Hintergrund: Neue Erkenntnisse zeigten, dass der Geruchssinn kein konstantes Merkmal ist, sondern durch zahlreiche interne und externe Faktoren beeinflusst wird und sich verändert. Studien an Tieren legen nahe, dass der Geruchssinn durch die innere Uhr reguliert wird und einer zirkadianen Rhythmik folgt. Allerdings sind Studien mit Menschen zu diesem Thema begrenzt. Die vorliegende Studie hatte daher das Ziel, die tageszeitlichen Schwankungen des Geruchssinns bei gesunden Erwachsenen zu untersuchen und potenzielle Einflussfaktoren zu identifizieren. Material und Methoden: Zu vier Testzeitpunkten innerhalb eines einzelnen Tages wurden 56 gesunde Testpersonen (Hauptgruppe) im Alter von 18-68 Jahren am Morgen (8-10 Uhr), am Mittag (12-14 Uhr), am Nachmittag (16-18 Uhr) und am Abend (20-22 Uhr) getestet. Bei einer kleinen Zusatzgruppe (n=4) wurden die vier Termine auf vier verschiedene Tage verteilt. Zum ersten Testzeitpunkt absolvierten die Teilnehmenden einen kompletten Riechtest, bestehend aus Schwellen-, Diskriminations- und Identifikationstest mittels Sniffin‘ Sticks und einen Konzentrationstest (d2-R-Test). Sie beantworteten umfassende Fragebögen zu Schlafqualität, Chronotyp, Vorerkrankungen und Nasensymptomatik, sowie Selbsteinschätzungen der Nasenatmung, des Riechvermögens, der Wachheit und der Konzentrationsfähigkeit mittels Visueller Analogskala (VAS). Außerdem erfolgten Messungen der Kreislaufparameter Herzfrequenz und Blutdruck und der Nasenatmung (PNIF). Bei den weiteren Terminen wurden die Messungen der Riechschwelle, Konzentrationsfähigkeit, PNIF, Blutdruck, Herzfrequenz und die Selbsteinschätzung (VAS) wiederholt. Ergebnisse: Die Riechschwellenwerte variierten signifikant zwischen den verschiedenen Tageszeiten, wobei der beste Wert am Abend und der schlechteste am Morgen gemessen wurde. Ähnliche Tendenzen wurden auch beim PNIF beobachtet, mit einer Verbesserung der Werte im Tagesverlauf (morgens<mittags<nachmittags<abends). Es gab jedoch keine signifikanten Korrelationen zwischen dem Riechschwellen- und PNIF-Wert zu den vier Testzeitpunkten und keinen signifikanten Zusammenhang zwischen der Differenz der Schwellenwerte (Schwelle Abend - Schwelle Morgen) und der Differenz der PNIF-Werte (PNIF Abend - PNIF Morgen). Außerdem wurde ein potenzieller Einfluss des Chronotyp auf das Riechvermögen beobachtet. Personen, die dem Morgentyp zugeteilt wurden, hatten morgens und mittags signifikant bessere Ergebnisse als Personen aus der Abendtyp-Gruppe. Ebenso lieferten Testpersonen der Abendtyp-Gruppe abends und nachmittags signifikant bessere Testergebnisse. Bei Personen mit Hyp- oder Anosmie wurden stärkere Schwankungen im Schwellentest im Laufe eines Tages dokumentiert. Personen mit höherem BMI und Personen mit subjektiv besserem Riechvermögen hatten signifikant bessere Testergebnisse im Schwellentest. Schlussfolgerung: Es kann aus den Ergebnissen der Studie, unter Berücksichtigung der experimentellen Limitationen, geschlussfolgert werden, dass sich der Geruchssinn des Menschen im Laufe eines Tages verändert. Die höchste Geruchsempfindlichkeit und parallel dazu die beste nasale Durchgängigkeit (PNIF) ist abends zu beobachten. Es scheint jedoch, dass die zirkadianen Veränderungen des Riechvermögens nicht wesentlich von den zirkadianen Veränderungen des nasalen Luftstroms abhängen. Außerdem könnten Chronotyp und BMI die beobachteten zirkadianen Schwankungen des Riechvermögens beeinflussen. Die Ergebnisse dieser Studie bieten wichtige Einblicke in die tageszeitlichen Veränderungen der Riechfunktion und liefern Erkenntnisse für die zukünftige Forschung auf dem Gebiet genauer Diagnosen und Behandlungen von Riechstörungen.:Abkürzungsverzeichnis 1. Einleitung 2. Wissenschaftliche Grundlagen 3. Material und Methoden 4. Ergebnisse 5. Diskussion 6. Zusammenfassung 7. Summary 8. Abbildungsverzeichnis 9. Tabellenverzeichnis 10. Wissenschaftliche Veröffentlichung 11. Literaturverzeichnis 12. Danksagung 13. Anhang

