Gotowa bibliografia na temat „Circadian strategies”

Background. Nowadays personalized medicine is actively developing and consists of individual approaches during patients' treatment, diagnoses and prognoses. Since the first use of DNA sequence analysis in 2009, many other directions and methods for precision medicine have been proposed, including metabolome, transcriptome, proteome, microbiome analysis etc., which reflect internal factors of organisms. Moreover, to take into account environmental influence on organisms including day/night activity, feeding and physical training regime, it was proposed to apply the descriptions of circadian system rhythmicity of each patient. Also, with organism aging, the sensitivity to external factors is raised that emphasizes the importance of the chronobiological approach in anti-aging concept. In this review we discussed available ways of the application of circadian system parameters to analyze human metabolic state. Methods. Search strategy: PubMed, Scopus, DOAJ (Directory of Open Access Journals) and Google Scholar were used to search for original research and articles review; no abstracts from meeting reports have been cited. ClinicalTrials.gov was used to search for clinical studies. Search terms included “chronotherapy”, “circadian system”, and “chronobiology”. Results. According to personalized medicine, the analysis of circadian system in the case of each patient is necessary as circadian rhythmicity varies in every person. Taking into account the peculiarities of patient’s circadian system it will be easy to choose the best time for drug administration resulting in high efficacy and low side effects. The analysis of circadian system can be performed on molecular, physiological and systemic (general, metabolic and inflammation markers) levels. There was shown the increase in the number of clinical trials which are based on the use of chronobiological approach during the treatment of different pathologies that increase with aging: depression, insomnia, metabolic and cardiovascular disease, cancer. More than 1,000 clinical trials involving circadian interventions and chronobiology have been registered worldwide. Conclusion. Chronobiological approach can be used as an additional measure to anti-aging therapy to diagnose metabolic state, to choose more effective treatment time as well as in preventive healthcare in terms of personalized medicine.

BACKGROUND: Human fatigue is an important factor within aviation, leading organizations to develop strategies to assess and mitigate associated risks. The U.S. Air Force’s Air Mobility Command (AMC) conducted the current pilot study to assess fatigue-related risks and issues in mobility operations. Specifically, we examined the relationship among fatigue perceptions, fatigue mitigation strategies, performance effectiveness graph reference, and circadian typology.METHODS: There were 21 volunteers from the Joint Base Charleston C-17 pilot community (Mage = 28.67; SDage = 2.11; Proportionmale = 85.71%) who completed a survey. Items referred to fatigue perceptions, fatigue mitigation strategies, performance effectiveness graph reference, and circadian typology. We examined descriptive statistics, correlations among the variables of interest, and possible moderation effects of circadian typology.RESULTS: Overall, aircrew perceived fatigue to be a serious safety of flight concern. Personal fatigue concerns and perceptions of pressure to continue missions despite fatigue were associated with increased use of the strategy of limiting light exposure during sleep episodes (r = 0.49 and 0.47). Fatigue perceptions were not directly associated with performance effectiveness graph usage. Results suggested that morning type participants might be more likely to utilize specific fatigue mitigation strategies when there are concerns of fatigue compared to evening types.DISCUSSION: Despite organizational efforts, fatigue continues to be a serious concern for the mobility community. This pilot study suggests that circadian typology might affect the relationship between fatigue perceptions and fatigue mitigation strategies and resource use. Future research should further examine these relationships and their impact within fatigue risk management (FRM) programs.Morris MB, Howland JP, Amaddio KM, Gunzelmann G. Aircrew fatigue perceptions, fatigue mitigation strategies, and circadian typology. Aerosp Med Hum Perform. 2020; 91(4):363–368.

Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a ‘24/7’ lifestyle where activity often occurs during the body’s ‘biological night’, resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility.

The circadian system in the human body responds to daily environmental changes to optimise behaviour according to the biological clock and also influences various physiological processes. The suprachiasmatic nuclei are located in the anterior hypothalamus of the brain, and they synchronise to the 24 h light/dark cycle. Human physiological functions are highly dependent on the regulation of the internal circadian clock. Skeletal muscles comprise the largest collection of peripheral clocks in the human body. Both central and peripheral clocks regulate the interaction between the musculoskeletal system and energy metabolism. The skeletal muscle circadian clock plays a vital role in lipid and glucose metabolism. The pathogenesis of osteoporosis is related to an alteration in the circadian rhythm. In the present review, we discuss the disturbance of the circadian rhythm and its resultant effect on the musculoskeletal system. We also discuss the nutritional strategies that are potentially effective in maintaining the system’s homeostasis. Active collaborations between nutritionists and physiologists in the field of chronobiological and chrononutrition will further clarify these interactions. This review may be necessary for successful interventions in reducing morbidity and mortality resulting from musculoskeletal disturbances.

