GAPs of G protein α-subunits to terminate G protein signaling. Previous studies have demonstrated that the Rgs16 transcripts exhibit robust circadian rhythms both in the suprachiasmatic nucleus (SCN, the master circadian light-entrainable oscillator (LEO of the hypothalamus, and in the liver. To investigate the role of RGS16 in the circadian clock in vivo, we generated two independent transgenic mouse lines using lentiviral vectors expressing short hairpin RNA (shRNA targeting the Rgs16 mRNA. The knockdown mice demonstrated significantly shorter free-running period of locomotor activity rhythms and reduced total activity as compared to the wild-type siblings. In addition, when feeding was restricted during the daytime, food-entrainable oscillator (FEO-driven elevated food-anticipatory activity (FAA observed prior to the scheduled feeding time was significantly attenuated in the knockdown mice. Whereas the restricted feeding phase-advanced the rhythmic expression of the Per2 clock gene in liver and thalamus in the wild-type animals, the above phase shift was not observed in the knockdown mice. This is the first in vivo demonstration that a common regulator of G protein signaling is involved in the two separate, but interactive circadian timing systems, LEO and FEO. The present study also suggests that liver and/or thalamus regulate the food-entrained circadian behavior through G protein-mediated signal transduction pathway(s.
Sletten, Julie; Cornelissen, Germaine; Assmus, Jørg; Kiserud, Torvid; Albrechtsen, Susanne; Kessler, Jörg
The knowledge on circadian rhythmicity is rapidly expanding. We aimed to define the longitudinal development of the circadian heart rate rhythm in the human fetus in an unrestricted, out-of-hospital setting, and to examine the effects of maternal physical activity, season and fetal sex. 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. Circadian rhythmicity in fetal heart rate and fetal heart rate variation was detected by cosinor analysis; developmental trends were calculated by population-mean cosinor and multilevel analysis. For the fetal heart rate and fetal heart rate variation, a significant circadian 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 (prhythm diversity was found in male fetuses, during higher maternal physical activity and during the summer season. The dynamic development of the fetal circadian heart rate rhythm during the second half of pregnancy is modified by fetal sex, maternal physical activity and season. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Baba, Kenkichi; Davidson, Alec J.; Tosini, Gianluca
Purpose Previous studies have reported the presence of a circadian rhythm in PERIOD2::LUCIFERASE (PER2::LUC) bioluminescence in mouse photoreceptors, retina, RPE, and cornea. Melatonin (MLT) modulates many physiological functions in the eye and it is believed to be one of the key circadian signals within the eye. The aim of the present study was to investigate the regulation of the PER2::LUC circadian rhythm in mouse cornea and to determine the role played by MLT. Methods Corneas were obtained from PER2::LUC mice and cultured to measure bioluminescence rhythmicity in isolated tissue using a Lumicycle or CCD camera. To determine the time-dependent resetting of the corneal circadian clocks in response to MLT or IIK7 (a melatonin type 2 receptor, MT2, agonist) was added to the cultured corneas at different times of the day. We also defined the location of the MT2 receptor within different corneal layers using immunohistochemistry. Results A long-lasting bioluminescence rhythm was recorded from cultured PER2::LUC cornea and PER2::LUC signal was localized to the corneal epithelium and endothelium. MLT administration in the early night delayed the cornea rhythm, whereas administration of MLT at late night to early morning advanced the cornea rhythm. Treatment with IIK7 mimicked the MLT phase-shifting effect. Consistent with these results, MT2 immunoreactivity was localized to the corneal epithelium and endothelium. Conclusions Our work demonstrates that MLT entrains the PER2::LUC bioluminescence rhythm in the cornea. Our data indicate that the cornea may represent a model to study the molecular mechanisms by which MLT affects the circadian clock. PMID:26207312
Gottlieb, Lisa A; Lubberding, Anniek; Larsen, Anders Peter; Thomsen, Morten B
Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2 -/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT 100 = QT/(RR/100) 1/2 ). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT mean-RR ). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2 -/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2 -/- mice. Circadian rhythms in QT 100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2 -/- , respectively (p = 0.15). A diurnal rhythm in QT 100 intervals was only found in WT mice. QT mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2 -/- . The amplitude of the circadian rhythm in QT mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2 -/- , respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.
Sandbichler, Adolf M; Jansen, Bianca; Peer, Bettina A; Paulitsch, Monika; Pelster, Bernd; Egg, Margit
Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts. Circadian oscillations of core clock gene mRNA´s were assessed using realtime qPCR with subsequent cosine wave fit analysis. Here we show that under normoxia primary metabolic activity of cells predominately occurs during day time and that after acute hypoxia of two hours, administrated immediately before each sampling point, steady state concentrations of glycolytic key metabolites such as glucose and lactate reveal to be highly rhythmic, following a circadian pattern with highest levels during the night periods and reflecting the circadian variation of the cellular response to hypoxia. Remarkably, rhythms in glycolysis are transferred to cellular energy states under normoxic conditions, so that ADP/ATP ratios oscillate as well, which is the first evidence for cycling ADP/ATP pools in a metazoan cell line to our knowledge. Furthermore, the hypoxia induced alterations in rhythms of glycolysis lead to the alignment of three major cellular redox systems, namely the circadian oscillations of NAD+/NADH and NADP+/NADPH ratios and of increased nocturnal levels of oxidized peroxiredoxins, resulting in a highly
Adolf M. Sandbichler
Full Text Available Background/Aims: Reduced oxygen availability, hypoxia, is frequently encountered by organisms, tissues and cells, in aquatic environments as well as in high altitude or under pathological conditions such as infarct, stroke or cancer. The hypoxic signaling pathway was found to be mutually intertwined with circadian timekeeping in vertebrates and, as reported recently, also in mammals. However, the impact of hypoxia on intracellular metabolic oscillations is still unknown. Methods: For determination of metabolites we used Multilabel Reader based fluorescence and luminescence assays, circadian levels of Hypoxia Inducible Factor 1 alpha and oxidized peroxiredoxins were semi quantified by Western blotting and ratiometric quantification of cytosolic and mitochondrial H2O2 was achieved with stable transfections of a redox sensitive green fluorescent protein sensor into zebrafish fibroblasts. Circadian oscillations of core clock gene mRNA´s were assessed using realtime qPCR with subsequent cosine wave fit analysis. Results: Here we show that under normoxia primary metabolic activity of cells predominately occurs during day time and that after acute hypoxia of two hours, administrated immediately before each sampling point, steady state concentrations of glycolytic key metabolites such as glucose and lactate reveal to be highly rhythmic, following a circadian pattern with highest levels during the night periods and reflecting the circadian variation of the cellular response to hypoxia. Remarkably, rhythms in glycolysis are transferred to cellular energy states under normoxic conditions, so that ADP/ATP ratios oscillate as well, which is the first evidence for cycling ADP/ATP pools in a metazoan cell line to our knowledge. Furthermore, the hypoxia induced alterations in rhythms of glycolysis lead to the alignment of three major cellular redox systems, namely the circadian oscillations of NAD+/NADH and NADP+/NADPH ratios and of increased nocturnal levels
Bruckner, James V; Ramanathan, Raghupathy; Lee, K Monica; Muralidhara, Srinivasa
The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.
Thun, Eirunn; Bjorvatn, Bjørn; Flo, Elisabeth; Harris, Anette; Pallesen, Ståle
Sleep deprivation and time of day are both known to influence performance. A growing body of research has focused on how sleep and circadian rhythms impact athletic performance. This review provides a systematic overview of this research. We searched three different databases for articles on these issues and inspected relevant reference lists. In all, 113 articles met our inclusion criteria. The most robust result is that athletic performance seems to be best in the evening around the time when the core body temperature typically is at its peak. Sleep deprivation was negatively associated with performance whereas sleep extension seems to improve performance. The effects of desynchronization of circadian rhythms depend on the local time at which performance occurs. The review includes a discussion of differences regarding types of skills involved as well as methodological issues. Copyright © 2014 Elsevier Ltd. All rights reserved.
Rath, Martin F; Rovsing, Louise; Møller, Morten
with conditional cell-specific clock gene deletions. This prompted us to analyze the molecular clockwork of the mouse neocortex and cerebellum in detail. Here, by use of in situ hybridization and quantitative RT-PCR, we show that clock genes are expressed in all six layers of the neocortex and the Purkinje...... and granular cell layers of the cerebellar cortex of the mouse brain. Among these, Per1, Per2, Cry1, Arntl, and Nr1d1 exhibit circadian rhythms suggesting that local running circadian oscillators reside within neurons of the mouse neocortex and cerebellar cortex. The temporal expression profiles of clock genes...... are similar in the neocortex and cerebellum, but they are delayed by 5 h as compared to the SCN, suggestively reflecting a master-slave relationship between the SCN and extra-hypothalamic oscillators. Furthermore, ARNTL protein products are detectable in neurons of the mouse neocortex and cerebellum...
circadian geber , 97,98 system precision, 4 Form factor Damped oscillators, mutual excitation of, and relationship to ratio of deviations, 37 self-sustainment...rhythms, 5-6 Forced internal desynebronization, by Zeit- incorporation of, into models of circadian geber , 97,98 system precision, 4 Form factor Damped...equation, for modeling of circadian geber phase, and modification by fre- rhythms, 19 quency coefficient, 54,55,56 Oscillatory range, effects of
Full Text Available Circadian clocks are endogenous and biological oscillations that occur with a period of <24 h. In mammals, the central circadian pacemaker is localized in the suprachiasmatic nucleus (SCN and is linked to peripheral tissues through neural and hormonal signals. In the present study, we investigated the physiological function of the molecular clock on bone remodeling. The results of loss-of-function and gain-of-function experiments both indicated that the rhythmic expression of Tnfrsf11b, which encodes osteoprotegerin (OPG, was regulated by Bmal1 in MC3T3-E1 cells. We also showed that REV-ERBα negatively regulated Tnfrsf11b as well as Bmal1 in MC3T3-E1 cells. We systematically investigated the relationship between the sympathetic nervous system and the circadian clock in osteoblasts. The administration of phenylephrine, a nonspecific α1-adrenergic receptor (AR agonist, stimulated the expression of Tnfrsf11b, whereas the genetic ablation of α1B-AR signaling led to the alteration of Tnfrsf11b expression concomitant with Bmal1 and Per2 in bone. Thus, this study demonstrated that the circadian regulation of Tnfrsf11b was regulated by the clock genes encoding REV-ERBα (Nr1d1 and Bmal1 (Bmal1, also known as Arntl, which are components of the core loop of the circadian clock in osteoblasts.
Kerri L. Kim
Full Text Available Pediatric bipolar disorder (BD rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine one component of sleep—i.e., circadian phase preference with the behavioral construct of morningness/eveningness (M/E. In comparing 30 BD and 45 typically developing control (TDC participants, ages 7–17 years, on the Morningness-Eveningness Scale for Children (MESC, no between-group differences emerged. Similar results were found when comparing three groups (BD−ADHD; BD+ADHD; TDC. Consistent with data available on circadian phase preference in adults with BD, however, we found that BD adolescents, ages 13 years and older, endorsed significantly greater eveningness compared to their TDC peers. While the current findings are limited by reliance on subjective report and the high-rate of comorbid ADHD among the BD group, this finding that BD teens demonstrate an exaggerated shift towards eveningness than would be developmentally expected is important. Future studies should compare the circadian rhythms across the lifespan for individuals diagnosed with BD, as well as identify the point at which BD youth part ways with their healthy peers in terms of phase preference. In addition, given our BD sample was overall euthymic, it may be that M/E is more state vs. trait specific in latency age youth. Further work would benefit from assessing circadian functioning using a combination of rating forms and laboratory-based measures. Improved understanding of sleep in BD may identify behavioral targets for inclusion in prevention and intervention protocols.
Full Text Available During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance and reward may be related to one another. This review will summarize data that describes the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes.
Pittendrigh, Colin S.; Daan, Serge
1. This paper is an attempt to integrate in a general model the major findings reported earlier in this series on: lability and history dependence of circadian period, τ; dependence of τ and α on light intensity as described in Aschoffs Rule; the interrelationships between τ and phase response
Daan, Serge; Pittendrigh, Colin S.
1. In a preceding paper differences in the lability of the freerunning circadian period (τ) in constant darkness (DD) were described among four species of rodents. This lability (i) is strongly correlated with the responses of τ to (ii) D2O-administration and to (iii) constant light (LL) of various
Voigt Hansen, Melissa; Simon Rasmussen, Lars; Jespersgaard, Cathrine
The specific clock-gene PERIOD3 is important with regard to circadian rhythmicity, sleep homeostasis, and cognitive function. The allele PER3(5/5) has been associated with worse cognitive performance in response to sleep deprivation. We hypothesized that patients with the PER3(5/5) genotype would...
.... Our work studies on retinally degenerate mammals have shown that visual blindness need not mean circadian blindness, and that two functionally distinct systems for processing light information must...