Actuellement, le diagnostic différentiel du trouble bipolaire (TB) et du trouble de personnalité limite (TPL) à l’adolescence s’avère difficile et complique le choix thérapeutique. Portant sur le TB et le TPL, ce mémoire fait le point sur la littérature scientifique adulte et adolescente, vérifie la faisabilité et présente les résultats d’une étude exploratoire portant sur les variables cliniques (instabilité émotionnelle, hostilité, impulsivité, tempraément) et le rythme veille-sommeil à l’adolescence. L’étude exploratoire comprend sept adolescents TB et huit TPL (12-17 ans), évalués par questionnaires autoadministrés pour les variables cliniques, et par actigraphie et agenda de sommeil pour le rythme veille-sommeil. Aucune différence significative n’existe entre les deux troubles pour les variables cliniques. En moyenne, les adolescents TB ont porté l'actigraphie pendant 9,9 jours et ont rempli un agenda de sommeil pendant 5,7 jours; chez les TPL, les chiffres sont respectivement 9,8 et 8,9 jours. Comparés aux TPL, les TB ont un plus grand intervalle d’éveil (p=0,035), ont un plus grand intervalle de sommeil (p>0,05), et ont une plus grand variabilité intrajournalière (p=0,04). Les données subjectives (agenda de sommeil) semblent refléter les données objectives (actigraphie) : aucune différence statistique n’est observée entre les deux mesures pour le délai d’endormissement, la durée du dernier réveil et le temps total de sommeil. La recension de la littérature montre un manque de données chez l’adolescent quant aux deux troubles. La faisabilité de l’étude est démontrée par la présence de résultats analysables. Ceci encourage la poursuite des recherches sur ces variables, afin de distinguer les deux psychopathologies à l’adolescence. / Presently, differential diagnosis between bipolar disorder (BD) and borderline personality disorder (BPD) in adolescents remains difficult and affects therapeutic choices. This master’s thesis reviews current scientific literature, both in adults and adolescents. It examines feasibility and presents results of a study on clinical dimensions and endophenotypes in adolescent BD and BPD. Seven BD and eight BPD adolescents (12-17 years old) were evaluated by self-reported questionnaires for clinical variables (affective instability, impulsivity, hostility and temperament) and by actigraphy and sleep diary for sleep-wake circadian rhythm. No significant difference was found between BD and BPD for the clinical variables. BD adolescents wore actigraphic device for 9.9 days and completed the sleep diary for 5.7 days on average; for BPD subjects, the numbers were respectively 9.8 days and 8.9 days. Compared to BPD, BD patients had longer active interval (p=0.035), tended to sleep longer, and had more intradaily variability (p=0.04). Subjective data (sleep diary) and objective data (actigraphy) did not significantly differ on sleep onset latency, last awakening duration and total sleep time, which suggested that BD and BPD adolescents had a good estimate of their sleep patterns. Literature review showed a dearth of research done on adolescent BD and BPD. Feasibility of this study was verified, since data was successfully collected. Research on these variables should continue, so differential diagnosis can be done in adolescent BD and BPD.

Cette thèse examine le rythme veille-sommeil et son association avec l’instabilité émotionnelle, l’agressivité et l’impulsivité dans le trouble de personnalité limite (TPL) à l’adolescence. Dans un premier temps, la revue de la littérature sur les perturbations objectives du sommeil dans le TPL a mis en lumière plusieurs difficultés similaires, évaluées par polysomnographie, à celles observées dans la dépression adulte. De 1980 à 2010, aucune recherche n’a examiné le rythme veille-sommeil, aucune n’a étudié les adolescents TPL et plusieurs n’ont pas contrôlé l’état dépressif comme facteur de confusion. De ce constat, il s’avérait pertinent de mener une étude sur le rythme veille-sommeil dans le TPL à l’adolescence en l’absence de dépression co-occurrente. L’adolescence comportant plusieurs caractéristiques physiologiques, psychologiques et sociales, tenir compte des aspects développementaux était essentiel. Dans un second temps, un protocole de recherche fût mis en place à la Clinique des troubles de l’humeur et le recrutement a été réalisé auprès d’adolescents souffrant d’un TPL et sans état dépressif actuel. Ils devaient porter pendant plus de neuf jours (période comprenant deux fins de semaine) un actigraphe, appareil non invasif évaluant l’alternance veille-sommeil dans l’environnement naturel. L’abandon précoce au traitement étant prévalent chez les patients TPL, la fiabilité de l’étude a été