Type 2 diabetes mellitus (T2DM) patients are at a higher risk of developing Alzheimer’s disease (AD). Mounting evidence suggests the emerging important role of circadian rhythms in many diseases. Circadian rhythm disruption is considered to contribute to both T2DM and AD. Here, we review the relationship among circadian rhythm disruption, T2DM and AD, and suggest that the occurrence and progression of T2DM and AD may in part be associated with circadian disruption. Then, we summarize the promising therapeutic strategies targeting circadian dysfunction for T2DM and AD, including pharmacological treatment such as melatonin, orexin, and circadian molecules, as well as non-pharmacological treatments like light therapy, feeding behavior, and exercise.

Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased metabolic and cardiac disorders. It is imperative to understand how disrupted circadian rhythms alter metabolic function to develop strategies to mitigate their negative effects. In this review, we provide an introduction to circadian rhythms, physiological regulation of homeostasis by the suprachiasmatic nucleus (SCN), and SCN-mediated hormones that display circadian rhythms, including melatonin and glucocorticoids. Next, we discuss circadian-gated physiological processes including sleep and food intake, followed by types of disrupted circadian rhythms and how modern lighting disrupts molecular clock rhythms. Lastly, we identify how disruptions to hormones and metabolism can increase susceptibility to metabolic syndrome and risk for cardiovascular diseases, and discuss various strategies to mitigate the harmful consequences associated with disrupted circadian rhythms on human health.

Throughout the evolutionary time, all organisms and species on Earth evolved with an adaptation to consistent oscillations of sunlight and darkness, now recognized as ‘circadian rhythm.’ Single-cellular to multisystem organisms use circadian biology to synchronize to the external environment and provide predictive adaptation to changes in cellular homeostasis. Dysregulation of circadian biology has been implicated in numerous prevalent human diseases, and subsequently targeting the circadian machinery may provide innovative preventative or treatment strategies. Discovery of ‘peripheral circadian clocks’ unleashed widespread investigations into the potential roles of clock biology in cellular, tissue, and organ function in healthy and diseased states. Particularly, oxygen-sensing pathways (e.g. hypoxia inducible factor, HIF1), are critical for adaptation to changes in oxygen availability in diseases such as myocardial ischemia. Recent investigations have identified a connection between the circadian rhythm protein Period 2 (PER2) and HIF1A that may elucidate an evolutionarily conserved cellular network that can be targeted to manipulate metabolic function in stressed conditions like hypoxia or ischemia. Understanding the link between circadian and hypoxia pathways may provide insights and subsequent innovative therapeutic strategies for patients with myocardial ischemia. This review addresses our current understanding of the connection between light-sensing pathways (PER2), and oxygen-sensing pathways (HIF1A), in the context of myocardial ischemia and lays the groundwork for future studies to take advantage of these two evolutionarily conserved pathways in the treatment of myocardial ischemia.