...: test the hypothesis that multiple nightly bouts of exercise will induce significant delays in the endogenous circadian rhythms of core body temperature, plasma melatonin, reaction time, alertness...
Ilia N Karatsoreos
Full Text Available Determining the cause of psychiatric disorders is a goal of modern neuroscience, and will hopefully lead to the discovery of treatments to either prevent or alleviate the suffering caused by these diseases. One roadblock to attaining this goal is the realization that neuropsychiatric diseases are rarely due to a single gene polymorphism, environmental exposure, or developmental insult. Rather, it is a complex interaction between these various influences that likely leads to the development of clinically relevant syndromes. Our lab is exploring the links between environmental exposures and neurobehavioral function by investigating how disruption of the circadian (daily clock alters the structure and function of neural circuits, with the hypothesis that disrupting this crucial homeostatic system can directly contribute to altered vulnerability of the organism to other factors that interact to produce psychiatric illness. This review explores some historical and more recent findings that link disrupted circadian clocks to neuropsychiatric disorders, particularly depression, mania, and schizophrenia. We take a comparative approach by exploring the effects observed in human populations, as well as some experimental models used in the laboratory to unravel mechanistic and causal relationships between disruption of the circadian clock and behavioral abnormalities. This is a rich area of research that we predict will contribute greatly to our understanding of how genes, environment, and development interact to modulate an individual’s vulnerability to psychiatric disorders.
Schnell, R C; Bozigian, H P; Davies, M H; Merrick, B A; Park, K S; McMillan, D A
Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.
Gustafson, Chelsea L; Parsley, Nicole C; Asimgil, Hande; Lee, Hsiau-Wei; Ahlbach, Christopher; Michael, Alicia K; Xu, Haiyan; Williams, Owen L; Davis, Tara L; Liu, Andrew C; Partch, Carrie L
The C-terminal transactivation domain (TAD) of BMAL1 (brain and muscle ARNT-like 1) is a regulatory hub for transcriptional coactivators and repressors that compete for binding and, consequently, contributes to period determination of the mammalian circadian clock. Here, we report the discovery of two distinct conformational states that slowly exchange within the dynamic TAD to control timing. This binary switch results from cis/trans isomerization about a highly conserved Trp-Pro imide bond in a region of the TAD that is required for normal circadian timekeeping. Both cis and trans isomers interact with transcriptional regulators, suggesting that isomerization could serve a role in assembling regulatory complexes in vivo. Toward this end, we show that locking the switch into the trans isomer leads to shortened circadian periods. Furthermore, isomerization is regulated by the cyclophilin family of peptidyl-prolyl isomerases, highlighting the potential for regulation of BMAL1 protein dynamics in period determination. Copyright © 2017 Elsevier Inc. All rights reserved.
Kim, Eun-San; Hirata, Kohji [National Lab. for High Energy Physics, Tsukuba, Ibaraki (Japan)
The mapping which shows equilibrium particle distribution in synchrotron phase space for electron storage rings is discussed with respect to some localized constant wake function based on the Gaussian approximation. This mapping shows multi-periodic states as well as double bifurcation in dynamical states of the equilibrium bunch length. When moving around parameter space, the system shows a transition/bifurcation which is not always reversible. These results derived by mapping are confirmed by multiparticle tracking. (author)
Prevalence of cardiac arrhythmias and their reversal after trach- ostomy . An. J. Ned., 63, 1977, 348-358. 69. Richardson, G. S., Carsk..on, M. A., Flagg, W...balanced distribution of sleep stages Avid the hoped for effect of refreshing sleep is disappointed. But snort periods Of 3leep Of about C haours can lead
Zhang, Ying; Markert, Matthew J; Groves, Shayna C; Hardin, Paul E; Merlin, Christine
Circadian repression of CLOCK-BMAL1 by PERIOD and CRYPTOCHROME (CRY) in mammals lies at the core of the circadian timekeeping mechanism. CRY repression of CLOCK-BMAL1 and regulation of circadian period are proposed to rely primarily on competition for binding with coactivators on an α-helix located within the transactivation domain (TAD) of the BMAL1 C terminus. This model has, however, not been tested in vivo. Here, we applied CRISPR/Cas9-mediated mutagenesis in the monarch butterfly ( Danaus plexippus ), which possesses a vertebrate-like CRY (dpCRY2) and an ortholog of BMAL1, to show that insect CRY2 regulates circadian repression through TAD α-helix-dependent and -independent mechanisms. Monarch mutants lacking the BMAL1 C terminus including the TAD exhibited arrhythmic eclosion behavior. In contrast, mutants lacking the TAD α-helix but retaining the most distal C-terminal residues exhibited robust rhythms during the first day of constant darkness (DD1), albeit with a delayed peak of eclosion. Phase delay in this mutant on DD1 was exacerbated in the presence of a single functional allele of dpCry2 , and rhythmicity was abolished in the absence of dpCRY2. Reporter assays in Drosophila S2 cells further revealed that dpCRY2 represses through two distinct mechanisms: a TAD-dependent mechanism that involves the dpBMAL1 TAD α-helix and dpCLK W328 and a TAD-independent mechanism involving dpCLK E333. Together, our results provide evidence for independent mechanisms of vertebrate-like CRY circadian regulation on the BMAL1 C terminus and the CLK PAS-B domain and demonstrate the importance of a BMAL1 TAD-independent mechanism for generating circadian rhythms in vivo.
Scheer, Frank A. J. L.; Shea, Thomas J.; Hilton, Michael F.; Shea, Steven A.
Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0°). Data were segregated according to: (1) circadian phase (60° bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300°, ~2300–0300 h in these subjects) than during the biological day (bin 180°, ~1500–1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive
Kitoh, H; Mishima, K; Matsushita, M; Nishida, Y; Ishiguro, N
Two types of fracture, early and late, have been reported following limb lengthening in patients with achondroplasia (ACH) and hypochondroplasia (HCH). We reviewed 25 patients with these conditions who underwent 72 segmental limb lengthening procedures involving the femur and/or tibia, between 2003 and 2011. Gender, age at surgery, lengthened segment, body mass index, the shape of the callus, the amount and percentage of lengthening and the healing index were evaluated to determine predictive factors for the occurrence of early (within three weeks after removal of the fixation pins) and late fracture (> three weeks after removal of the pins). The Mann‑Whitney U test and Pearson's chi-squared test for univariate analysis and stepwise regression model for multivariate analysis were used to identify the predictive factor for each fracture. Only one patient (two tibiae) was excluded from the analysis due to excessively slow formation of the regenerate, which required supplementary measures. A total of 24 patients with 70 limbs were included in the study. There were 11 early fractures in eight patients. The shape of the callus (lateral or central callus) was the only statistical variable related to the occurrence of early fracture in univariate and multivariate analyses. Late fracture was observed in six limbs and the mean time between removal of the fixation pins and fracture was 18.3 weeks (3.3 to 38.4). Lengthening of the tibia, larger healing index, and lateral or central callus were related to the occurrence of a late fracture in univariate analysis. A multivariate analysis demonstrated that the shape of the callus was the strongest predictor for late fracture (odds ratio: 19.3, 95% confidence interval: 2.91 to 128). Lateral or central callus had a significantly larger risk of fracture than fusiform, cylindrical, or concave callus. Radiological monitoring of the shape of the callus during distraction is important to prevent early and late fracture of lengthened
Full Text Available Introduction: Preservation of the health of periodontium is very important for the long-term success of restored teeth and a balance should always be created between the patients’ esthetic requirements and the periodontal health. Failures of crown lengthening procedures are classified into early and late failures. The aim of this study was to evaluate the prevalence of early failures of crown leathering surgical procedures. Materials and methods: In this descriptive/cross-sectional study, 96 patients were selected from those referring to the Department of Periodontitis, Tabriz Faculty of Dentistry, who required crown lengthening procedures. The particulars of these patients were recorded in special forms and the reasons for the failure of surgical procedures were separately determined at 2- and 6-week intervals. In addition, the frequencies of the reasons for failures were determined in percentages and absolute frequencies. Data were analyzed with descriptive statistics (frequencies and percentages using SPSS 21. Statistical significance was set at P<0.05. Results: Evaluation of patients 6 weeks after surgery showed a failure rate of 14.5% for crown lengthening procedures in patients referring to the Department of Periodontics, Tabriz Faculty of Dentistry. The most common reasons for such early failures in the 6th week, in descending order, were a lack of sufficient keratinized gingiva around in tooth in question, fracture of the tooth structure after surgery, inadequate surgery (not creating a proper distance between the healthy margin and the crest and the coronal returning of the gingival tissue on the tooth. A lack of sufficient keratinized gingiva around the tooth was the most frequent reason for the early failure of crown lengthening procedure at both study intervals. Conclusion: It can be concluded from the results of the present study that during the 6th postoperative week the crown lengthening procedures exhibited a 14.5% failure rate
Full Text Available Abstract Background Reproductive systems of male moths contain circadian clocks, which time the release of sperm bundles from the testis to the upper vas deferens (UVD and their subsequent transfer from the UVD to the seminal vesicles. Sperm bundles are released from the testis in the evening and are retained in the vas deferens lumen overnight before being transferred to the seminal vesicles. The biological significance of periodic sperm retention in the UVD lumen is not understood. In this study we asked whether there are circadian rhythms in the UVD that are correlated with sperm retention. Results We investigated the carbohydrate-rich material present in the UVD wall and lumen during the daily cycle of sperm release using the periodic acid-Shiff reaction (PAS. Males raised in 16:8 light-dark cycles (LD showed a clear rhythm in the levels of PAS-positive granules in the apical portion of the UVD epithelium. The peak of granule accumulation occurred in the middle of the night and coincided with the maximum presence of sperm bundles in the UVD lumen. These rhythms persisted in constant darkness (DD, indicating that they have circadian nature. They were abolished, however, in constant light (LL resulting in random patterns of PAS-positive material in the UVD wall. Gel-separation of the UVD homogenates from LD moths followed by detection of carbohydrates on blots revealed daily rhythms in the abundance of specific glycoproteins in the wall and lumen of the UVD. Conclusion Secretory activity of the vas deferens epithelium is regulated by the circadian clock. Daily rhythms in accumulation and secretion of several glycoproteins are co-ordinated with periodic retention of sperm in the vas deferens lumen.
Mihmanli, Ahmet; Dolanmaz, Doğan; Tüz, Hakan; Pampu, Alper; Dönmez, Hasan Hüseyin
The purpose of this study was to evaluate long-term histomorphometric changes in temporomandibular joints (TMJs) of rabbits after mandibular distraction osteogenesis (DO). Twenty-six rabbits were used in this study. Two of them served as control subjects, and the remaining 24 underwent DO procedures in their left mandibular bodies. After a latency period of 5 days, 5 mm lengthening was performed at a rate of 1 mm/d. The rabbits in the experimental group were randomly divided into 4 subgroups and killed after 1, 2, 4, and 6 months. TMJs from both sides were harvested and prepared with hematoxylin and eosin stain for histomorphometric examination under an optical microscope. Compared with control subjects and nondistracted sides, fibrous articular, proliferative, and hypertrophic areas were significantly increased (P distracted sides. The changes were insignificant in the fourth and sixth postoperative months. Unilateral mandibular distraction of 5 mm was found to be well tolerated and no degenerative changes were observed histologically in the rabbit TMJs in the long-term period. Copyright © 2012 Elsevier Inc. All rights reserved.
Torres-Ruiz, J; Sulli, A; Cutolo, M; Shoenfeld, Y
Biological rhythms are fundamental for homeostasis and have recently been involved in the regulatory processes of various organs and systems. Circadian cycle proteins and hormones have a direct effect on the inflammatory response and have shown pro- or anti-inflammatory effects in animal models of autoimmune diseases. The cells of the immune system have their own circadian rhythm, and the light-dark cycle directly influences the inflammatory response. On the other hand, patients with autoimmune diseases characteristically have sleep disorders and fatigue, and in certain disease, such as rheumatoid arthritis (RA), a frank periodicity in the signs and symptoms is recognized. The joint symptoms predominate in the morning, and apparently, subjects with RA have relative adrenal insufficiency, with a cortisol peak unable to control the late night load of pro-inflammatory cytokines. Transatlantic flights represent a challenge in the adjustment of biological rhythms, since they imply sleep deprivation, time zone changes, and potential difficulties for drug administration. In patients with autoimmune diseases, the use of DMARDs and prednisone at night is probably best suited to lessen morning symptoms. It is also essential to sleep during the trip to improve adaptation to the new time zone and to avoid, as far as possible, works involving flexible or nocturnal shifts. The study of proteins and hormones related to biological rhythms will demonstrate new pathophysiological pathways of autoimmune diseases, which will emphasize the use of general measures for sleep respect and methods for drug administration at key daily times to optimize their anti-inflammatory and immune modulatory effects.