examinée afin de déterminer les raisons favorisant et celles nuisant au recrutement et à la collecte des données. La réflexion sur les aspects méthodologiques de l’étude actigraphique a permis d’expliquer les limites de ce type de protocole. Dans un troisième temps, le rythme veille-sommeil des adolescents TPL (n=18) a été caractérisé et comparé à celui des jeunes ayant un trouble bipolaire (n=6), trouble psychiatrique partageant plusieurs manifestations communes avec le TPL, et à celui des adolescents sans trouble de santé mentale (n=20). Les résultats suggèrent que l’adolescent TPL passe plus de temps en éveil durant la période de repos que les jeunes appartenant aux deux autres groupes. De plus, les adolescents TPL présentent une plus grande variabilité inter journalière des heures de lever et du temps total de sommeil que les autres adolescents. Ils se réveillent une heure de plus, et dorment donc une heure supplémentaire, que les adolescents sans trouble mental lors des journées sans routine. Dans un quatrième temps, les analyses corrélationnelles entre les données actigraphiques et les scores aux questionnaires auto-rapportés évaluant l’instabilité émotionnelle, l’agressivité et l’impulsivité suggèrent que plus l’adolescent TPL passe du temps éveillé alors qu’il est au lit, plus il déclare présenter des comportements agressifs, surtout physiques, durant le jour. En résumé, cette thèse contribue à la littérature scientifique en explorant pour la première fois le rythme veille-sommeil et son lien avec les manifestations symptomatiques dans le TPL à l’adolescence. Les résultats suggèrent fortement l’importance d’évaluer et de traiter les problèmes du rythme veille-sommeil que présentent ces jeunes lors de la prise en charge. / This dissertation examines sleep-wake patterns and their associations with emotional instability, aggressiveness, and impulsivity in adolescents with Borderline Personality Disorder (BPD). First, a literature review showed in BPD adults similar objective sleep disturbances, as assessed with polysomnography, to those observed in adult depression. Between 1980 and 2010, no study has examined sleep-wake patterns, none has recruited BPD adolescents, and many did not control depression as a confounding factor. Considering these limitations, it became relevant to conduct a study on sleep-wake patterns in euthymic adolescents with BPD. Having a developmental perspective in mind is crucial since adolescence presents many physiological, psychological and social characteristics. Second, a research protocol was set up at the Mood Disorders Clinic. Adolescents with BPD and without current depression were recruited. They wore for nine days or more (period covering two weekends) an actigraph, a non-invasive device assessing ecologically sleep-wake patterns. Because treatment dropout is highly prevalent in BPD adolescents, study feasibility was examined to determine the reasons promoting and those interfering with recruitment and data collection. Reflections on methodological aspects of this study allowed explaining the limits of this type of research protocol. Third, sleep-wake patterns in BPD adolescents (n=18) was characterised. They were compared to youth with Bipolar Disorder (n=6), a mental disorder sharing many common manifestations with BPD, and to adolescents without mental disorder (n=20). Results suggest that BPD adolescents spend more time awake during the rest interval than teenagers from the two other groups. Furthermore, BPD adolescents present higher interdaily variability for rising time and total sleep time than the other adolescents. They wake up an hour later, therefore sleeping one more hour, than adolescents without mental disorder on schedule-free days. Fourth, correlation analyses between actigraphy data and self-report questionnaire scores assessing emotional instability, aggressiveness, and impulsivity suggest that time spent awake during time in bed is associated with more daily physical aggressiveness in BPD adolescents. To summarise, this dissertation adds to the current scientific literature by exploring for the first time sleep-wake patterns and its associations with symptomatic manifestations of BPD in adolescents. From these results, it is highly recommended to assess and treat their sleep-wake disturbances during their therapeutic care.