Thesis (MSc)--Stellenbosch University, 2014.
ENGLISH ABSTRACT: Introduction: Mammalian circadian rhythms form an integral physiological system allowing for the synchronisation of all metabolic processes to daily light/dark cycles, thereby optimising their efficacy. Circadian disruptions have been implicated in the onset and progression of different types of cancers, including those arising in the breast. Several links between the circadian protein Per2 and DNA damage responses exist. Aberrant Per2 expression results in potent downstream effects to both cell cycle and apoptotic targets, suggestive of a tumour suppressive role for Per2. Due to the severe dose limiting side effects associated with current chemotherapeutic strategies, including the use of doxorubicin, a need for more effective adjuvant therapies to increase cancer cell susceptibility has arisen. We therefore hypothesize, that the manipulation of the circadian Per2 protein in conjunction with doxorubicin may provide a more effective chemotherapeutic strategy for the treatment of breast cancer. The aims of this project were thus to: (i) Characterize the role of Per2 in normal breast epithelial cells as well as in ER+ and ER- breast cancer cells; (ii) to determine the role of Per2 in doxorubicin-induced cell death, (iii) to determine the role of Per2 in autophagy and finally (iv) to assess whether the pharmacological inhibition of Per2 with metformin, can sensitize chemo-resistant MDA-MB-231 breast cancer cells to doxorubicin-induced cell death. Methods: An in vitro model of breast cancer was employed using the normal MCF-12A breast epithelial, estrogen receptor positive (ER+) MCF-7 and estrogen receptor negative (ER-) MDA-MB-231 breast adenocarcinoma cell lines. Circadian rhythmicity of Per2 protein expression was determined using western blotting, and Per2 cellular localization was assessed using fluorescent confocal microscopy. Per2 was then silenced by means of an endoribonuclease-prepared siRNA, and silencing efficiency was determined with the use of western blotting. The roles of Per2 in doxorubicin-induced cell death and autophagy were assessed by treating MDA-MB-231 breast cancer cells under the following conditions (1) Control, (2) 2.5 μM doxorubicin or 10 nM bafilomycin A1 (3) 30 nM esiPer2 and (4) 30 nM esiPer2 in combination with 2.5 μM doxorubicin or 10 nM bafilomycin A1. Following treatments cell viability was assessed using the MTT assay, western blotting for markers of apoptosis including p-MDM2 (Ser166), p-p53 (Ser15), cleaved caspase-3 and –PARP as well as markers of autophagy (AMPKα, mTOR and LC3). Furthermore, cell cycle analysis, G2/M transition and cell death (Hoechst 33342 and propidium iodide staining) were assessed by means of flow cytometry. The pharmacological inhibition of Per2 was achieved by treating MDA-MB-231 cells with 40 mM metformin as well as in combination with 2.5 μM doxorubicin. MTT cell viability assays, cell cycle analysis (flow cytometry) and western blotting for apoptosis (Per2, p-AMPKα (Thr172), p53, caspase-3 and PARP) were assessed. Results and discussion: A circadian pattern of Per2 protein expression was observed in the normal MCF-12A and MDA-MB-231 cancer cells with protein levels peaking at ±700% and ±500% of baseline was observed. However, no rhythmic expression was observed in the MCF-7 cancer cells. Immunostaining for Per2 showed localization OF Per2 in the cytoplasm as well as in the nucleus of both the MCF-12A and MDA-MB-231 cells. Concentration curves showed a significant reduction in cell viability following 2.5 μM doxorubicin treatment for 24 hours. Per2 protein expression was significantly reduced with both esiPer2 and metformin treatment. Silencing of Per2 in combination with doxorubicin treatment resulted in cell cycle arrest with a significant increase in apoptosis, indicating that Per2 silencing effectively sensitized the MDA-MB-231 cancer cells to the anti-carcinogenic properties of doxorubicin. Modulation of Per2 protein expression was effectively achieved with the use metformin although this decrease occurred independently of AMPKα phosphorylation. A significant increase in apoptosis was observed following treatment with metformin in combination with doxorubicin treatment. However, no changes in cell cycle regulation were observed. Per2 appears to be involved in the regulation of autophagy as a significant increase in autophagy flux was observed when Per2 was silenced. Additionally, this increase in autophagic flux resulted in a significant increase in MDA-MB-231 cancer cell death which was enhanced further when autophagy was inhibited with bafilomycin A1 subsequent to Per2 silencing. Conclusions: Per2 protein expression was shown to display a 24 hour circadian rhythm in the MCF-12A cells, and to a lesser extent in the MDA-MB-231 cells. However, the MCF-7 cells failed to show rhythmic changes in Per2 protein expression. Per2 was shown to be located predominantly in the cytoplasm, with nuclear localization observed when cytoplasmic fluorescent intensity was lower. Per2 silencing effectively sensitized the chemo-resistant MDA-MB-231 breast cancer cells to both doxorubicin-induced cell death and autophagic inhibition.
AFRIKKANSE OPSOMMING: Inleiding: Sirkadiese ritmes vorm ‘n integrale fisiologiese sisteem wat die sinkronisasie van alle metaboliese prosesse asook lig/donker siklusse se effektiwiteit optimaliseer. Onderbreking van hierdie sirkadiese ritmes word geïmpliseer in die ontstaan en bevordering van verskillende kankertipes, insluitend borskanker. Verskeie raakpunte bestaan tussen die sirkadiese proteïen, Per2, en die DNA skade-respons. Abnormale Per2 uitdrukking veroorsaak afstroom effekte op beide die selsiklus en apoptotiese teikens wat moontlik aanduidend van ‘n tumor-onderdrukkende rol vir Per2 kan wees. Daar bestaan ‘n groot nood vir meer effektiewe adjuvante terapieë om kankersel vatbaarheid vir chemoterapie te verhoog as gevolg van dosis-beperkende newe-effekte wat geassosieer word met huidige chemoterapeutiese strategieë, insluitende dié van doxorubicin. Ons hipotese is dus dat die manipulering van die sirkadiese Per2 proteïen tesame met doxorubicin ‘n meer effektiewe chemoterapeutiese strategie vir die behandeling van borskanker sal wees. Die doelwitte van hierdie projek was dus om: (i) Die rol van Per2 in normale borsepiteelselle sowel as in ER+ en ER- borsepiteel kankerselle te karakteriseer; (ii) die rol van Per2 in doxorubicin-geïnduseerde seldood te bepaal; (iii) te bepaal of Per2 ‘n rol in autofagie speel en laastens (iv) te bepaal of die farmakologiese inhibisie van Per2 met metformin chemo-weerstandbiedende MDA-MB-231 kankerselle kan sensitiseer vir doxorubicin-geïnduseerde seldood. Metodes: ‘n In vitro model vir borskanker is gebruik wat normale MCF-12A borsepiteelselle, estrogeen reseptor positiewe (ER+) MCF-7 en estrogeen reseptor negatiewe (ER-) MDA-MB-231 bors adenokarsenoomselle insluit. Sirkadiese ritmisiteit van Per2 proteïen uitdrukking is deur middel van die westelike kladtegniek bepaal en die sellulêre ligging van Per2 deur middel van fluoresensie mikroskopie. siPer2 is voorberei deur middel van endoribonuklease-siRNA en die effektiwiteit daarvan is deur middel van westelike kladtegniek getoon. Die rol van Per2 in doxorubicin-geinduseerde seldood en autofagie is bepaal deur MDA-MB-231 borskankerselle onder die volgende omstandighede te toets: (1) Kontrole, (2) 2.5 μM doxorubicin of 10 nM bafilomycin A1 (3) 30 nM esiPer2 en (4) 30 nM esiPer2 in kombinasie met 2.5 μM doxorubicin of 10 nM bafilomycin A1. Na die behandeling, is sellewensvatbaarheid bepaal deur gebruik te maak van ‘n MTT toets; westelike kladtegniek is gebruik om vir merkers van apoptose soos p-MDM2 (Ser166), p-p53 (Ser15), gekliefde caspase-3 en -PARP asook vir merkers van autofagie (AMPKα, mTOR en LC3) te toets. Die selsiklus, G2/M oorgang en seldood (Hoechst 33342 en propidium iodide kleuring) is deur middel van vloeisitometrie bepaal. Per2 is ook farmakologies geïnhibeer deur MDA-MB-231 selle met 40 mM metformin asook in kombinasie met 2.5 μM doxorubicin te behandel. Daarna is sellewensvatbaarheid (MTT) sowel as die selsiklus (vloeisitometrie) en apoptose (westelike kladtegniek vir Per2, p-AMPKα (Thr172), p53, caspase-3 and PARP) gemeet. Resultate en bespreking: ‘n Sirkadiese patroon vir Per2 proteïen uitdrukking is in die normale MCF-12A selle asook in die MDA-MB-231 kankerselle waargeneem met proteïenvlakke wat hul piek by ±700% and ±500% onderskeidelik in vergelyking met basislyn bereik het. Geen ritmiese patroon van Per2 proteïen uitdrukking is egter in die MCF-7 kankerselle waargeneem nie. Immunokleuring om Per2 ligging te bepaal het getoon dat Per2 in the sitoplasma sowel as in die nukleus in beide MCF-12A en MDA-MB-231 selle voorgekom het. Konsentrasie kurwes het aangetoon dat daar ‘n insiggewende vermindering in sellewensvatbaarheid voorgekom het na die behandeling van die selle met 2.5 μM doxorubicin vir 24 uur. Per2 proteïen uitdrukking is insiggewend verlaag met beide esiPer2 en metformin behandeling van die selle. esiPer2 aleen of in kombinasie met doxorubicin behandeling het selsiklus staking tot gevolg gehad asook ‘n beduidende toename in apoptose veroorsaak wat dus aangedui het dat esiPer2 effektief was om MDA-MB-231 kankerselle te sensitiseer vir die anti-karsinogeniese doxorubicin behandeling. Modulering van Per2 proteïen uitdrukking was effektief met metformin behandeling, alhoewel die afname onafhanklik van AMPKα fosforilasie plaasgevind het. ‘n Insiggewende toename in apoptose is waargeneem na metformin behandeling in kombinasie met doxorubicin. Geen veranderinge in die selsiklus is egter onder hierdie omstandighede waargeneem nie. Per2 blyk betrokke te wees in die regulering van autofagie aangesien ‘n insiggewende verhoging in autofagie omsetting waargeneem is na esiPer2 behandeling. Die toename in autofagie omsetting is geassosieer met ‘n insiggewende toename in seldood in MDA-MB-231 kankerselle wat verder verhoog is wanneer autofagie met bafilomycin A1 (autofagie inhibitor) in kombinasie met esiPer2 behandel is. Gevolgtrekkings: Per2 proteïen uitdrukking het ‘n 24 uur sirkadiese ritme in die MCF-12A normale selle, en tot ‘n mindere mate in die MDA-MB-231 selle getoon. Die MCF-7 selle het egter geen ritmiese patroon van Per2 proteïen uitdrukking getoon nie. Per2 kom hoofsaaklik in die sitoplasma voor en het slegs in die nukleus voorgekom wanneer die sitoplasmiese fluoresensie intensiteit laer was. esiPer2 was dus effektief om die chemo-weerstandbiedende MDA-MB-231 borskankerselle te sensitiseer vir doxorubicin-geïnduseerde seldood.
National Research Foundation