Carrie E Mahoney
Full Text Available Cells of the dorsomedial/lateral hypothalamus (DMH/LH that produce hypocretin (HCRT promote arousal in part by activation of cells of the locus coeruleus (LC which express tyrosine hydroxylase (TH. The suprachiasmatic nucleus (SCN drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature.
FRANCAVILLA, ANTONIO; EAGON, PATRICIA K.; DiLEO, ALFREDO; VAN THIEL, DAVID H.; PANELLA, CARMINE; POLIMENO, LORENZO; AMORUSO, CINZIA; INGROSSO, MARCELLO; AQUILINO, A. MARIA; STARZL, THOMAS E.
Mammalian liver is a sex steroid-responsive tissue. The effects of these hormones presumably are mediated by hepatic estrogen receptors (ER) and androgen receptors (AR). Serum levels of sex hormones display circadian rhythms. Further, estrogens and androgens are commonly administered; administration of these agents is associated frequently with liver disease. Therefore, we investigated whether the cytosolic and nuclear sex steroid receptors also display a similar circadian rhythm, and whether variations occurred in the distribution of receptors between cytosolic and nuclear compartments. Animals were killed every 4 h from midnight till the following midnight; cytosolic and nuclear levels of both ER and AR were measured. Cytosolic ER reached a maximum level at 4 AM, and a minimum at 8 PM and midnight of both days. Nuclear ER was highest at 8 AM and lowest at 4 PM and 8 PM, a pattern which parallels variations in serum estradiol levels. Cytosolic AR was highest at 8 PM and lowest at midnight and 4 AM. Nuclear AR was highest at 4 AM and lowest at 4 PM and 8 PM. The highest level of nuclear AR does not correspond to the maximum serum testosterone level, which occurred at 4 PM. The total hepatic content of both ER and AR was not constant over the 24-h period, but varied considerably with time of day. These studies suggest that both ER and AR show a distinct circadian rhythm in subcellular compartmentalization, and that total hepatic content of ER and AR varies significantly during a 24-h period. PMID:3710067
Kervezee, Laura; Cuesta, Marc; Cermakian, Nicolas; Boivin, Diane B
Misalignment of the endogenous circadian timing system leads to disruption of physiological rhythms and may contribute to the development of the deleterious health effects associated with night shift work. However, the molecular underpinnings remain to be elucidated. Here, we investigated the effect of a 4-day simulated night shift work protocol on the circadian regulation of the human transcriptome. Repeated blood samples were collected over two 24-hour measurement periods from eight healthy subjects under highly controlled laboratory conditions before and 4 days after a 10-hour delay of their habitual sleep period. RNA was extracted from peripheral blood mononuclear cells to obtain transcriptomic data. Cosinor analysis revealed a marked reduction of significantly rhythmic transcripts in the night shift condition compared with baseline at group and individual levels. Subsequent analysis using a mixed-effects model selection approach indicated that this decrease is mainly due to dampened rhythms rather than to a complete loss of rhythmicity: 73% of transcripts rhythmically expressed at baseline remained rhythmic during the night shift condition with a similar phase relative to habitual bedtimes, but with lower amplitudes. Functional analysis revealed that key biological processes are affected by the night shift protocol, most notably the natural killer cell-mediated immune response and Jun/AP1 and STAT pathways. These results show that 4 days of simulated night shifts leads to a loss in temporal coordination between the human circadian transcriptome and the external environment and impacts biological processes related to the adverse health effects associated to night shift work.
Michaud, Martin; Dumont, Marie; Paquet, Jean; Desautels, Alex; Fantini, Maria Livia; Montplaisir, Jacques
It is now well established that symptoms of restless legs syndrome (RLS) are worsened by immobility and that their severity fluctuates according to a circadian pattern with a maximum occurring in the late evening or during the night. However, no study has ever attempted to dissociate these two effects. The objective of this study was to evaluate the nycthemeral variations in the effects of duration of immobility on symptoms of RLS. A 28-hour modified constant routine protocol. Sleep Disorders Center, Montreal Sacré-Coeur Hospital. Seven patients with primary RLS (3 men, 4 women; mean age: 43.9 years) and seven controls matched for age (42.4 years) and gender. None. A 40-minute Suggested Immobilization Test (SIT) was repeated every 2 hours during the 28-hour protocol in order to quantify both subjective leg discomfort and periodic leg movements (PLM). Regarding leg discomfort, a two-way ANOVA performed on patients' data revealed a significant interaction (p = 0.037) between Time within the SIT and Time of day. Simple effect analyses performed to decompose the interaction showed that the increase in leg discomfort with duration of immobility was found only on SIT 7, 8, 9, 10 and 12, which corresponds to the period between 21:20 and 08:00. In addition, in patients, a significant circadian variation (p immobility is closely linked to their intrinsic circadian variation.
Hassan M Fathallah-Shaykh
Full Text Available BACKGROUND: Electronic clocks exhibit undesirable jitter or time variations in periodic signals. The circadian clocks of humans, some animals, and plants consist of oscillating molecular networks with peak-to-peak time of approximately 24 hours. Clockwork orange (CWO is a transcriptional repressor of Drosophila direct target genes. METHODOLOGY/PRINCIPAL FINDINGS: Theory and data from a model of the Drosophila circadian clock support the idea that CWO controls anti-jitter negative circuits that stabilize peak-to-peak time in light-dark cycles (LD. The orbit is confined to chaotic attractors in both LD and dark cycles and is almost periodic in LD; furthermore, CWO diminishes the Euclidean dimension of the chaotic attractor in LD. Light resets the clock each day by restricting each molecular peak to the proximity of a prescribed time. CONCLUSIONS/SIGNIFICANCE: The theoretical results suggest that chaos plays a central role in the dynamics of the Drosophila circadian clock and that a single molecule, CWO, may sense jitter and repress it by its negative loops.
Paijmans, Joris; Bosman, Mark; Ten Wolde, Pieter Rein; Lubensky, David K
Many organisms possess both a cell cycle to control DNA replication and a circadian clock to anticipate changes between day and night. In some cases, these two rhythmic systems are known to be coupled by specific, cross-regulatory interactions. Here, we use mathematical modeling to show that, additionally, the cell cycle generically influences circadian clocks in a nonspecific fashion: The regular, discrete jumps in gene-copy number arising from DNA replication during the cell cycle cause a periodic driving of the circadian clock, which can dramatically alter its behavior and impair its function. A clock built on negative transcriptional feedback either phase-locks to the cell cycle, so that the clock period tracks the cell division time, or exhibits erratic behavior. We argue that the cyanobacterium Synechococcus elongatus has evolved two features that protect its clock from such disturbances, both of which are needed to fully insulate it from the cell cycle and give it its observed robustness: a phosphorylation-based protein modification oscillator, together with its accompanying push-pull read-out circuit that responds primarily to the ratios of different phosphoform concentrations, makes the clock less susceptible to perturbations in protein synthesis; the presence of multiple, asynchronously replicating copies of the same chromosome diminishes the effect of replicating any single copy of a gene.
Haberfehlner, Helga; Jaspers, Richard T; Rutz, Erich; Harlaar, Jaap; van der Sluijs, Johannes A; Witbreuk, Melinda M; van Hutten, Kim; Romkes, Jacqueline; Freslier, Marie; Brunner, Reinald; Becher, Jules G; Maas, Huub; Buizer, Annemieke I
To improve gait in children with spastic paresis due to cerebral palsy or hereditary spastic paresis, the semitendinosus muscle is frequently lengthened amongst other medial hamstring muscles by orthopaedic surgery. Side effects on gait due to weakening of the hamstring muscles and overcorrections have been reported. How these side effects relate to semitendinosus morphology is unknown. This study assessed the effects of bilateral medial hamstring lengthening as part of single-event multilevel surgery (SEMLS) on (1) knee joint mechanics (2) semitendinosus muscle morphology and (3) gait kinematics. All variables were assessed for the right side only. Six children with spastic paresis selected for surgery to counteract limited knee range of motion were measured before and about a year after surgery. After surgery, in most subjects popliteal angle decreased and knee moment-angle curves were shifted towards a more extended knee joint, semitendinosus muscle belly length was approximately 30% decreased, while at all assessed knee angles tendon length was increased by about 80%. In the majority of children muscle volume of the semitendinosus muscle decreased substantially suggesting a reduction of physiological cross-sectional area. Gait kinematics showed more knee extension during stance (mean change ± standard deviation: 34±13°), but also increased pelvic anterior tilt (mean change ± standard deviation: 23±5°). In most subjects, surgical lengthening of semitendinosus tendon contributed to more extended knee joint angle during static measurements as well as during gait, whereas extensibility of semitendinosus muscle belly was decreased. Post-surgical treatment to maintain muscle belly length and physiological cross-sectional area may improve treatment outcome of medial hamstring lengthening.
Djordjevic, Miroslav L; Bizic, Marta R
Metoidioplasty presents one of the variants of phalloplasty in female transsexuals. Urethral lengthening is the most difficult part in this surgery and poses many challenges. We evaluated 207 patients who underwent metoidioplasty, aiming to compare two different surgical techniques of urethral lengthening, postoperative results, and complications. The study encompassed a total of 207 patients, aged from 18 to 62 years, who underwent single stage metoidioplasty between September 2002 and July 2011. The procedure included lengthening and straightening of the clitoris, urethral reconstruction, and scrotoplasty with implantation of testicular prostheses. Buccal mucosa graft was used in all cases for dorsal urethral plate formation and joined with one of the two different flaps: I-longitudinal dorsal clitoral skin flap (49 patients) and II-labia minora flap (158 patients). Results were analyzed using Z-test to evaluate the statistical difference between the two approaches. Also, postoperative questionnaire was used, which included questions on functioning and esthetical appearance of participating subjects as well as overall satisfaction. The median follow-up was 39 months (ranged 12-116 months). The total length of reconstructed urethra was measured during surgery in both groups. It ranged from 9.1 to 12.3 cm (median 9.5) in group I and from 9.4 to 14.2 cm (median 10.8) in group II. Voiding while standing was significantly better in group II (93%) than in group I (87.82%) (P lengthening confirmed combined buccal mucosa graft and labia minora flap as a method of choice for urethroplasty in metoidioplasty, minimizing postoperative complications. © 2013 International Society for Sexual Medicine.
Yeo, S; Perrot, P; Duteille, F
The realization of free flaps with lack of reliable vessels nearby the loss of substance is a difficult problem for plastic surgeons. We report 10 cases of free tissue transfers with a one-stage technique lengthening the vascular pedicle of the free flap with interpositional vein grafts. Taking into consideration the good results and the low rate of morbidity, the authors emphasize the use of this technique rather than a two-stage procedure. Copyright 2009 Elsevier Masson SAS. All rights reserved.
Tomić, S; Krajcinović, O; Blagojević, Z; Apostolović, M; Lalosević, V
We analyzed 30 patients with infected diaphyseal defect of femur, which have been treated by lengthening one of the bone fragments with Ilizarov apparatus. The mean length of the bone defect was 6 cm. Substitution of the defect, bone healing and elimination of the infection was achieved in 27 patients. The mean time of apparatus fixation was 10 months. According to Palley scoring system, 10 patients had excellent functional results.
Full Text Available Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well-established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis-elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i drought stress affects gene expression of circadian clock components and (ii several stress responsive genes display diurnal oscillation in soybeans.
Karen A. Hudson
Full Text Available A number of metabolic and physiological processes in plants are controlled by the circadian clock, which enables a plant to anticipate daily changes in the environment. Relatively little is known about circadian rhythms in developing seeds, which may be important for determining the extent and timing of nutrient storage in grain. Microarray expression profiling was used to identify genes expressed in developing soybean ( seeds that are controlled by the circadian clock. Genes with predicted functions in protein synthesis, fatty acid metabolism, and photosynthesis totaling 1.8% of the mRNAs detected in seed were found to be expressed in a circadian rhythm. Known circadian and light-controlled promoter elements were identified as over-represented in the promoters of clock-controlled seed genes, with the over-represented elements varying according to the phase of circadian expression. A subset of circadian-regulated genes were found to be expressed in different phases in developing seeds with respect to leaves from the same plants, many of which have roles in photosynthesis and carbon metabolism. These results help to characterize the genes and processes in seeds that may be regulated by the circadian clock, and provide some insight into organ-specific phasing of clock controlled gene expression.
Lyons, Lisa C.; Roman, Gregg
Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term…
Boumans, Iris J.M.M.; Boer, de Imke J.M.; Hofstede, Gert Jan; Fleur, la Susanne E.; Bokkers, Eddy
The interaction between hormonal circadian rhythms and feeding behaviour is not well understood. This study aimed to deepen our understanding of mechanisms underlying circadian feeding behaviour in animals, using pigs, Sus scrofa, as a case study. Pigs show an alternans feeding pattern, that is,
Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
Hut, R. A.; Van der Zee, E. A.