O uso de répteis como modelos experimentais é limitado, principalmente devido às particularidades fisiológicas da classe, como as oscilações diárias e sazonais em seu comportamento. O objetivo deste estudo foi avaliar a atividade locomotora e nociceptiva de teiús (Salvator merianae) e iguanas-verdes (Iguana iguana) submetidos a testes comportamentais, ao longo do dia e do ano. Foram utilizados seis exemplares de cada espécie, mantidos em sala com temperatura ambiental (24 a 30°C) e fotoperíodo (12h:12h) controlados. Esses foram avaliados ao longo do dia (0:00h, 6:00h, 12:00h, 18:00h) e ao longo do ano (análise mensal). A análise locomotora foi realizada através do teste de campo aberto (teiús e iguanas), no qual o animal foi colocado no centro de uma arena circular por 15 minutos, e recebeu um ponto por cada ultrapassagem pelas subdivisões da mesma; e pelo teste de natação forçada (iguanas), no qual o tempo de atividade foi mensurado em piscina sem saída por 2 minutos. A resposta nociceptiva foi avaliada por meio de mensuração do período de latência do membro em resposta a estímulo nocivo térmico (25 segundos; 245 ± 7 mW/cm2) na superfície plantar do membro do animal. Não foram detectadas oscilações ao longo do ano no teste de campo aberto em nenhuma das espécies. Ao longo do dia, oscilações foram detectadas de Fevereiro a Dezembro em teiús; e em Abril, Maio, Junho e Outubro em iguanas. O tempo de atividade das iguanas foi menor em Janeiro e às 0:00h. Maiores latências de retirada do membro foram observadas nos meses de Maio e Agosto e às 6:00h em ambas espécies. Conclue-se que teiús e iguanas-verdes em ambiente controlado apresentam oscilações significativas em comportamento observado em teste de campo aberto, teste de natação forçada (somente iguanas) e teste plantar, que aparentemente não seguem padrões anuais claros, sendo provavelmente influenciado por fatores múltiplos ainda não compreendidos para as espécies. / The use of reptiles as experimental models is limited due to their physiological particularities, such as daily and annual fluctuations in behavior. The aim of this study was to evaluate locomotor and nociceptive activities of tegus (Salvator merianae) and green iguanas (Iguana iguana) throughout the day and the year, when undergoing behavioral tests. Six animals from each species, kept under controlled room temperature (24 to 30°C) and photoperiod (12h:12h), were used. They were evaluated throughout the day (0:00h, 6:00h, 12:00h and 18:00) and the year (monthly). Locomotor activity was measured by the open field test, in which the animal was placed in the center of a round arena for 15 minutes and the number of crossings through the subdivisions of the arena was counted, and by the forced swim test (iguanas), in which the activity period was timed after animals were placed in a pool with no scape for 2 minutes. Nociceptive activity was measured as the latency to limb withdrawal reflex in response to a noxious thermal stimulus (25 seconds, 245 ± 7 mW/cm2) in the plantar surface of the animal\'s limb. No differences were detected in locomotor activity in the open field test throughout the year in both species. Throughout the day, fluctuations were detected from February to December in tegus, and in April, May, June and October in iguanas. Activity period in iguanas were shorter in January and at 0:00h. Longer latencies to withdrawal reflex were detected in May and August and at 6:00h in both species. In conclusion, tegus and green iguanas kept in controlled environment have fluctuations in behavior presented in the open field test, the forced swim (only iguanas) test and the plantar test, which apparently do not follow a clear seasonal pattern and are probably influenced by multiple factors that are still unknown for both species.

<p>Cilj: Cilj ovog istraživanja bio je da se utvrde promene koje arterijska hipertenzija dvojakim mehanizmima (dnevno-noćnim ritmom i svojim trajanjem) ostavlja na funkciju i geometriju leve pretkomore i komore srca. Ispitanici i metode: u ovo istraživanje bilo je uključeno 180 ispitanika koji su bili podeljeni u ispitivane grupe u odnosu na dnevno-noćni ritam arterijskog krvnog pritiska tokom 24-časovnog monitoringa arterijskog krvnog pritiska i to na sledeći način: grupa ispitanika sa očuvanim dnevno-noćnim ritmom arterijskog krvnog pritiska sastojala se od ukupno 90 ispitanika, a grupu onih sa naru&scaron;enim dnevno-noćnim ritmom arterijskog krvnog pritiska takođe je činilo 90 ispitanika. U svakoj od ovih grupa izvr&scaron;ena je dodatna podela ispitanika prema dužini trajanja arterijske hipertenzije na one kod kojih je arterijska hipertenzija trajala do 5 godina, one kod kojih je trajala od 5 do 10 godina i na one sa trajanjem arterijske hipertenzije vi&scaron;e od 10 godina. Svim ispitanicima rađen je incijalno 24-časovni ambulantni monitoring arterijskog krvnog pritiska, a nakon toga i ehokardiografski pregled radi određivanja parametara morfologije leve pretkomore i komore, kao i dijastolne funkcije leve komore. Rezultati i diskusija: nakon statističke obrade podataka dobijeni su rezultati koji ukazuju da se dijastolna disfunkcija stepena većeg od I