[ITA]La demenza consiste nel deterioramento, spesso progressivo, dello stato cognitivo di un individuo. Chi è affetto da demenza, presenta alterazioni a livello cognitivo, comportamentale e motorio, ad esempio compiendo gesti ossessivi, ripetitivi, senza uno scopo preciso. La condizione dei pazienti affetti da demenza è valutata clinicamente tramite apposite scale e le informazioni relative al comportamento vengono raccolte intervistando chi se ne occupa, come familiari, il personale infermieristico o il medico curante. Spesso queste valutazioni si rivelano inaccurate, possono essere fortemente influenzate da considerazioni soggettive, e sono dispendiose in termini di tempo. Si ha quindi l'esigenza di disporre di metodiche oggettive per valutare il comportamento motorio dei pazienti e le sue alterazioni patologiche; i sensori inerziali indossabili potrebbero costituire una valida soluzione, per questo scopo. L'obiettivo principale della presente attività di tesi è stato definire e implementare un software per una valutazione oggettiva, basata su sensori, del pattern motorio circadiano, in pazienti affetti da demenza ricoverati in un'unità di terapia a lungo termine, che potrebbe evidenziare differenze nei sintomi della malattia che interessano il comportamento motorio, come descritto in ambito clinico. Lo scopo secondario è stato quello di verificare i cambiamenti motori pre- e post-intervento in un sottogruppo di pazienti, a seguito della somministrazione di un programma sperimentale di intervento basato su esercizi fisici. --------------- [ENG]Dementia involves deterioration, often progressive, of a person's cognitive status. Those who suffer from dementia, present alterations in cognitive and motor behavior, for example performing obsessive and repetitive gestures, without a purpose. The condition of patients suffering from dementia is clinically assessed by means of specific scales and information relating to the behavior are collected by interviewing caregivers, such as the family, nurses, or the doctor. Often it turns out that these are inaccurate assessments that may be heavily influenced by subjective evaluations and are costly in terms of time. Therefore, there is the need for objective methods to assess the patients' motor behavior and the pathological changes; wearable inertial sensors may represent a viable option, so this aim. The main objective of this thesis project was to define and implement a software for a sensor-based assessment of the circadian motor pattern in patients suffering from dementia, hospitalized in a long-term care unit, which could highlight differences in the disease symptoms affecting the motor behavior, as described in the clinical setting. The secondary objective was to verify pre- and post-intervention changes in the motor patterns of a subgroup of patients, following the administration of an experimental program of intervention based on physical exercises.