This review provides an overview of the interaction between the mammalian cholinergic system and circadian system, and its possible role in time memory. Several studies made clear that circadian (daily) fluctuations in acetylcholine (ACh) release, cholinergic enzyme activity and cholinergic receptor
Polidarová, Lenka; Olejníková, Lucie; Paušlyová, Lucia; Sládek, Martin; Soták, Matúš; Pácha, Jiří; Sumová, Alena
Roč. 306, č. 4 (2014), G346-G356 ISSN 0193-1857 R&D Projects: GA ČR(CZ) GAP303/12/1108 Institutional support: RVO:67985823 Keywords : circadian clock * clock gene * ontogenesis * circadian entrainment Subject RIV: ED - Physiology Impact factor: 3.798, year: 2014
van Acker, B. A.; Koomen, G. C.; Koopman, M. G.; Krediet, R. T.; Arisz, L.
To elucidate the disparity between circadian rhythmicity of inulin and creatinine clearance, we simultaneously measured inulin and creatinine clearances every 3 hours during 1 day in 14 normal subjects and in 8 patients with nephrotic syndrome. All patients and normal subjects had a circadian rhythm
Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial respon...
Watts, Barbara L.
Many physiological and psychological processes fluctuate throughout the day in fairly stable, rhythmic patterns. The relationship between individual differences in circadian activity rhythms and a sense of time urgency were explored as well as a number of achievement-related variables. Undergraduates (N=308), whose circadian activity rhythms were…
Uduak S. Udoh
Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.
Simons, S.S.H.; Cillessen, A.H.N.; Weerth, C. de
Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm
Douma, C. E.; van der Post, J. A.; van Acker, B. A.; Boer, K.; Koopman, M. G.
OBJECTIVE: The hypothesis was tested that circadian variations in urinary albumin excretion of pregnant women in the third trimester of normal pregnancy are different from nonpregnant individuals. DESIGN: Circadian variability in urinary albumin excretion was studied both in pregnant women and in
In our attempts to understand the circadian system, we unavoidably rely on abstractions. Instead of describing the behavior of the circadian system in all its complexity, we try to derive basic features from which we form a global concept on how the system works. Such a basic concept is a model of
Ezzat, Abdelrahman E M; El-Begermy, Marwa M; Eid, Mustafa I; Akel, Mabrouk M
This study was designed to compare intravelar veloplasty with and without V-Y pushback palatoplasty regarding postoperative functional and speech outcomes. is to find out the importance and influence of palatal lengthening on the functional and speech outcomes after SMCP repair. This is a prospective randomized comparative study of 20 patients divided into 2 equal groups. The study was conducted between February 2008 and January 2015. Radical Intravelar Veloplasty (RIVVP group): included 10 patients with a mean age of 5.539±1.335 years and V-Y Pushback Pharyngoplasty and Radical Intravelar Veloplasty (VYP+RIVVP group): included 10 patients with a mean age of 5.688±1.341 years for non-syndromic SMCP. Academic tertiary care medical centres. In both groups there was a significant change in Eustachian tube function, nasal emission and nasal tone of voice postoperatively than preoperatively, while there was no significant difference between both groups in the postoperative outcomes as regards the same parameters (ET function, nasal emission and resonance) (p=0.558, 0.563 and 0.164 respectively). However, there was a significant difference between both groups as regards palatal lengthening, no statistically significant difference was present between both groups as regards the postoperative mean pharyngeal gap, using videoendoscopic analysis. In conclusion, RIVVP and VYP+RIVVP are both effective methods to repair non-syndromic SMCP. Moreover, the lengthening of the palate in non-syndromic SMCP is an unnecessary process.
Hosie, S; Loff, S; Wirth, H; Rapp, H-J; von Buch, C; Waag, K-L
Forty-nine patients with a mean age of 25 months underwent a longitudinal intestinal lengthening procedure for short bowel syndrome (SBS) in our institution. Indications for the operation were dependence on parenteral nutrition in spite of adequate conservative management. The small bowel was lengthened from a mean of 27 cm to a mean of 51 cm. There was no intraoperative mortality. The following early complications occurred in our early series: ischemia of a short bowel segment of 2 cm, requiring resection in two patients, insufficiency of the longitudinal anastomosis in two patients and an intra-abdominal abscess in one. Four of 9 non-survivors died of liver failure and 3 of sepsis. Follow-up showed that 19 patients were weaned from parenteral nutrition after a mean of 9.1 months. Long-term complications encountered were dismotility with malabsorption due to bacterial overgrowth caused by progressive dilatation of the bowel, d-lactic acidosis, cholelithiasis and urolithiasis. A longitudinal intestinal lengthening procedure is an effective and safe surgical approach for SBS, provided it is performed in time, the patient's preoperative condition is optimized and technical surgical details are taken into account.
McIntosh, Emily I; Power, Geoffrey A; Dalton, Brian H
The purpose was to investigate whether exercise-induced muscle weakness of the plantar and dorsiflexors through high-intensity lengthening contractions increases the vestibulomyogenic balance response. Nine males (∼25 years) participated in three experimental testing days to evaluate the vestibular control of standing balance and neuromuscular function of the plantar and dorsiflexors pre- and post (30 min, and 1 and 7 days) high-intensity lengthening plantar and dorsiflexions. To evaluate the vestibular-evoked balance response, participants stood quietly on a force plate while exposed to continuous, random electrical vestibular stimulation (EVS) for two 90-s trials. Relationships between EVS-antero-posterior (AP) forces and EVS-medial gastrocnemius electromyography (EMG) were estimated in the frequency domain (i.e., coherence). Weakness of the right plantar and dorsiflexors were assessed using maximal voluntary contraction (MVC) torque. The lengthening contractions induced a 13 and 24% reduction in plantar and dorsiflexor MVC torque, respectively (p balance response when muscle strength is reduced. Copyright © 2018 Elsevier B.V. All rights reserved.
Demetracopoulos, Constantine A; Nair, Pallavi; Malzberg, Andrew; Deland, Jonathan T
Lateral column lengthening is used to correct abduction deformity at the midfoot and improve talar head coverage in patients with flatfoot deformity. It was our hypothesis that following a stepcut lengthening calcaneal osteotomy (SLCO), patients would have adequate correction of the deformity, a high union rate of the osteotomy, and improvement in clinical outcome scores. We retrospectively reviewed 37 consecutive patients who underwent SLCO for the treatment of stage IIB flatfoot deformity with a minimum 2-year follow-up. Deformity correction was assessed using preoperative and postoperative weight-bearing radiographs. Healing of the osteotomy was assessed by computed tomography. Clinical outcomes included the FAOS and SF-36 questionnaires. The Wilcoxon signed-rank test was used to compare clinical outcome scores. An alpha level of .05 was deemed statistically significant. Healing of the osteotomy occurred at a mean of 7.7 weeks postoperatively. The talonavicular (TN) coverage angle improved from 34.0 to 8.8 (P lengthening. Level IV, retrospective case review. © The Author(s) 2015.
Nieto, Paula S; Revelli, Jorge A; Garbarino-Pico, Eduardo; Condat, Carlos A; Guido, Mario E; Tamarit, Francisco A
Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis.
Arjona, Alvaro; Silver, Adam C; Walker, Wendy E; Fikrig, Erol
The circadian system ensures the generation and maintenance of self-sustained ~24-h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related disease. Here, we discuss the molecular links between the circadian and immune systems and examine their outputs and disease implications. Understanding the mechanisms that underlie circadian-immune crosstalk may prove valuable for devising novel prophylactic and therapeutic interventions. Copyright © 2012 Elsevier Ltd. All rights reserved.
Sato, Shogo; Solanas, Guiomar; Peixoto, Francisca Oliveira; Bee, Leonardo; Symeonidi, Aikaterini; Schmidt, Mark S; Brenner, Charles; Masri, Selma; Benitah, Salvador Aznar; Sassone-Corsi, Paolo
The process of aging and circadian rhythms are intimately intertwined, but how peripheral clocks involved in metabolic homeostasis contribute to aging remains unknown. Importantly, caloric restriction (CR) extends lifespan in several organisms and rewires circadian metabolism. Using young versus old mice, fed ad libitum or under CR, we reveal reprogramming of the circadian transcriptome in the liver. These age-dependent changes occur in a highly tissue-specific manner, as demonstrated by comparing circadian gene expression in the liver versus epidermal and skeletal muscle stem cells. Moreover, de novo oscillating genes under CR show an enrichment in SIRT1 targets in the liver. This is accompanied by distinct circadian hepatic signatures in NAD + -related metabolites and cyclic global protein acetylation. Strikingly, this oscillation in acetylation is absent in old mice while CR robustly rescues global protein acetylation. Our findings indicate that the clock operates at the crossroad between protein acetylation, liver metabolism, and aging. Copyright © 2017 Elsevier Inc. All rights reserved.
Full Text Available Growing evidence shows that intrinsic circadian clocks are tightly related to cardiovascular functions. The diurnal changes in blood pressure and heart rate are well known circadian rhythms. Endothelial function, platelet aggregation and thrombus formation exhibit circadian changes as well. The onset of many cardiovascular diseases (CVDs or events, such as myocardial infarction, stroke, arrhythmia, and sudden cardiac death, also exhibits temporal trends. Furthermore, there is strong evidence from animal models and epidemiological studies showing that disruption of circadian rhythms is a significant risk factor for many CVDs, and the intervention of CVDs may have a time dependent effect. In this mini review, we summarized recent advances in our understanding of the relationship between circadian rhythm and cardiovascular physiology and diseases including blood pressure regulation and myocardial infarction.
Jun-Wei, Wang; Ai-Min, Chen; Jia-Jun, Zhang; Zhan-Jiang, Yuan; Tian-Shou, Zhou
In circadian rhythm generation, intercellular signaling factors are shown to play a crucial role in both sustaining intrinsic cellular rhythmicity and acquiring collective behaviours across a population of circadian neurons. However, the physical mechanism behind their role remains to be fully understood. In this paper, we propose an indirectly coupled multicellular model for the synchronization of Drosophila circadian oscillators combining both intracellular and intercellular dynamics. By simulating different experimental conditions, we find that such an indirect coupling way can synchronize both heterogeneous self-sustained circadian neurons and heterogeneous mutational damped circadian neurons. Moreover, they can also be entrained to ambient light-dark (LD) cycles depending on intercellular signaling. (cross-disciplinary physics and related areas of science and technology)
Kim, Jee Hyun; Duffy, Jeanne F
The timing, duration, and consolidation of sleep result from the interaction of the circadian timing system with a sleep-wake homeostatic process. When aligned and functioning optimally, this allows wakefulness throughout the day and a long consolidated sleep episode at night. Mismatch between the desired timing of sleep and the ability to fall and remain asleep is a hallmark of the circadian rhythm sleep-wake disorders. This article discusses changes in circadian regulation of sleep with aging; how age influences the prevalence, diagnosis, and treatment of circadian rhythm sleep-wake disorders; and how neurologic diseases in older patients affect circadian rhythms and sleep. Copyright © 2017 Elsevier Inc. All rights reserved.
Full Text Available The rich mammalian cellular circadian output affects thousands of genes in many cell types and has been the subject of genome-wide transcriptome and proteome studies. The results have been enigmatic because transcript peak abundances do not always follow the peaks of gene-expression activity in time. We posited that circadian degradation of mRNAs and proteins plays a pivotal role in setting their peak times. To establish guiding principles, we derived a theoretical framework that fully describes the amplitudes and phases of biomolecules with circadian half-lives. We were able to explain the circadian transcriptome and proteome studies with the same unifying theory, including cases in which transcripts or proteins appeared before the onset of increased production rates. Furthermore, we estimate that 30% of the circadian transcripts in mouse liver and Drosophila heads are affected by rhythmic posttranscriptional regulation.
Clegg, Benjamin A.; Wickens, Christopher D.; Vieane, Alex Z.; Gutzwiller, Robert S.; Sebok, Angelia L.
The goal of this study was to advance understanding and prediction of the impact of circadian rhythm on aspects of complex task performance during unexpected automation failures, and subsequent fault management. Participants trained on two tasks: a process control simulation, featuring automated support; and a multi-tasking platform. Participants then completed one task in a very early morning (circadian night) session, and the other during a late afternoon (circadian day) session. Small effects of time of day were seen on simple components of task performance, but impacts on more demanding components, such as those that occur following an automation failure, were muted relative to previous studies where circadian rhythm was compounded with sleep deprivation and fatigue. Circadian low participants engaged in compensatory strategies, rather than passively monitoring the automation. The findings and implications are discussed in the context of a model that includes the effects of sleep and fatigue factors.