statistički značajno če&scaron;će (p=0,011) uočava kod onih ispitanika koji nemaju očuvan dnevno-noćni ritam arterijskog krvnog pritiska. Naru&scaron;en dnevno-noćni ritam arterijskog krvnog pritiska takođe dovodi do povećanja indeksirane mase miokarda leve komore prema povr&scaron;ini tela ispitanika (LVM/BSA) &ndash; p=0,001; do zadebljanja zidova leve komore (IVS/PLW) &ndash; p=0,025, kao i do smanjenja sistolne brzine miokarda na nivou septalnog dela mitralnog anulusa (s&rsquo;) - p&lt;0,0005. Pored ovoga, u grupi onih sa naru&scaron;enim dnevno-noćnim ritmom arterijskog krvnog pritiska primećeno je če&scaron;će prisustvo ekscentrične hipertrofije miokarda leve komore (p=0,027). U odnosu na geometriju i funkciju leve pretkomore, naru&scaron;en dnevno-noćni ritam arterijskog krvnog pritiska dovodi do promena u smislu povećanja antero-posteriornog dijametra leve pretkomore (LA)-p=0,003; maksimalnog volumena leve pretkomore u komorskoj sistoli (LAVs) &ndash;p=0,007; indeksiranog LAVs prema povr&scaron;ini tela ispitanika (LAVs/BSA)-p&lt;,0005; E/e&rsquo; odnosa &ndash;p=0,040; rezervoarnog strain-a leve pretkomore (PLAS)- p=0,004; krutosti leve pretkomore (stiffness)-p=0,047, kao i brzine propagacije talasa kroz mitralni otvor (Vp)-p=0,029. Sa povećanjem dužine trajanja arterijske hipertenzije takođe su pokazane promene u morfologiji i funkciji leve pretkomore i leve komore srca. Dijastolna disfunkcija stepena većeg od I retko je bila uočena u grupi onih koji su arterijsku hipertenziju lečili kraće od 5 godina, a njeno prisustvo u ispitivanim grupama trajanja od 5 do 10 godina i duže od 10 godina bilo je statistički značajno če&scaron;će (p&lt;0,0005). Takođe, sa trajanjem arterijske hipertenzije statistički značajno se menjaju i parametri leve komore za koje smo pokazali da su pogor&scaron;ani kada dnevno-noćni ritam arterijskog krvnog pritiska nije očuvan, s tim &scaron;to smo ovde uočili i značajne promene u smislu postojanja lo&scaron;ijih vrednosti strain-a leve komore (LVGS)-p&lt;0,0005. Na sličan način kao i u odnosu na dnevno-noćni ritam arterijskog krvnog pritiska, menjao se predominantni oblik hipertrofije miokarda leve komore, te je uočeno značajno če&scaron;će (p=0,017) prisustvo ekscentrične hipertrofije kod ispitanika koji su duže lečili arterijsku hipertenziju. Uz ove promene, sa trajanjem arterijske hipertenzije, uočene su i promene sledećih ehokardiografskih parametara leve pretkomore (p&lt;0,0005): LA, LAVs, LAVs/BSA, E/e&rsquo;, PLAS, stiffness, Vp. Na kraju, formiran je i model za dijagnostiku dijastolne disfunkcije stepena većeg od I koji je testiran na 30 novih ispitanika i koji se pokazao kao kvalitetan uz visoku senzitivnost i specifičnost. Zaključak: arterijska hipertenzija dnevno-noćnim oscilacijama (ritmom), ali i svojim trajanjem dovodi do promena u funkciji i geometriji leve pretkomore i komore srca. Noviji ehokardiografski parametri (PLAS, LVGS, stiffness) su dobri pokazatelji ranih promena na nivou leve pretkomore i komore srca kod pacijenata sa arterijskom hipertenzijom.</p> / <p><!--[if gte mso 9]><xml> <o:DocumentProperties> <o:Author>Vukadin Milankov</o:Author> <o:Version>16.00</o:Version> </o:DocumentProperties> <o:OfficeDocumentSettings> <o:AllowPNG/> </o:OfficeDocumentSettings></xml><![endif]--><!--[if gte mso 9]><xml> <w:WordDocument> <w:View>Normal</w:View> <w:Zoom>0</w:Zoom> <w:TrackMoves/> <w:TrackFormatting/> <w:PunctuationKerning/> <w:ValidateAgainstSchemas/> <w:SaveIfXMLInvalid>false</w:SaveIfXMLInvalid> <w:IgnoreMixedContent>false</w:IgnoreMixedContent> <w:AlwaysShowPlaceholderText>false</w:AlwaysShowPlaceholderText> <w:DoNotPromoteQF/> <w:LidThemeOther>EN-US</w:LidThemeOther> <w:LidThemeAsian>X-NONE</w:LidThemeAsian> <w:LidThemeComplexScript>X-NONE</w:LidThemeComplexScript> <w:Compatibility> <w:BreakWrappedTables/> <w:SnapToGridInCell/> <w:WrapTextWithPunct/> 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Introdução: o ciclo de sono-vigília é o comportamento rítmico circadiano mais onipresente nos humanos. Ele é estabelecido por um sistema temporizador circadiano endógeno que é regulado pela presença ou ausência de luz no ambiente. O comportamento em relação a dormir e acordar varia entre os indivíduos e essa característica nomeia-se cronotipo. Efeitos negativos à saúde têm sido associados ao cronotipo que apresenta horários para iniciar e terminar o sono mais tarde. A hipótese considerada para explicar esses achados é de que demandas sociais, que não levam em conta essa variabilidade individual, sejam mediadoras dessa relação. Objetivos: avaliar a associação entre cronotipo e saúde mental (bem-estar psicológico e sintomas depressivos) levando-se em conta fatores demográficos (sexo e idade) e as rotinas de escola ou trabalho. Materiais e métodos: estudos transversais aninhados a um estudo epidemiológico em uma amostra de indivíduos do Vale do Taquari, no sul do Brasil. Na primeira avaliação, 6.506 participantes foram avaliados quanto a variáveis demográficas, dados de saúde, sintomas depressivos (Inventário de Depressão de Beck – BDI) e cronotipo (Questionário de Cronotipo de Munique – MCTQ). Na segunda etapa, 1.127 indivíduos entre 18 e 65 