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O organismo humano apresenta uma ritmicidade de eventos bioquímicos, fisiológicos e comportamentais durante as 24 horas do dia, fazendo com que o mesmo tenha peculiaridades distintas nos diferentes horários diurnos e noturnos. Esta ritmicidade circadiana encontra-se intimamente ligada a sincronizadores externos: ciclo claro/escuro; ritmos sociais; a organizaçäo temporal da atividade laborativa do indivíduo, dentre outros. A organizaçäo temporal do trabalho dos aeronautas caracteriza-se pela alternância dos seus turnos, o que em última análise, significa dizer que este trabalhador muitas vezes desempenha suas atividades profissionais em diferentes momentos do dia e da noite. Esta inversäo de horários de repouso por momentos de trabalho acarreta alteraçöes na ritmicidade biológica. Objetiva-se investigar a percepçäo de comandantes, da aviaçäo civil brasileira, que realizam jornadas transmeridionais sobre as repercussöes que estas condiçöes de trabalho podem ter sobre sua saúde. Para a coleta dos dados, foram distribuídos questionários para todos os comandantes de Boeing 767 da base Rio de Janeiro, das companhias VARIG e Transbrasil. Do total de 87 questionários enviados, obteve-se um retorno de 25. Os resultados demonstraram que as condiçöes de trabalho dos comandantes apresentam sérias e inúmeras implicaçöes sobre a sua saúde. A sensaçäo de fadiga, as alteraçöes do ciclo sono-vigília e dos hábitos alimentares e o afastamento familiar foram os fatores que mais apareceram no relato dos comandantes como sendo os mais comprometidos, causando consequências como sonolência, distúrbios gratrointestinais, comprometimentos na vida familiar como divórcios, dentre outros. Com o intuito de minimizar estes sintomas, os comandantes desenvolveram algumas estratégias como dormir assim que chegam ao local de destino, praticar algum tipo de atividade física e seguir os horários do local, que säo utilizadas com frequência e, segundo seus próprios relatos, com êxito no que se propöem.
The human body presents a rhythmicity of biochemical, physiological and behavioral events throughout the 24 hours of a day. It means that this body has different peculiarities during the day and others at night. This circadian rhythmicity is closely linked to “zeitgebers” (external synchronizers): sleep/wake cycle, social rhythms, shiftwork and so on. One of the most important characteristics within the aviation profession is the alternation of shifts, which means that the aeronauts have to develop their professional activities at different hours of the day and night. This inversion of work periods in lieu of resting ones results in rhythmicity changes. The aim of this study was to investigate the perception of Brazilian civil aviation captains and the influences of their type of work conditions upon their health. The data collection was made using questionnaires which were distributed to all Rio de Janeiro-based Boeing 767 captains employed by VARIG and Transbrasil during the research period. From all the 87 questionnaires sent, 25 returned. The results showed that flight captains` working conditions present several and serious implications on their health. The fatigue, the changes both in the sleep/wake cycle and in the eating habits and the deleterious effects on social events were the aspects cited by the captains as being the most affected ones causing consequences like sleepiness, gastro-intestinal disturbances, relationship difficulties, among others. In order to minimize these symptoms the captains developed some strategies like sleeping as soon as they arrive at their destination, practicing some physical activities and following the local time, which are used very often and successfully.