Full Text Available Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR and cardiac activity period (CAP of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays
Zeng, Xianxu; Tate, Rebecca E.; McKee, Mary L.; Capen, Diane E.; Zhang, Zhan; Tanzi, Rudolph E.; Zhou, Chao
Circadian rhythms are endogenous, entrainable oscillations of physical, mental and behavioural processes in response to local environmental cues such as daylight, which are present in the living beings, including humans. Circadian rhythms have been related to cardiovascular function and pathology. However, the role that circadian clock genes play in heart development and function in a whole animal in vivo are poorly understood. The Drosophila cryptochrome (dCry) is a circadian clock gene that encodes a major component of the circadian clock negative feedback loop. Compared to the embryonic stage, the relative expression levels of dCry showed a significant increase (>100-fold) in Drosophila during the pupa and adult stages. In this study, we utilized an ultrahigh resolution optical coherence microscopy (OCM) system to perform non-invasive and longitudinal analysis of functional and morphological changes in the Drosophila heart throughout its post-embryonic lifecycle for the first time. The Drosophila heart exhibited major morphological and functional alterations during its development. Notably, heart rate (HR) and cardiac activity period (CAP) of Drosophila showed significant variations during the pupa stage, when heart remodeling took place. From the M-mode (2D + time) OCM images, cardiac structural and functional parameters of Drosophila at different developmental stages were quantitatively determined. In order to study the functional role of dCry on Drosophila heart development, we silenced dCry by RNAi in the Drosophila heart and mesoderm, and quantitatively measured heart morphology and function in those flies throughout its development. Silencing of dCry resulted in slower HR, reduced CAP, smaller heart chamber size, pupal lethality and disrupted posterior segmentation that was related to increased expression of a posterior compartment protein, wingless. Collectively, our studies provided novel evidence that the circadian clock gene, dCry, plays an essential
Lance J Kriegsfeld
Full Text Available Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary-gonadal (HPG axis functioning. In mammals, the master circadian pacemaker in the suprachaismatic nucleus (SCN of the anterior hypothalamus coordinates reproductively-relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the GnRH system in control of the preovulatory LH surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.
Kim, Seung-Ju; Balce, Gracia Cielo; Agashe, Mandar Vikas; Song, Sang-Heon; Song, Hae-Ryong
Use of the Ilizarov technique for limb lengthening in patients with achondroplasia is controversial, with a high risk of complications balancing cosmetic gains. Although several articles have described the complications of this procedure and satisfaction of patients after surgery, it remains unclear whether lengthening improves the quality of life (QOL) of these patients. We asked whether bilateral lower limb lengthenings with deformity correction in patients with achondroplasia would improve QOL and investigated the correlation between complication rate and QOL. We retrospectively reviewed 22 patients (average age, 12.7 years) diagnosed with achondroplasia who underwent bilateral lower limb lengthenings between 2002 and 2005. These patients were compared with 22 patients with achondroplasia for whom limb lengthening was not performed. The two groups were assessed using the American Academy of Orthopaedic Surgeons (AAOS) lower limb, SF-36, and Rosenberg self-esteem scores. Minimum followup was 4.5 years (range, 4.5-6.9 years). Among the lengthening group, the average gain in length was 10.21 ± 2.39 cm for the femur and 9.13 ± 2.12 cm for the tibia. A total of 123 complications occurred in these 88 segments. The surgical group had higher Rosenberg self-esteem scores than the nonsurgical group although there were no differences in the AAOS and the SF-36 scores. The self-esteem scores decreased with the increase in the number of complications. Our data suggest that despite frequent complications, bilateral lower limb lengthening increases patients' QOL. We believe lengthening is a reasonable option in selected patients. Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
T. A. Stupina; N. A. Schoudlo; N. V. Petrovskaya; M. A. Stepanov
The knee articular cartilage and synovial membrane have been studied for metadiaphyseal leg lengthening using the methods of light miscroscopy, computer morpho- and stereometry. The manner of bone integrity breaking, the rate and rhythm of distraction conformed to the lengthening technique most often used in the clinic. The results of the histomorphometric analysis have demonstrated that when osteotomy at the level of metadiaphysis and manual distraction by 1 mm a day for 4 times is performed...
Fenske, Myles P; Imaizumi, Takato
To successfully recruit pollinators, plants often release attractive floral scents at specific times of day to coincide with pollinator foraging. This timing of scent emission is thought to be evolutionarily beneficial to maximize resource efficiency while attracting only useful pollinators. Temporal regulation of scent emission is tied to the activity of the specific metabolic pathways responsible for scent production. Although floral volatile profiling in various plants indicated a contribution by the circadian clock, the mechanisms by which the circadian clock regulates timing of floral scent emission remained elusive. Recent studies using two species in the Solanaceae family provided initial insight into molecular clock regulation of scent emission timing. In Petunia hybrida, the floral volatile benzenoid/phenylpropanoid (FVBP) pathway is the major metabolic pathway that produces floral volatiles. Three MYB-type transcription factors, ODORANT 1 (ODO1), EMISSION OF BENZENOIDS I (EOBI), and EOBII, all of which show diurnal rhythms in mRNA expression, act as positive regulators for several enzyme genes in the FVBP pathway. Recently, in P. hybrida and Nicotiana attenuata, homologs of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL (LHY) have been shown to have a similar role in the circadian clock in these plants, and to also determine the timing of scent emission. In addition, in P. hybrida, PhLHY directly represses ODO1 and several enzyme genes in the FVBP pathway during the morning as an important negative regulator of scent emission. These findings facilitate our understanding of the relationship between a molecular timekeeper and the timing of scent emission, which may influence reproductive success.
Full Text Available To successfully recruit pollinators, plants often release attractive floral scents at specific times of day to coincide with pollinator foraging. This timing of scent emission is thought to be evolutionarily beneficial to maximize resource efficiency while attracting only useful pollinators. Temporal regulation of scent emission is tied to the activity of the specific metabolic pathways responsible for scent production. Although floral volatile profiling in various plants indicated a contribution by the circadian clock, the mechanisms by which the circadian clock regulates timing of floral scent emission remained elusive. Recent studies using two species in the Solanaceae family provided initial insight into molecular clock regulation of scent emission timing. In Petunia hybrida, the benzenoid/phenylpropanoid (FVBP pathway is the major metabolic pathway that produces floral volatiles. Three MYB-type transcription factors, ODORANT1 (ODO1, EMISSION OF BENZENOIDS I (EOBI, and EOBII, all of which show diurnal rhythms in mRNA expression, act as positive regulators for several enzyme genes in the FVBP pathway. Recently, in P. hybrida and Nicotiana attenuata, homologs of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL (LHY have been shown to have a similar role in the circadian clock in these plants, and to also determine the timing of scent emission. In addition, in P. hybrida, PhLHY directly represses ODO1 and several enzyme genes in the FVBP pathway during the morning as an important negative regulator of scent emission. These findings facilitate our understanding of the relationship between a molecular timekeeper and the timing of scent emission, which may influence reproductive success.
Sumová, Alena; Sládek, Martin; Polidarová, Lenka; Nováková, Marta; Houdek, Pavel
Roč. 199, č. 2012 (2012), s. 83-103 ISSN 0079-6123 R&D Projects: GA ČR(CZ) GA305/09/0321; GA ČR(CZ) GAP303/11/0668; GA MŠk(CZ) LC554; GA MZd(CZ) NT11474; GA ČR(CZ) GAP303/12/1108 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : ontogenesis * suprachiasmatic nucleus * peripheral circadian clocks * clock gene Subject RIV: ED - Physiology Impact factor: 4.191, year: 2012
Zhao, Li; Fan, Qing; Venkatesh, K P; Park, Man S; Song, Hae Ryong
During limb lengthening over an intramedullary nail, decisions regarding external fixator removal and weightbearing depend on the amount of callus seen at the lengthening area on radiographs. However, this method is subjective and objective evaluation of the amount of callus likely would minimize nail or interlocking screw breakage and refracture after fixator removal. We asked how many cortices with full corticalization of the newly formed bone at the lengthening area are needed to allow fixator removal and full weightbearing and how to radiographically determine the stage of corticalization. We retrospectively reviewed 17 patients (34 lengthenings) who underwent bilateral tibial lengthenings over an intramedullary nail. The average gain in length was 7.2 +/- 3.4 cm. We determined the pixel value ratio (ratio of pixel value of regenerate versus the mean pixel value of adjacent bone) of the lengthened area on radiographs. There were no nail or screw breakage and refracture. Partial weightbearing with crutches was permitted when the pixel value ratio was 1 in two cortices and full weightbearing without crutches was permitted when the pixel value ratio was 1 in three cortices. The pixel value ratio on radiographs can be an objective parameter for callus measurement and may provide guidelines for the timing of external fixator removal. We cannot determine from our limited data the minimum pixel value in how many cortices would suggest safe removal, but we can say our criteria were not associated with subsequent refracture.
Kozlov, Anatoly; Jaumouillé, Edouard; Machado Almeida, Pedro; Koch, Rafael; Rodriguez, Joseph; Abruzzi, Katharine C; Nagoshi, Emi
Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled ( unf ) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period ( per ) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837 , which we termed R and B ( Rnb ), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit. SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics
Full Text Available Circadian timing largely modifies efficacy and toxicity of many anticancer drugs. Recent findings suggest that optimal circadian delivery patterns depend on the patient genetic background. We present here a combined experimental and mathematical approach for the design of chronomodulated administration schedules tailored to the patient molecular profile. As a proof of concept we optimized exposure of Caco-2 colon cancer cells to irinotecan (CPT11, a cytotoxic drug approved for the treatment of colorectal cancer. CPT11 was bioactivated into SN38 and its efflux was mediated by ATP-Binding-Cassette (ABC transporters in Caco-2 cells. After cell synchronization with a serum shock defining Circadian Time (CT 0, circadian rhythms with a period of 26 h 50 (SD 63 min were observed in the mRNA expression of clock genes REV-ERBα, PER2, BMAL1, the drug target topoisomerase 1 (TOP1, the activation enzyme carboxylesterase 2 (CES2, the deactivation enzyme UDP-glucuronosyltransferase 1, polypeptide A1 (UGT1A1, and efflux transporters ABCB1, ABCC1, ABCC2 and ABCG2. DNA-bound TOP1 protein amount in presence of CPT11, a marker of the drug PD, also displayed circadian variations. A mathematical model of CPT11 molecular pharmacokinetics-pharmacodynamics (PK-PD was designed and fitted to experimental data. It predicted that CPT11 bioactivation was the main determinant of CPT11 PD circadian rhythm. We then adopted the therapeutics strategy of maximizing efficacy in non-synchronized cells, considered as cancer cells, under a constraint of maximum toxicity in synchronized cells, representing healthy ones. We considered exposure schemes in the form of an initial concentration of CPT11 given at a particular CT, over a duration ranging from 1 to 27 h. For any dose of CPT11, optimal exposure durations varied from 3h40 to 7h10. Optimal schemes started between CT2h10 and CT2h30, a time interval corresponding to 1h30 to 1h50 before the nadir of CPT11 bioactivation rhythm in
Boivin, Diane B; James, Francine O
In this combined field and laboratory investigation, the authors tested the efficacy of an intervention designed to promote circadian adaptation to night-shift work. Fifteen nurses working permanent night schedules (> or = 8 shifts/ 15 days) were recruited from area hospitals. Following avacation period of > or = 10 days on a regular daytime schedule, workers were admitted to the laboratory for the assessment of circadian phase via a 36-h constant routine. They returned to work approximately 12 night shifts on their regular schedules under one of two conditions. Treatment group workers (n = 10, mean age +/- SD = 41.7 +/- 8.8 years) received an intervention including 6 h of intermittent bright-light exposure in the workplace (approximately 3,243 lux) and shielding from bright morning outdoor light with tinted goggles (15% visual light transmission). Control group workers (n = 9, mean age +/- SD = 42.0 +/- 7.2 years) were observed in their habitual work environments. On work days, participants maintained regular sleep/wake schedules including a single 8-h sleep/darkness episode beginning 2 h after the end of the night shift. A second 36-h constant routine was performed following the series of night shifts. In the presence of the intervention, circadian rhythms of core body temperature and salivary melatonin cycles were delayed by an average (+/- SEM) of -9.32 +/- 1.06 h and -11.31 +/- 1.13 h, respectively. These were significantly greater than the phase delays of -4.09 +/- 1.94 h and -5.08 +/- 2.32 h displayed by the control group (p = 0.03 and p = 0.02, respectively). The phase angle between circadian markers and the shifted schedule was reestablished to its baseline position only in the treatment group of workers. These results support the efficacy of a practical intervention for promoting circadian adaptation to night-shift work under field conditions. They also underline the importance of controlling the overall pattern of exposure to light and darkness in
Full Text Available Learning, memory consolidation, and retrieval are processes known to be modulated by the circadian (circa: about; dies: day system. The circadian regulation of memory performance is evolutionarily conserved, independent of the type and complexity of the learning paradigm tested, and not specific to crepuscular, nocturnal, or diurnal organisms. In mammals, long-term memory (LTM formation is tightly coupled to de novo gene expression of plasticity-related proteins and posttranslational modifications and relies on intact cAMP/protein kinase A (PKA/protein kinase C (PKC/mitogen-activated protein kinase (MAPK/cyclic adenosine monophosphate response element-binding protein (CREB signaling. These memory-essential signaling components cycle rhythmically in the hippocampus across the day and night and are clearly molded by an intricate interplay between the circadian system and memory. Important components of the circadian timing mechanism and its plasticity are members of the Period clock gene family (Per1, Per2. Interestingly, Per1 is rhythmically expressed in mouse hippocampus. Observations suggest important and largely unexplored roles of the clock gene protein PER1 in synaptic plasticity and in the daytime-dependent modulation of learning and memory. Here, we review the latest findings on the role of the clock gene Period 1 (Per1 as a candidate molecular and mechanistic blueprint for gating the daytime dependency of memory processing.