anos, selecionados a partir de seu cronotipo foram avaliados através do Índice de bem-estar de 5-itens da Organização Mundial da Saúde (OMS). O ponto médio do sono nos dias de rotinas de trabalho ou escolares foi utilizado como indicador do cronotipo, sendo “atrasado” aquele que tem o ponto médio mais tarde em relação ao início da noite e “avançado”, mais cedo. Resultados: no primeiro artigo, estudou-se a relação entre cronotipo e depressão em uma amostra de estudantes adolescentes. O modelo de regressão que melhor explicou a diferença entre os grupos com diferentes níveis de sintomas de depressão (BDI<10 X BDI!10) incluiu o sexo feminino e o cronotipo atrasado. O segundo artigo demonstrou que a escala de Bem-estar de 5-itens da OMS tem uma estrutura unidimensional, boa validade interna e externa e utilidade como instrumento de triagem para depressão quando comparada ao BDI. Assim, no terceiro artigo, foi avaliada a relação entre cronotipo e bem-estar, em indivíduos entre 18 e 65 anos. O modelo de regressão que incluiu o cronotipo atrasado, maior carga de trabalho, rotinas de trabalho mais cedo no dia e menor exposição à luz do sol, como variáveis preditoras, e piores escores na Escala de Bem-estar, como desfecho, foi significativo para o sexo feminino. Discussão: a presente tese explicitou a importância de considerar os fatores idade e sexo na expressão do cronotipo e na relação deste com saúde mental. Corroborou com a hipótese de que as demandas sociais mediam a relação entre cronotipo e os desfechos estudados. A expressão do cronotipo nos dias de rotinas escolares ou de trabalho foi identificada como a variável que estabeleceu a mais forte relação com piores escores de bemestar e com mais sintomas de depressão. Por fim, reforçou a necessidade de revermos as rotinas de trabalho e escolares que, ao não considerarem as diferenças fisiológicas individuais, têm-se associado, de forma consistente, a conseqüências negativas à saúde. / Introduction: the sleep-wake cycle is the most ubiquitous human circadian rhythmic behavior. It is established by an endogenous circadian timing system that is regulated by the presence or absence of light in the environment. Sleep and wake behavior varies among individuals and this feature has been termed chronotype. Negative health effects have been associated with the chronotype that presents later start and end sleep times. A hypothesis to explain these findings is that social demands, which do not take into account individual variability, are mediators of this relationship. Objectives: to evaluate the association between chronotype and mental health (psychological well-being and depressive symptoms) taking into account demographic factors (age and sex) and the routines of school or work. Materials and methods: the studies included here are cross-sectional nested to an epidemiological study in a sample of individuals from “Vale do Taquari”, in southern Brazil. In the first evaluation, 6,506 participants were assessed for demographic variables, health data, depressive symptoms (Beck Depression Inventory - BDI) and chronotype (Munich Chronotype Questionnaire - MCTQ). In the second stage, 1,127 individuals between 18 and 65 years, selected based on their chronotype, were evaluated through the Well-being 5 items Index from the World Health Organization (WHO). The midpoint of sleep on working or school days was used as an indicator of chronotype, and considered "delayed" or “late” those who have later midpoints in relation to environmental night and "advanced" or “early”, earlier. Results: in the first article, we studied the relationship between chronotype and depression in a sample of adolescent students. The regression model that best explained the difference between groups with different levels of depression symptoms (BDI<10 X BDI!10) included female sex and late chronotype. The second article demonstrated that the Well-being index has a unidimensional structure, good internal and external validities and might be usefulness as a screening tool for depression when compared to the BDI. Thus, in the third article, we evaluated the relationship between chronotype and well-being in individuals between 18 and 65 years. The regression model that included late chronotype, increased workload, earlier working routines in the day and less exposure to sunlight, as predictor variables, and worse scores on the well-being index, as the outcome was significant for females. Discussion: the present thesis content highlighted the importance of considering age and sex as factors influencing the expression of chronotype and the relationship with mental health outcomes. It corroborated the hypothesis that social demands mediate the relationship between chronotype and the studied outcomes. The expression of chronotype during the days of work or school routines was identified as the variable that established the strongest relationship with worse well-being scores and more depression symptoms. Finally, it reinforced the need to reconsider work and school routines that, by not taking into acount individual physiological differences, have been associated consistently with negative health consequences.