Demand for 24-h access to services and goods has led to an increase in the number of employees engaged in shiftwork. However, while shiftwork has become necessary to meet community expectations, it has serious consequences for health and safety. The risk of fatigue-related accidents and injuries is a significant problem for the shift working population. This is because shiftwork places restrictions on the opportunities available for workers to obtain sleep. Shiftworkers, especially those who work night shifts, must often stay awake for long hours and sleep at times inconsistent with their body clocks, so sleep loss is common. This dissertation evaluates alternative options for arranging sleep that could potentially optimise neurobehavioural function in circumstances where long nocturnal sleep episodes are not possible. Two main approaches were used to address these aims. The first was to assess the effectiveness of split sleep-wake schedules at sustaining neurobehavioural function around the clock – with and without sleep restriction – which could have implications for work rosters in certain safety-critical industries. The second approach was to assess the effectiveness of different arrangements of daytime sleep at ameliorating the decline of night-time performance, which could have implications for the sleep strategies shiftworkers employ before and after night shifts.

This chapter provides an overview of the incidence, presentation, assessment, diagnosis, and management of the four main circadian rhythm sleep disorders: advanced sleep phase disorder (ASPD), delayed sleep phase disorder (DSPD), free-running (non-24-hour) sleep disorder (FRSD), and irregular sleep–wake rhythm disorder (ISWRD). Following a brief discussion of the daily entrainment of the human circadian clock to the light cycle, and the shifting effects of light and melatonin on the clock, each of the four different disorders are considered in turn. The aim of this chapter is to provide a concise overview of the disorders and the potential treatment strategies for each. The chapter is extensively referenced for further information.

Fatigue can significantly impair healthcare providers, potentially increasing the possibility of an adverse event. The study of fatigue incorporates concepts from neuroscience, dynamic systems, human factors, and risk management, and relates these elements to circumstances faced by all healthcare professionals. An understanding of the circadian rhythm can help physicians and administrators to develop shift strategies that mitigate the effects of fatigue on human performance. Strategies such as duty-hour limits, “power naps,” and judicious use of caffeine can all help providers who must work at night or during extended shifts.

This book chapter reviews the most common sleep disorders in older adults and their treatment. It begins with a brief review of sleep physiology and then gives an outline on how to take a comprehensive sleep history. Sleep is commonly defined as a periodic temporary loss of consciousness with restorative effects. There are physiological sleep changes related to ageing, but sleep disorders are not part of normal ageing and are often associated with mental or physical disorders, pain and neurodegenerative disease. The most common sleep disorders include insomnia, obstructive sleep apnoea, restless legs syndrome, REM sleep behaviour disorder, excessive daytime somnolence and circadian rhythms disorders. An in depth clinical history, including if possible bed-partner’s information, is the key to diagnosis. Patients need to be informed about the physiological sleep changes and the principles of sleep hygiene. They can benefit from pharmacological and non-pharmacological treatment strategies.

Circadian rhythm disorders are a group of sleep conditions that involve a misalignment of an individual’s internal timekeeping system with that of one’s desired sleep-wake time. This desynchrony can compromise sleep health as well as the functioning of other organ system, and significantly diminish one’s quality of life. There are six well-defined circadian rhythm disorders that can be classified as either intrinsic or extrinsic, based on the underlying factors that contribute to the condition. Intrinsic circadian disorders include the following: 1) advanced sleep-wake phase disorder, 2) delayed sleep-wake phase disorder, 3) irregular sleep-wake rhythm disorder, and 4) non-24-hour sleep-wake rhythm disorder. The two circadian disorders caused by external factors include 1) shift work disorder, and 2) jet lag disorder, both of which are due to behaviorally mediated misalignments of circadian system. This chapter serves to summarize these disorders, guide clinicians towards screening and evaluation of these conditions, and introduce basic treatment strategies that can be applied by non-sleep medicine clinicians.

Introduction Normal sleep: stages and cycles Assessment of sleep disorders Insomnia 1: overview Insomnia 2: general management strategies Sleep-related breathing disorders Hypersomnia 1: overview Hypersomnia 2: narcolepsy Hypersomnia 3: other causes Circadian rhythm sleep disorders 1: overview Circadian rhythm sleep disorders 2: management Parasomnias 1: overview...

This chapter reviews the most common sleep disorders in older adults and their treatment. It begins with a brief review of sleep physiology and then gives an outline on how to take a comprehensive sleep history. There are physiological sleep changes related to ageing, but sleep disorders are not part of normal ageing and are often associated with mental or physical disorders, pain, and neurodegenerative disease. The most common sleep disorders include insomnia, obstructive sleep apnoea, restless legs syndrome, REM sleep behaviour disorder, excessive daytime somnolence, and circadian rhythm disorders. An in-depth clinical history, including if possible, bed-partner’s information, is the key to diagnosis. Patients need to be informed about the physiological sleep changes and the principles of sleep hygiene. Many sleep disorders have effective therapies and patients will benefit from pharmacological and nonpharmacological treatment strategies.