Circadian clocks evolved to allow plants and animals to adapt their behaviors to the 24-hr change in the external environment due to the Earth's rotation. While the first scientific observation of circadian rhythm in the plant leaf movement may be dated back to the early 18th century, it took 200 years to realize that the leaf movement is controlled by an endogenous circadian clock. The cloning and characterization of the first Drosophila clock gene period in the early 1980s, independently by Jeffery C. Hall and Michael Rosbash at Brandeis University and Michael Young at Rockefeller University, paved the way for their further discoveries of additional genes and proteins, culminating in establishing the so-called transcriptional translational feedback loop (TTFL) model for the generation of autonomous oscillator with a period of ∼24 h. The 2017 Nobel Prize in Physiology or Medicine was awarded to honor their discoveries of molecular mechanisms controlling the circadian rhythm. Copyright © 2018 Chang Gung University. Published by Elsevier B.V. All rights reserved.
Reyes, Catalina; Milsom, William K
Endogenous circadian and circannual rhythms may exist in the metabolism, ventilation, and breathing pattern of turtles that could further prolong dive times during daily and seasonal periods of reduced activity. To test this hypothesis, turtles were held under seasonal or constant environmental conditions over a 1-yr period, and in each season, V(O)(2) and respiratory variables were measured in all animals under both the prevailing seasonal conditions and the constant conditions for 24 h. Endogenous circadian and circannual rhythms in metabolism and ventilation occurred independent of ambient temperature, photoperiod, and activity, although long-term entrainment to daily and seasonal changes in temperature and photoperiod were required for them to be expressed. Metabolism and ventilation were always higher during the photophase, and the day-night difference was greater at any given temperature when the photoperiod was provided. When corrected for temperature, turtles had elevated metabolic and ventilation rates in the fall and spring (corresponding to the reproductive seasons) and suppressed metabolism and ventilation during winter. The strength of the circadian rhythm varied seasonally, with proportionately larger day-night differences in colder seasons. Daily and seasonal cycles in ventilation largely followed metabolism, although daily and seasonal changes did occur in the breathing pattern independent of levels of total ventilation. These endogenous circadian and circannual changes in metabolism, ventilation, and breathing pattern prolonged dive times at night and in winter and may serve to reduce the costs of breathing and transport and risk of predation.
Bendová, Z; Sumová, A; Mikkelsen, Jens D.
The circadian rhythms of mammals are generated by the circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Its intrinsic period is entrained to a 24 h cycle by external cues, mainly by light. Light impinging on the SCN at night causes either advancing or delaying phase...... shifts of the circadian clock. N-methyl-d-aspartate receptors (NMDAR) are the main glutamate receptors mediating the effect of light on the molecular clockwork in the SCN. They are composed of multiple subunits, each with specific characteristics whose mutual interactions strongly determine properties...
Rolph, R.; Mahoney, A. R.
Using ice concentration data from the Alaska Sea Ice Atlas from 1953-2013 for selected communities in Alaska, we find a consistent trend toward later freeze up and earlier breakup, leading a lengthened open water period. Such changes are often considered to bring a variety of "frontline" local impacts to Arctic coastal communities such as increased rates of coastal erosion. However, direct consequences of these changes to local food security (e.g. through impacts on subsistence activities and marine transport of goods) may be outweighed at least in the short term by the effects of large scale Arctic sea ice change coupled with global oil markets. For example, a later freeze-up might delay local hunters' transition from boats to snow-machines, but whether this trend will affect hunting success, especially in the next few years, is uncertain. Likewise, the magnitude of change in open water season length is unlikely to be sufficient to increase the frequency with which communities are served by barges. However, an expanding open water season throughout the Arctic has implications for the global economy, which can have indirect effects on local communities. In the Chukchi and Beaufort Seas, where rapid sea ice change has been accompanied by increased interest in oil and gas development, the U.S. Bureau of Ocean Energy Management currently requires drilling operations to cease 38 days prior to freeze up. Taking this into account, the lengthening open water season has effectively extended the drilling season for oil companies by 184% since the 1950s. If oil development goes ahead, local communities will likely experience a range of indirect impacts on food security due to increased vessel traffic and demand on infrastructure coupled with changes in local economies and employment opportunities. Increased likelihood of an oil spill in coastal waters also poses a significant threat to local food security. Thus, while Arctic coastal communities are already experiencing
Bai Zhenguo; Zhou Yicang
This paper studies the global dynamics of a viral infection model that takes into account circadian rhythm and time delay in the CTL response. It is shown that the basic reproduction numbers, R 0 and R 1 , determine the outcome of viral infection. Numerical simulations demonstrate that the changes in the amplitude of lytic component can generate a variety of dynamical patterns, ranging from simple daily oscillation to multi-day dynamics and eventually chaos, whereas time delay can alter the period of oscillation for the larger level of periodic forcing. These results can help to explain the viral oscillation behaviors, which were observed in chronic HBV and HCV infection patients.
Wells, Audrey M; Ridener, Elysia; Bourbonais, Clinton A; Kim, Woori; Pantazopoulos, Harry; Carroll, F Ivy; Kim, Kwang-Soo; Cohen, Bruce M; Carlezon, William A
Stress plays a critical role in the neurobiology of mood and anxiety disorders. Sleep and circadian rhythms are affected in many of these conditions. Here we examined the effects of chronic social defeat stress (CSDS), an ethological form of stress, on sleep and circadian rhythms. We exposed male mice implanted with wireless telemetry transmitters to a 10 day CSDS regimen known to produce anhedonia (a depressive-like effect) and social avoidance (an anxiety-like effect). EEG, EMG, body temperature, and locomotor activity data were collected continuously during the CSDS regimen and a 5 day recovery period. CSDS affected numerous endpoints, including paradoxical sleep (PS) and slow-wave sleep (SWS), as well as the circadian rhythmicity of body temperature and locomotor activity. The magnitude of the effects increased with repeated stress, and some changes (PS bouts, SWS time, body temperature, locomotor activity) persisted after the CSDS regimen had ended. CSDS also altered mRNA levels of the circadian rhythm-related gene mPer2 within brain areas that regulate motivation and emotion. Administration of the κ-opioid receptor (KOR) antagonist JDTic (30 mg/kg, i.p.) before CSDS reduced stress effects on both sleep and circadian rhythms, or hastened their recovery, and attenuated changes in mPer2 Our findings show that CSDS produces persistent disruptions in sleep and circadian rhythmicity, mimicking attributes of stress-related conditions as they appear in humans. The ability of KOR antagonists to mitigate these disruptions is consistent with previously reported antistress effects. Studying homologous endpoints across species may facilitate the development of improved treatments for psychiatric illness. SIGNIFICANCE STATEMENT Stress plays a critical role in the neurobiology of mood and anxiety disorders. We show that chronic social defeat stress in mice produces progressive alterations in sleep and circadian rhythms that resemble features of depression as it appears in
Full Text Available Mariana G Figueiro, Andrew Bierman, Mark S ReaLighting Research Center, Rensselaer Polytechnic Institute, Troy, NY, USAAbstract: A model of circadian phototransduction was published in 2005 to predict the spectral sensitivity of the human circadian system to narrow-band and polychromatic light sources by combining responses to light from the spectral-opponent “blue” versus “yellow” cone bipolar pathway with direct responses to light by the intrinsically photosensitive retinal ganglion cells. In the model, depolarizing “blue” responses, but not hyperpolarizing “yellow” responses, from the “blue” versus “yellow” pathway are combined with the intrinsically photosensitive retinal ganglion cell responses. Intrinsically photosensitive retinal ganglion cell neurons are known to be much slower to respond to light than the cone pathway, so an implication of the model is that periodic flashes of “blue” light, but not “yellow” light, would be effective for stimulating the circadian system. A within-subjects study was designed to test the implications of the model regarding retinal exposures to brief flashes of light. The study was also aimed at broadening the foundation for clinical treatment of circadian sleep disorders by delivering flashing light through closed eyelids while people were asleep. In addition to a dark control night, the eyelids of 16 subjects were exposed to three light-stimulus conditions in the phase delay portion of the phase response curve while they were asleep: (1 2-second flashes of 111 W/m2 of blue (λmax ≈ 480 nm light once every minute for 1 hour, (2 131 W/m2 of green (λmax ≈ 527 nm light, continuously on for 1 hour, and (3 2-second flashes of the same green light once every minute for 1 hour. Inferential statistics showed that the blue flash light-stimulus condition significantly delayed circadian phase and significantly suppressed nocturnal melatonin. The results of this study further our
Van Dongen, Hans P.A.; Belenky, Gregory; Vila, Bryan J.
Objectives: Under simulated shift-work conditions, we investigated the efficacy of a restart break for maintaining neurobehavioral functioning across consecutive duty cycles, as a function of the circadian timing of the duty periods. Design: As part of a 14-day experiment, subjects underwent two cycles of five simulated daytime or nighttime duty days, separated by a 34-hour restart break. Cognitive functioning and high-fidelity driving simulator performance were tested 4 times per day during the two duty cycles. Lapses on a psychomotor vigilance test (PVT) served as the primary outcome variable. Selected sleep periods were recorded polysomnographically. Setting: The experiment was conducted under standardized, controlled laboratory conditions with continuous monitoring. Participants: Twenty-seven healthy adults (13 men, 14 women; aged 22–39 years) participated in the study. Interventions: Subjects were randomly assigned to a nighttime duty (experimental) condition or a daytime duty (control) condition. The efficacy of the 34-hour restart break for maintaining neurobehavioral functioning from the pre-restart duty cycle to the post-restart duty cycle was compared between these two conditions. Results: Relative to the daytime duty condition, the nighttime duty condition was associated with reduced amounts of sleep, whereas sleep latencies were shortened and slow-wave sleep appeared to be conserved. Neurobehavioral performance measures ranging from lapses of attention on the PVT to calculated fuel consumption on the driving simulators remained optimal across time of day in the daytime duty schedule, but degraded across time of night in the nighttime duty schedule. The 34-hour restart break was efficacious for maintaining PVT performance and other objective neurobehavioral functioning profiles from one duty cycle to the next in the daytime duty condition, but not in the nighttime duty condition. Subjective sleepiness did not reliably track objective neurobehavioral
Full Text Available Pavol Svorc,1,2 Alexander Marossy,1 Pavol Svorc Jr2 1Department of Physiology, Medical Faculty, Safarik University, Kosice, Slovak Republic; 2Department of Physiology, Medical Faculty, Ostrava University, Ostrava, Czech Republic Objective: Respiratory alkalosis is an extremely common and complicated problem affecting virtually every organ system where the etiologies may be related to pulmonary or cardiovascular disorders. However, there are only few works describing daytime experiments or synchronization of animals to the external environmental periodicity. The aim of the study is to describe the circadian rhythm of the electrical stability of the heart under hyperventilatory conditions. Methods: Circadian rhythms of the electrical stability of the heart, measured by ventricular arrhythmia threshold ([VAT] measurement in 3 hour intervals, were followed during normal artificial ventilation (40 breaths/minute, tidal volume = 1 mL/100 g; n = 17 and hyperventilation (80 breaths/minute, tidal volume = 2 mL/100 g; n = 7 in pentobarbital (40 mg/kg administered intraperitoneally anesthetized female Wistar rats, after 4 week adaptation on the light/dark regime of 12 hour light/12 hour dark (40%–60% humidity, room temperature of 24°C in cages, two animals/cage with access to food and water ad libitum, with the dark period from 18.00h to 06.00h for 4 weeks. Results: The 24 hour course of the VAT showed the highest susceptibility of the rat ventricular myocardium to arrhythmias between 12.00h and 15.00h, and highest resistance between 19.20h and 00.28h (acrophase −338° in time at 22.53h with confidence intervals −2,880° to −70°, under normoxic conditions. Mesor was 2.59 ± 0.53 mA and amplitude 0.33 ± 0.11 mA. Hyperventilation increased the VAT at each interval of the measurement, but did not change the character of its circadian rhythm. Acrophase was on −40° (02.40h, mesor was increased (2.91 mA, and amplitude was decreased (0.13 m
Camargo-Sanchez, Andrés; Niño, Carmen L; Sánchez, Leonardo; Echeverri, Sonia; Gutiérrez, Diana P; Duque, Andrés F; Pianeta, Oscar; Jaramillo-Gómez, Jenny A; Pilonieta, Martin A; Cataño, Nhora; Arboleda, Humberto; Agostino, Patricia V; Alvarez-Baron, Claudia P; Vargas, Rafael
The circadian system controls the daily rhythms of a variety of physiological processes. Most organisms show physiological, metabolic and behavioral rhythms that are coupled to environmental signals. In humans, the main synchronizer is the light/dark cycle, although non-photic cues such as food availability, noise, and work schedules are also involved. In a continuously operating hospital, the lack of rhythmicity in these elements can alter the patient’s biological rhythms and resilience. This paper presents a Theory of Inpatient Circadian Care (TICC) grounded in circadian principles. We conducted a literature search on biological rhythms, chronobiology, nursing care, and middle-range theories in the databases PubMed, SciELO Public Health, and Google Scholar. The search was performed considering a period of 6 decades from 1950 to 2013. Information was analyzed to look for links between chronobiology concepts and characteristics of inpatient care. TICC aims to integrate multidisciplinary knowledge of biomedical sciences and apply it to clinical practice in a formal way. The conceptual points of this theory are supported by abundant literature related to disease and altered biological rhythms. Our theory will be able to enrich current and future professional practice. PMID:25767632
Ostrowska, Z.; Zwirska-Korczala, K.; Kajdaniuk, D.; Gorski, J.; Buntner, B.