Arterial blood pressure (BP) undergoes a 24-hour oscillation that peaks in the active day and reaches a nadir at night during sleep in humans. Reduced nocturnal BP fall (also known as non-dipper) is the most common disruption of BP circadian rhythm and is associated with increased risk of untoward cardiovascular events and target organ injury. Up to 75% of diabetic patients are non-dippers. However, the mechanisms underlying diabetes associated non-dipping BP are largely unknown. To address this important question, we generated a novel diabetic db/db-mPer2Luc mouse model (db/db-mPer2Luc) that allows quantitatively measuring of mPER2 protein oscillation by real-time mPer2Luc bioluminescence monitoring in vitro and in vivo. Using this model, we demonstrated that the db/db-mPer2Luc mice have a diminished BP daily rhythm. The phase of the mPER2 daily oscillation is advanced to different extents in explanted peripheral tissues from the db/db-mPer2Luc mice relative to that in the control mice. However, no phase shift is found in the central oscillator, the suprachiasmatic nucleus (SCN). The results indicate that the desynchrony of mPER2 daily oscillation in the peripheral tissues contributes to the loss of BP daily oscillation in diabetes. Extensive research over the past decades has been focused on how the components of food (what we eat) and the amount of food (how much we eat) affect metabolic diseases. Only recently has it become appreciated that the timing of food intake (when we eat), independent of total caloric and macronutrient quality, is also critical for metabolic health. To investigate the potential effect of the timing of food intake on the BP circadian rhythm, we simultaneously monitored the BP and food intake profiles in the diabetic db/db and control mice using radiotelemetry and BioDAQ systems. We found the loss of BP daily rhythm is associated with disrupted food intake rhythm in the db/db mice. In addition, the normal BP daily rhythm is altered in the healthy mice with abnormal feeding pattern, in which the food is available only during the inactive-phase. To explore whether imposing a normal food intake pattern is able to prevent and restore the disruption of BP circadian rhythm, we conducted active-time restricted feeding (ATRF) in the db/db mice. Strikingly, ATRF completely prevents and restorers the disrupted BP daily rhythm in the db/db mice. While multiple mechanisms likely contribute to the protection of ATRF on the BP daily rhythm, we found that ATRF improves the rhythms of energy metabolism, sleep-wake cycle, BP-regulatory hormones and autonomic nervous system (ANS) in the db/db mice. To further investigate the molecular mechanism by which ATRF regulates BP circadian rhythm, we determined the effect of ATRF on the mRNA expressions of core clock genes and clock target genes in the db/db mice. Of particular interest is that we found among all the genes we examined, the mRNA oscillation of Bmal1, a key core clock gene, is disrupted by diabetes and selectively restored by the ATRF in multiple peripheral tissues in the db/db mice. More importantly, we demonstrated that Bmal1 is partially required for ATRF to protect the BP circadian rhythm. In summary, our findings indicate that the desynchrony of peripheral clocks contributes to the abnormal BP circadian pattern in diabetes. Moreover, our studies suggest ATRF as a novel and effective chronotherapy against the disruption of BP circadian rhythm in diabetes.