COVID-19 is a highly contagious viral illness that has claimed millions of lives worldwide. Since its emergence, it has exerted a negative impact on many sectors globally without the exception of frontline COVID-19 healthcare providers. Specifically, in frontline COVID-19 healthcare workers, occupational stress-related sleep disorders such as insomnia and daytime somnolence have been extensively reported and were characterized by neuro-immunological changes. However, the possible mechanisms that underlie the sleep disorders have not been elucidated. The review was designed to highlight possible sleep mechanisms responsible for insomnia and daytime somnolence reported in frontline COVID-19 health workers. Available evidence shows that emotional perturbation, hypertension, chronobiological disruption and prolonged exposure to artificial light are among the events orchestrating occupational-stress-related sleep disorders in frontline COVID-19 healthcare workers. Anxiety-associated sleep anomaly is attributable to stimulation of the reticular activating system which occurs as a result of activation of noradrenergic fiber and sympatho-adrenal axis. Another mechanism includes depletion of hippocampal and brain glycogen by anxiety-induced activation of corticotropin releasing hormone (CRH)-secreting brain neurons and hypothalamic-corticotropic-adrenal cortex axis. Spontaneous discharge of noradrenergic fiber during basal state and changes in normal secretory rhythm of hypnosis-related chemical messengers may be responsible for hypertension- and chronobiological disruption-induced sleep disorders, respectively. Lastly, prolonged light exposure-induced suppression of melatonin secretion may elicit disruption of normal circadian sleep.

Sleep problems are common in childhood and are associated significant morbidities negatively impacting the patient and family and thus necessitating early intervention and treatment. This chapter is focused on management addressing the etiology and predisposing and precipitating factors of sleep disorders spanning from infancy to childhood and adolescence. Current recommendations for safe infant sleep, promotion of sleep hygiene strategies in childhood, and treatment options of representative pediatric sleep disorders such as sleep-disordered breathing, insomnia, sleep-related movement disorders, circadian rhythm disorders, and hypersomnia are reviewed. Additionally, management of sleep disorders unique to medical disorders such as Prader-Willi syndrome, Down syndrome, and autism also are addressed.

Clinical depression can disrupt sleep patterns, and chronic insomnia contributes to the development of depressive symptoms in later life. This chapter supports providers as they help middle-aged and older adults to regulate sleep patterns and develop healthy sleep habits. Contents of this module provide psychoeducation about sleep to shape expectations and use circadian rhythms to support healthy sleep, build sleep debt, and reduce nighttime arousal. This chapter also describes the Practice forms provided in the workbook for clients’ use between psychotherapy and integrated primary care sessions to remember and use these skills. This chapter directs clinicians to apply recommended strategies that are responsive to the needs of culturally diverse aging clients, including within the context of telehealth.

The circadian disruption associated with bipolar disorder and the success of social rhythm therapies in ameliorating distress and improving functioning make it clear that “healthy habits”—sufficient sleep, nutritious eating, and plentiful exercise—are important components of successful outcomes for persons with bipolar spectrum disorders. Additionally, evidence for the benefits of nutritional interventions and phototherapy is growing. Finally, mood charting and other self-help strategies are increasingly recognized as important components of recovery. Given that 20 to 50% of adults with bipolar disorder use some form of nonconventional therapy, it is important for mental health providers of all disciplines to be familiar with the literature in this area. This chapter provides an overview of integrative interventions and reviews evidence supporting their use.

With the latest initiative of the government to develop a high speed passenger rail system in the United States the first and most important strategic transportation goal is to “Ensure safe and efficient transportation choices. A key element of safe railroad operation is to address the issue of fatigue among railroad operating employees and how to fight it. In this paper, we are presenting a novel approach to estimating fatigue levels of train conductors by analyzing the speech signal in the communication between the conductor and dispatch. We extract vocal indicators of fatigue from the speech signal and use Fuzzy Logic to generate an estimate of the mental state of the train conductor. Previous research has shown that sleeping disorders, reduced hours of rest and disrupted circadian rhythms lead to significantly increased fatigue levels which manifest themselves in alterations of speech patterns as compared to alert states of mind. To make a decision about the level of fatigue, we are proposing a Fuzzy Logic algorithm which combines inputs such as word production rate and speech intensity to generate a Fatigue Quotient at any moment in time when speech is present. The computation of the Fatigue Quotient relies on a rule base which draws from existing knowledge about fatigue indicators and their relation to the level of fatigue of the subject. For this project, the rule base and the membership functions associated with it were derived from real time testing and the subsequent tuning of parameters to refine the detection of changes in patterns. It was successfully shown that Fuzzy Logic can be implemented to estimate alertness levels from speech metrics in real-time and that the membership functions for this purpose can be found empirically through iterative testing. Furthermore, this study has proven that the framework to run such an analysis continuously as a monitoring function in locomotive cabins is feasible and can be realized with relatively inexpensive hardware.