The effect of pinealectomy and exogenous melatonin on the circadian testosterone variations was investigated (using the radioimmunoassay method) after 3 weeks of 50% food restriction in sexually mature male Wistar rats at 3-h intervals under 12:12 light-dark cycle. The circadian periodicity of testosterone secretion was maintained after caloric deprivation, however its mean 24-h concentration was lower and rhythm disturbances appeared in the form of acrophase shifts from 18.00 to 0.50 h. In pinealectomized animals the mean 24-h testosterone level and amplitude values were significantly increased without the rhythm disturbances. As compared to the control animals, underfed pinealectomized rats had a partial recovery of reduced testosterone levels during the 24-h cycle and showed a normalization of the rhythm acrophase. Melatonin administration was found to inhibit the testosterone mesor value in pinealectomized rats with acrophase shifts from 16.58 to 14.51 h. In comparison with the pinealectomized ones the underfed pinealectomized rats had a greater reduction of the mesor and amplitude values after the melatonin administration. These findings indicate that long-term food restriction sensitizes the circadian testicular axis to antigonadotropic action of the pineal gland. (author). 42 refs, 3 figs, 1 tab
Howard J Gritton
Full Text Available The suprachiasmatic nucleus (SCN is the primary circadian pacemaker in mammals that can synchronize or entrain to environmental cues. Although light exerts powerful influences on SCN output, other non-photic stimuli can modulate the SCN as well. We recently demonstrated that daily performance of a cognitive task requiring sustained periods of attentional effort that relies upon basal forebrain (BF cholinergic activity dramatically alters circadian rhythms in rats. In particular, normally nocturnal rats adopt a robust diurnal activity pattern that persists for several days in the absence of cognitive training. Although anatomical and pharmacological data from non-performing animals support a relationship between cholinergic signaling and circadian rhythms, little is known about how endogenous cholinergic signaling influences SCN function in behaving animals. Here we report that BF cholinergic projections to the SCN provide the principal signal allowing for the expression of cognitive entrainment in light-phase trained animals. We also reveal that oscillator(s outside of the SCN drive cognitive entrainment as daily timed cognitive training robustly entrains SCN-lesioned arrhythmic animals. Ablation of the SCN, however, resulted in significant impairments in task acquisition, indicating that SCN-mediated timekeeping benefits new learning and cognitive performance. Taken together, we conclude that cognition entrains non-photic oscillators, and cholinergic signaling to the SCN serves as a temporal timestamp attenuating SCN photic-driven rhythms, thereby permitting cognitive demands to modulate behavior.
Liu, Tianxin; Mahesh, Guruswamy; Houl, Jerry H; Hardin, Paul E
Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. Copyright © 2015 the authors 0270-6474/15/358662-10$15.00/0.
Saini, Camille; Morf, Jörg; Stratmann, Markus; Gos, Pascal; Schibler, Ueli
The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles. PMID:22379191
Saini, Camille; Morf, Jörg; Stratmann, Markus; Gos, Pascal; Schibler, Ueli
The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles.
Escobar, Carolina; Salgado, Roberto; Rodriguez, Katia; Blancas Vázquez, Aurea Susana; Angeles-Castellanos, Manuel; Buijs, Ruud M
Food is a potent time signal for the circadian system and has shown to entrain and override temporal signals transmitted by the biological clock, the suprachiasmatic nucleus, which adjusts mainly to the daily light/dark (LD) alternation. Organisms mostly ingest food in their active period and this permits a correct coordination between the LD and the food elicited time signals with the circadian system. Under conditions when feeding opportunities are shifted to the usual resting/sleep phase, the potent entraining force of food, shifts circadian fluctuations in several tissues, organs, and brain structures toward meal time, resulting a desynchrony within the body and between the organism and the external LD cycle. The daily scheduled access to a palatable snack exerts similar changes specifically to brain areas involved in motivation and reward responses. This review describes the phenomenology of food entrainment and entrainment by a palatable snack. It suggests how scheduled feeding can lead to food addiction and how shifted feeding schedules toward the sleep phase can result in altered ingestive behavior, obesity and disturbed metabolic responses. Copyright © 2011 Elsevier Inc. All rights reserved.
Westerterp-Plantenga, Margriet S
Circadian alignment is crucial for body-weight management, and for metabolic health. In this context, circadian alignment consists of alignment of sleep, meal patterns and physical activity. During puberty a significant reduction in sleep duration occurs, and pubertal status is inversely associated with sleep duration. A consistent inverse association between habitual sleep duration and body-weight development occurs, independent of possible confounders. Research on misalignment reveals that circadian misalignment affects sleep-architecture and subsequently disturbs glucose-insulin metabolism, substrate oxidation, leptin- and ghrelin concentrations, appetite, food reward, hypothalamic-pituitary-adrenal-axis activity and gut-peptide concentrations enhancing positive energy balance and metabolic disturbance. Not only aligning meals and sleep in a circadian way is crucial, also regular physical activity during the day strongly promotes the stability and amplitude of circadian rhythm, and thus may serve as an instrument to restore poor circadian rhythms. Endogenicity may play a role in interaction of these environmental variables with a genetic predisposition. In conclusion, notwithstanding the separate favourable effects of sufficient daily physical activity, regular meal patterns, sufficient sleep duration and quality sleep on energy balance, the overall effect of the amplitude and stability of the circadian rhythm, perhaps including genetic predisposition, may integrate the separate effects in an additive way.
Bluhm, Burton H; Burnham, A Michele; Dunkle, Larry D
Many metabolic and developmental processes in fungi are controlled by biological rhythms. Circadian rhythms approximate a daily (24 h) cycle and have been thoroughly studied in the model fungus, Neurospora crassa. However relatively few examples of true circadian rhythms have been documented among other filamentous fungi. In this study we describe a circadian rhythm underlying hyphal melanization in Cercospora kikuchii, an important pathogen of soybean. After growth in light or light : dark cycles, colonies transferred to darkness produced zonate bands of melanized hyphae interspersed with bands of hyaline hyphae. Rhythmic production of bands was remarkably persistent in the absence of external cues, lasting at least 7 d after transfer to darkness, and was compensated over a range of temperatures. As in N. crassa, blue light but not red light was sufficient to entrain the circadian rhythm in C. kikuchii, and a putative ortholog of white collar-1, one of the genes required for light responses in N. crassa, was identified in C. kikuchii. Circadian regulation of melanization is conserved in other members of the genus: Similar rhythms were identified in another field isolate of C. kikuchii as well as field isolates of C. beticola and C. sorghi, but not in wild-type strains of C. zeae-maydis or C. zeina. This report represents the first documented circadian rhythm among Dothideomycete fungi and provides a new opportunity to dissect the molecular basis of circadian rhythms among filamentous fungi.
Simons, Sterre S H; Cillessen, Antonius H N; de Weerth, Carolina
Hypothalamic-pituitary-adrenal (HPA) axis functioning is characterized by the baseline production of cortisol following a circadian rhythm, as well as by the superimposed production of cortisol in response to a stressor. However, it is relatively unknown whether the basal cortisol circadian rhythm is associated with the cortisol stress response in children. Since alterations in cortisol stress responses have been associated with mental and physical health, this study investigated whether the cortisol circadian rhythm is associated with cortisol stress responses in 6-year-old children. To this end, 149 normally developing children (M age = 6.09 years; 70 girls) participated in an innovative social evaluative stress test that effectively provoked increases in cortisol. To determine the cortisol stress response, six cortisol saliva samples were collected and two cortisol stress response indices were calculated: total stress cortisol and cortisol stress reactivity. To determine children's cortisol circadian rhythm eight cortisol circadian samples were collected during two days. Total diurnal cortisol and diurnal cortisol decline scores were calculated as indices of the cortisol circadian rhythm. Hierarchical regression analyses indicated that higher total diurnal cortisol as well as a smaller diurnal cortisol decline, were both uniquely associated with higher total stress cortisol. No associations were found between the cortisol circadian rhythm indices and cortisol stress reactivity. Possible explanations for the patterns found are links with children's self-regulatory capacities and parenting quality.
Full Text Available Since Bünning’s observation of circadian rhythms and photoperiodism in the runner bean Phaseolus multiflorus in 1936, many studies have shown that photoperiodism is based on the circadian clock system. In insects, involvement of circadian clock genes or neurons has been recently shown in the photoperiodic control of developmental arrests, diapause. Based on molecular and neuronal studies in Drosophila melanogaster, photoperiodic changes have been reported for expression patterns of the circadian clock genes, subcellular distribution of clock proteins, fiber distribution, or the number of plausible clock neurons in different species. Photoperiod sets peaks of per or tim mRNA abundance at lights-off in Sarcophaga crassipalpis, Chymomyza costata and Protophormia terraenovae. Abundance of per and Clock mRNA changes by photoperiod in Pyrrhocoris apterus. Subcellular Per distribution in circadian clock neurons changes with photoperiod in P. terraenovae. Although photoperiodism is not known in Leucophaea maderae, under longer day length, more stomata and longer commissural fibers of circadian clock neurons have been found. These plastic changes in the circadian clock neurons could be an important constituent for photoperiodic clock mechanisms to integrate repetitive photoperiodic information and produce different outputs based on day length.
Potter, Gregory D M; Skene, Debra J; Arendt, Josephine; Cade, Janet E; Grant, Peter J; Hardie, Laura J
Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important.
Li, Siyue; Wang, Yali; Wang, Fen; Hu, Li-Fang; Liu, Chun-Feng
Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.
Skene, Debra J.; Arendt, Josephine; Cade, Janet E.; Grant, Peter J.; Hardie, Laura J.
Circadian (∼24-hour) timing systems pervade all kingdoms of life and temporally optimize behavior and physiology in humans. Relatively recent changes to our environments, such as the introduction of artificial lighting, can disorganize the circadian system, from the level of the molecular clocks that regulate the timing of cellular activities to the level of synchronization between our daily cycles of behavior and the solar day. Sleep/wake cycles are intertwined with the circadian system, and global trends indicate that these, too, are increasingly subject to disruption. A large proportion of the world's population is at increased risk of environmentally driven circadian rhythm and sleep disruption, and a minority of individuals are also genetically predisposed to circadian misalignment and sleep disorders. The consequences of disruption to the circadian system and sleep are profound and include myriad metabolic ramifications, some of which may be compounded by adverse effects on dietary choices. If not addressed, the deleterious effects of such disruption will continue to cause widespread health problems; therefore, implementation of the numerous behavioral and pharmaceutical interventions that can help restore circadian system alignment and enhance sleep will be important. PMID:27763782
Lauren M. DePoy
Full Text Available Circadian rhythms are endogenously generated near 24-hour variations of physiological and behavioral functions. In humans, disruptions to the circadian system are associated with negative health outcomes, including metabolic, immune, and psychiatric diseases, such as addiction. Animal models suggest bidirectional relationships between the circadian system and drugs of abuse, whereby desynchrony, misalignment, or disruption may promote vulnerability to drug use and the transition to addiction, while exposure to drugs of abuse may entrain, disrupt, or perturb the circadian timing system. Recent evidence suggests natural (i.e., food and drug rewards may influence overlapping neural circuitry, and the circadian system may modulate the physiological and behavioral responses to these stimuli. Environmental disruptions, such as shifting schedules or shorter/longer days, influence food and drug intake, and certain mutations of circadian genes that control cellular rhythms are associated with altered behavioral reward. We highlight the more recent findings associating circadian rhythms to reward function, linking environmental and genetic evidence to natural and drug reward and related neural circuitry.