The original objectives of the approved proposal included: 1. Establishment of the biosynthetic pathways for pheromone production using labeled precursors and GC-MS. 2. The elucidation of a circadian regulation of key enzymes in the biosynthetic pathway. 3. The identification, characterization and confirmation of functional expression of the delta-desaturases. 4. The identification of gene regulatory processes involved in the expression of the key enzymes in the biosynthetic pathway. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilized by a variety of moth species to attract conspecific mates. The sex pheromones used are commonly composed of blends of aliphatic molecules that vary in chain length, geometry, degree and position of double bonds and functional groups. They are formed by various actions of specific delta-desaturases to which chain shortening, elongation, reduction, acetylation, and oxidation of a common fatty acyl precursor is coupled. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). The development of specific and safe insect control strategies utilizing pheromone systems depends on a clear knowledge of the molecular mechanisms involved. In this proposal we aimed at identifying and characterizing specific desaturases involved in the biosynthetic pathway of two moth pest-speciesof stored products, P. interpunctella and S. cerealella, and to elucidate the regulation of the enzymes involved in pheromone biosynthesis. Due to technical difficulties the second stored product pest was excluded from the study at an early phase of the research project. Major conclusions: Within the framework of the planned objectives we confirmed the pheromone biosynthetic pathway of P. interpunctella and H. armigera by using labeled precursor molecules. In addition, in conjunction with various inhibitors we determined the PBAN-stimulated rate-limiting step for these biosynthetic pathways. We thereby present conclusive evidence that the enzyme Acetyl Coenzyme A Carboxylase is activated as a result of PBAN stimulation. We also found that P. interpunctella produce the main pheromone component Z9, E12 Tetradecenyl acetate through the action of a D11 desaturase working on the 16:Acid precursor. This is evidenced by the high amount of incorporation of ²H-labeled 16:Acid into pheromone when compared to the incorporation of ²H-labeled 14:Acid. However, in contrast to reports on other moth species, P. interpunctella is also capable of utilizing the 14:Acid precursor, although to a much lesser extent than the 16:Acid precursor. Despite the discovery of nine different desaturase gene transcripts in this species, from the present study it is evident that although PCR detected all nine gene transcripts, specific to female pheromone glands, only two are highly expressed whereas the other 7 are expressed at levels of at least 10⁵ fold lower showing very low abundance. These two genes correspond to D11-like desaturases strengthening the hypothesis that the main biosynthetic pathway involves a D11 desaturase.

The original objectives of the approved proposal included: (a) The determination of species- and tissue-specificity of the PBAN-R; (b) the elucidation of the role of juvenile hormone in gene regulation of the PBAN-R; (c) the identificationof the ligand binding domains in the PBAN-R and (d) the development of efficient screening assays in order to screen potential antagonists that will block the PBAN-R. Background to the topic: Moths constitute one of the major groups of pest insects in agriculture and their reproductive behavior is dependent on chemical communication. Sex-pheromone blends are utilised by a variety of moth species to attract conspecific mates. In most of the moth species sex-pheromone biosynthesis is under circadian control by the neurohormone, PBAN (pheromone-biosynthesis-activating neuropeptide). In order to devise ideal strategies for mating disruption/prevention, we proposed to study the interactions between PBAN and its membrane-bound receptor in order to devise potential antagonists. Major conclusions: Within the framework of the planned objectives we have confirmed the similarities between the two Helicoverpa species: armigera and zea. Receptor sequences of the two Helicoverpa spp. are 98% identical with most changes taking place in the C-terminal. Our findings indicate that PBAN or PBAN-like receptors are also present in the neural tissues and may represent a neurotransmitter-like function for PBAN-like peptides. Surprisingly the gene encoding the PBAN-receptor was also present in the male homologous tissue, but it is absent at the protein level. The presence of the receptor (at the gene- and protein-levels), and the subsequent pheromonotropic activity are age-dependent and up-regulated by Juvenile Hormone in pharate females but down-regulated by Juvenile Hormone in adult females. Lower levels of pheromonotropic activity were observed when challenged with pyrokinin-like peptides than with HezPBAN as ligand. A model of the 3D structure of the receptor was created using the X-ray structure of rhodopsin as a template after sequence alignment of the HezPBAN-R with several other GPCRs and computer simulated docking with the model predicted putative binding sites. Using in silico mutagenesis the predicted docking model was validated with experimental data obtained from expressed chimera receptors in Sf9 cells created by exchanging between the three extracellular loops of the HezPBAN-R and the Drosophila Pyrokinin-R (CG9918). The chimera receptors also indicated that the 3ʳᵈ extracellular loop is important for recognition of PBAN or Diapause hormone ligands. Implications: The project has successfully completed all the objectives and we are now in a position to be able to design and screen potential antagonists for pheromone production. The successful docking simulation-experiments encourage the use of in silico experiments for initial (high-throughput) screening of potential antagonists. However, the differential responses between the expressed receptor (Sf9 cells) and the endogenous receptor (pheromone glands) emphasize the importance of assaying lead compounds using several alternative bioassays (at the cellular, tissue and organism levels). The surprising discovery of the presence of the gene encoding the PBAN-R in the male homologous tissue, but its absence at the protein level, launches opportunities for studying molecular regulation pathways and the evolution of these GPCRs. Overall this research will advance research towards the goal of finding antagonists for this important class of receptors that might encompass a variety of essential insect functions.