Pendergast, Julie S.; Branecky, Katrina L.; Huang, Roya; Niswender, Kevin D.; Yamazaki, Shin
Consumption of high-fat diet acutely alters the daily rhythm of eating behavior and circadian organization (the phase relationship between oscillators in central and peripheral tissues) in mice. Voluntary wheel-running activity counteracts the obesogenic effects of high-fat diet and also modulates circadian rhythms in mice. In this study, we sought to determine whether voluntary wheel-running activity could prevent the proximate effects of high-fat diet consumption on circadian organization and behavioral rhythms in mice. Mice were housed with locked or freely rotating running wheels and fed chow or high-fat diet for 1 week and rhythms of locomotor activity, eating behavior, and molecular timekeeping (PERIOD2::LUCIFERASE luminescence rhythms) in ex vivo tissues were measured. Wheel-running activity delayed the phase of the liver rhythm by 4 h in both chow- and high-fat diet-fed mice. The delayed liver phase was specific to wheel-running activity since an enriched environment without the running wheel did not alter the phase of the liver rhythm. In addition, wheel-running activity modulated the effect of high-fat diet consumption on the daily rhythm of eating behavior. While high-fat diet consumption caused eating events to be more evenly dispersed across the 24 h-day in both locked-wheel and wheel-running mice, the effect of high-fat diet was much less pronounced in wheel-running mice. Together these data demonstrate that wheel-running activity is a salient factor that modulates liver phase and eating behavior rhythms in both chow- and high-fat-diet fed mice. Wheel-running activity in mice is both a source of exercise and a self-motivating, rewarding behavior. Understanding the putative reward-related mechanisms whereby wheel-running activity alters circadian rhythms could have implications for human obesity since palatable food and exercise may modulate similar reward circuits. PMID:24624109
Gu, Changgui; Yang, Huijie
In mammals, the master clock is located in the suprachiasmatic nucleus (SCN), which is composed of about 20 000 nonidentical neuronal oscillators expressing different intrinsic periods. These neurons are coupled through neurotransmitters to form a network consisting of two subgroups, i.e., a ventrolateral (VL) subgroup and a dorsomedial (DM) subgroup. The VL contains about 25% SCN neurons that receive photic input from the retina, and the DM comprises the remaining 75% SCN neurons which are coupled to the VL. The synapses from the VL to the DM are evidently denser than that from the DM to the VL, in which the VL dominates the DM. Therefore, the SCN is a heterogeneous network where the neurons of the VL are linked with a large number of SCN neurons. In the present study, we mimicked the SCN network based on Goodwin model considering four types of networks including an all-to-all network, a Newman-Watts (NW) small world network, an Erdös-Rényi (ER) random network, and a Barabási-Albert (BA) scale free network. We found that the circadian rhythm was induced in the BA, ER, and NW networks, while the circadian rhythm was absent in the all-to-all network with weak cellular coupling, where the amplitude of the circadian rhythm is largest in the BA network which is most heterogeneous in the network structure. Our finding provides an alternative explanation for the induction or enhancement of circadian rhythm by the heterogeneity of the network structure.
Wang, Tao; Yang, Ping; Zhan, Yibei; Xia, Lin; Hua, Zichun; Zhang, Jianfa
The severity of ethanol-induced liver injury is associated with oxidative stress and lipid accumulation in the liver. Core circadian clock is known to mediate antioxidative enzyme activity and lipid metabolism. However, the link between circadian clock and ethanol-induced hepatotoxicity remains unclear. Here we showed that extents of acute ethanol-induced liver injury and steatosis in mice exhibit circadian variations consistent with hepatic expression of Period (Per) genes. Mice lacking clock gene Per1 displayed less susceptible to ethanol-induced liver injury, as evidenced by lower serum transaminase activity and less severe histopathological changes. Ethanol-induced lipid peroxidation was alleviated in Per1−/− mice. However, Per1 deletion had no effect on antioxidants depletion caused by ethanol administration. Ethanol-induced triglycerides (TG) accumulation in the serum and liver was significantly decreased in Per1−/− mice compared with that in wild-type (WT) mice. Analysis of gene expression in the liver revealed peroxisome proliferators activated receptor-gamma (PPARγ) and its target genes related to TG synthesis are remarkably down-regulated in Per1−/− mice. HepG2 cells were treated with ethanol at 150 mM for 3 days. Per1 overexpression augmented lipid accumulation after treatment with ethanol in HepG2 cells, but had no effect on ethanol-induced oxidative stress. Expression of genes related to lipogenesis, including PPARγ and its target genes, was up-regulated in cells overexpressing Per1. In conclusion, these results indicated that circadian rhythms of ethanol-induced hepatotoxicity are controlled by clock gene Per1, and deletion of Per1 protected mice from ethanol-induced liver injury by decreasing hepatic lipid accumulation
Videnovic, Aleksandar; Noble, Charleston; Reid, Kathryn J; Peng, Jie; Turek, Fred W; Marconi, Angelica; Rademaker, Alfred W; Simuni, Tanya; Zadikoff, Cindy; Zee, Phyllis C
Diurnal fluctuations of motor and nonmotor symptoms and a high prevalence of sleep-wake disturbances in Parkinson disease (PD) suggest a role of the circadian system in the modulation of these symptoms. However, surprisingly little is known regarding circadian function in PD and whether circadian dysfunction is involved in the development of sleep-wake disturbances in PD. To determine the relationship between the timing and amplitude of the 24-hour melatonin rhythm, a marker of endogenous circadian rhythmicity, with self-reported sleep quality, the severity of daytime sleepiness, and disease metrics. A cross-sectional study from January 1, 2009, through December 31, 2012, of 20 patients with PD receiving stable dopaminergic therapy and 15 age-matched control participants. Both groups underwent blood sampling for the measurement of serum melatonin levels at 30-minute intervals for 24 hours under modified constant routine conditions at the Parkinson's Disease and Movement Disorders Center of Northwestern University. Twenty-four hour monitoring of serum melatonin secretion. Clinical and demographic data, self-reported measures of sleep quality (Pittsburgh Sleep Quality Index) and daytime sleepiness (Epworth Sleepiness Scale), and circadian markers of the melatonin rhythm, including the amplitude, area under the curve (AUC), and phase of the 24-hour rhythm. Patients with PD had blunted circadian rhythms of melatonin secretion compared with controls; the amplitude of the melatonin rhythm and the 24-hour AUC for circulating melatonin levels were significantly lower in PD patients (P hour melatonin AUC (P = .001). Disease duration, Unified Parkinson's Disease Rating Scale scores, levodopa equivalent dose, and global Pittsburgh Sleep Quality Index score in the PD group were not significantly related to measures of the melatonin circadian rhythm. Circadian dysfunction may underlie excessive sleepiness in PD. The nature of this association needs to be explored further
Brown, Steven A; Zumbrunn, Gottlieb; Fleury-Olela, Fabienne; Preitner, Nicolas; Schibler, Ueli
Low-amplitude temperature oscillations can entrain the phase of circadian rhythms in several unicellular and multicellular organisms, including Neurospora and Drosophila. Because mammalian body temperature is subject to circadian variations of 1 degrees C-4 degrees C, we wished to determine whether these temperature cycles could serve as a Zeitgeber for circadian gene expression in peripheral cell types. In RAT1 fibroblasts cultured in vitro, circadian gene expression could be established by a square wave temperature rhythm with a (Delta)T of 4 degrees C (12 hr 37 degrees C/12 hr 33 degrees C). To examine whether natural body temperature rhythms can also affect circadian gene expression, we first measured core body temperature cycles in the peritoneal cavities of mice by radiotelemetry. We then reproduced these rhythms with high precision in the liquid medium of cultured fibroblasts for several days by means of a homemade computer-driven incubator. While these "in vivo" temperature rhythms were incapable of establishing circadian gene expression de novo, they could maintain previously induced rhythms for multiple days; by contrast, the rhythms of control cells kept at constant temperature rapidly dampened. Moreover, circadian oscillations of environmental temperature could reentrain circadian clocks in the livers of mice, probably via the changes they imposed upon both body temperature and feeding behavior. Interestingly, these changes in ambient temperature did not affect the phase of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. We postulate that both endogenous and environmental temperature cycles can participate in the synchronization of peripheral clocks in mammals.
The circadian rhythm of tyrosine aminotransferase (TAT) was investigated during 48 hours in the liver of mice subjected to: a/ subcutaneous inflammatory reaction, b/ ionizing radiation. The cyclic changes in the circadian enzyme activity were described with a harmonic function. In relation to the control mice in the experimental mice statistically significant changes were demonstrated in the activity of tyrosine aminotransferase associated with desynchronization of the circadian TAT rhythm, particularly evident in the first hours of the first day of the experiment. The functions of enzyme activity changed in the second 24-hours period showed, both qualitatively and quantitatively, a tendency for a gradual return of normal TAT activity in the 24-hour periods. (author)
Traynard, Pauline; Feillet, Céline; Soliman, Sylvain; Delaunay, Franck; Fages, François
Experimental observations have put in evidence autonomous self-sustained circadian oscillators in most mammalian cells, and proved the existence of molecular links between the circadian clock and the cell cycle. Some mathematical models have also been built to assess conditions of control of the cell cycle by the circadian clock. However, recent studies in individual NIH3T3 fibroblasts have shown an unexpected acceleration of the circadian clock together with the cell cycle when the culture medium is enriched with growth factors, and the absence of such acceleration in confluent cells. In order to explain these observations, we study a possible entrainment of the circadian clock by the cell cycle through a regulation of clock genes around the mitosis phase. We develop a computational model and a formal specification of the observed behavior to investigate the conditions of entrainment in period and phase. We show that either the selective activation of RevErb-α or the selective inhibition of Bmal1 transcription during the mitosis phase, allow us to fit the experimental data on both period and phase, while a uniform inhibition of transcription during mitosis seems incompatible with the phase data. We conclude on the arguments favoring the RevErb-α up-regulation hypothesis and on some further predictions of the model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.
Kannan, R.; Latha, G.; Prashanthi Devi, M.
An ambient noise system consisting of a vertical linear hydrophone array was deployed in the shallow waters off Chennai, southeast coast of India from 1 August to 16 September 2013 to record ambient ocean noise of frequencies up to 10kHz. Biological sounds, which are broadband, short duration signals resulting from Terapon theraps, a native species, are a prominent feature of the ocean soundscape. Terapon activity peaks at 8pm and 11pm, and its presence is not observed after 12 midnight in both the months. In the other period, the ambient noise fluctuation is due to wind and vessel traffic. Hence, the present study focuses on the description of the ambient noise fluctuation over two 12h periods, i.e., 12 midnight-12 noon considered as period I, and 12 noon-12 midnight as period II in order to show the circadian rhythm of ambient noise. In this study area, Terapon vocalization reached 25dB above the ambient noise level and it dominates the short-term spectra records in the 0.4-4kHz range. All Terapon signals had daily patterns of sound production with highest levels of activity after dusk during the study period. The result shows that the circadian rhythm of ambient noise is mainly of biological sound generated by Terapon and it is reported first time in the shallow waters off the southeast coast of India.
Kim, Heung Bae; Vakili, Khashayar; Ramos-Gonzalez, Gabriel J; Stein, Deborah R; Ferguson, Michael A; Porras, Diego; Lock, James E; Chaudry, Gulraiz; Alomari, Ahmad; Fishman, Steven J
Midaortic syndrome (MAS) is a rare condition characterized by stenosis of the abdominal aorta. Patients with disease refractory to medical management will usually require either endovascular therapy or surgery with use of prosthetic graft material for bypass or patch angioplasty. We report our early experience with a novel approach using a tissue expander (TE) to lengthen the normal native arteries in children with MAS, allowing primary aortic repair without the need for prosthetic graft material. We conducted a retrospective review of patients with MAS undergoing the TE-stimulated lengthening of arteries (TESLA) procedure at our institution from 2010 to 2014. Data are presented as mean (range). Five patients aged 4.8 years (3-8 years) underwent the TESLA procedure. Stages of this procedure include the following: stage I, insertion of retroaortic TE; stage II, serial TE injections; and stage III, final repair with excision of aortic stenosis and primary end-to-end aortic anastomosis. Stage II was completed in 4 months (1-9 months) with 12 (7-20) TE injections. Goal lengthening was achieved in all patients. Stage III could not be completed in one patient because of extreme aortic inflammation, which precluded safe excision of the aortic stenosis and required use of a prosthetic bypass graft. The other four patients completed stage III with two (one to three) additional vessels also requiring reconstruction (renal or mesenteric arteries). At 3.2 years (1-6 years) of follow-up, all patients are doing well. The TESLA procedure allows surgical correction of MAS without the need for prosthetic grafts in young children who are still growing. Copyright © 2017 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.