Actuellement, le diagnostic différentiel du trouble bipolaire (TB) et du trouble de personnalité limite (TPL) à l’adolescence s’avère difficile et complique le choix thérapeutique. Portant sur le TB et le TPL, ce mémoire fait le point sur la littérature scientifique adulte et adolescente, vérifie la faisabilité et présente les résultats d’une étude exploratoire portant sur les variables cliniques (instabilité émotionnelle, hostilité, impulsivité, tempraément) et le rythme veille-sommeil à l’adolescence. L’étude exploratoire comprend sept adolescents TB et huit TPL (12-17 ans), évalués par questionnaires autoadministrés pour les variables cliniques, et par actigraphie et agenda de sommeil pour le rythme veille-sommeil. Aucune différence significative n’existe entre les deux troubles pour les variables cliniques. En moyenne, les adolescents TB ont porté l'actigraphie pendant 9,9 jours et ont rempli un agenda de sommeil pendant 5,7 jours; chez les TPL, les chiffres sont respectivement 9,8 et 8,9 jours. Comparés aux TPL, les TB ont un plus grand intervalle d’éveil (p=0,035), ont un plus grand intervalle de sommeil (p>0,05), et ont une plus grand variabilité intrajournalière (p=0,04). Les données subjectives (agenda de sommeil) semblent refléter les données objectives (actigraphie) : aucune différence statistique n’est observée entre les deux mesures pour le délai d’endormissement, la durée du dernier réveil et le temps total de sommeil. La recension de la littérature montre un manque de données chez l’adolescent quant aux deux troubles. La faisabilité de l’étude est démontrée par la présence de résultats analysables. Ceci encourage la poursuite des recherches sur ces variables, afin de distinguer les deux psychopathologies à l’adolescence. / Presently, differential diagnosis between bipolar disorder (BD) and borderline personality disorder (BPD) in adolescents remains difficult and affects therapeutic choices. This master’s thesis reviews current scientific literature, both in adults and adolescents. It examines feasibility and presents results of a study on clinical dimensions and endophenotypes in adolescent BD and BPD. Seven BD and eight BPD adolescents (12-17 years old) were evaluated by self-reported questionnaires for clinical variables (affective instability, impulsivity, hostility and temperament) and by actigraphy and sleep diary for sleep-wake circadian rhythm. No significant difference was found between BD and BPD for the clinical variables. BD adolescents wore actigraphic device for 9.9 days and completed the sleep diary for 5.7 days on average; for BPD subjects, the numbers were respectively 9.8 days and 8.9 days. Compared to BPD, BD patients had longer active interval (p=0.035), tended to sleep longer, and had more intradaily variability (p=0.04). Subjective data (sleep diary) and objective data (actigraphy) did not significantly differ on sleep onset latency, last awakening duration and total sleep time, which suggested that BD and BPD adolescents had a good estimate of their sleep patterns. Literature review showed a dearth of research done on adolescent BD and BPD. Feasibility of this study was verified, since data was successfully collected. Research on these variables should continue, so differential diagnosis can be done in adolescent BD and BPD.

Cette thèse examine le rythme veille-sommeil et son association avec l’instabilité émotionnelle, l’agressivité et l’impulsivité dans le trouble de personnalité limite (TPL) à l’adolescence. Dans un premier temps, la revue de la littérature sur les perturbations objectives du sommeil dans le TPL a mis en lumière plusieurs difficultés similaires, évaluées par polysomnographie, à celles observées dans la dépression adulte. De 1980 à 2010, aucune recherche n’a examiné le rythme veille-sommeil, aucune n’a étudié les adolescents TPL et plusieurs n’ont pas contrôlé l’état dépressif comme facteur de confusion. De ce constat, il s’avérait pertinent de mener une étude sur le rythme veille-sommeil dans le TPL à l’adolescence en l’absence de dépression co-occurrente. L’adolescence comportant plusieurs caractéristiques physiologiques, psychologiques et sociales, tenir compte des aspects développementaux était essentiel. Dans un second temps, un protocole de recherche fût mis en place à la Clinique des troubles de l’humeur et le recrutement a été réalisé auprès d’adolescents souffrant d’un TPL et sans état dépressif actuel. Ils devaient porter pendant plus de neuf jours (période comprenant deux fins de semaine) un actigraphe, appareil non invasif évaluant l’alternance veille-sommeil dans l’environnement naturel. L’abandon précoce au traitement étant prévalent chez les patients TPL, la fiabilité de l’étude a été examinée afin de déterminer les raisons favorisant et celles nuisant au recrutement et à la collecte des données. La réflexion sur les aspects méthodologiques de l’étude actigraphique a permis d’expliquer les limites de ce type de protocole. Dans un troisième temps, le rythme veille-sommeil des adolescents TPL (n=18) a été caractérisé et comparé à celui des jeunes ayant un trouble bipolaire (n=6), trouble psychiatrique partageant plusieurs manifestations communes avec le TPL, et à celui des adolescents sans trouble de santé mentale (n=20). Les résultats suggèrent que l’adolescent TPL passe plus de temps en éveil durant la période de repos que les jeunes appartenant aux deux autres groupes. De plus, les adolescents TPL présentent une plus grande variabilité inter journalière des heures de lever et du temps total de sommeil que les autres adolescents. Ils se réveillent une heure de plus, et dorment donc une heure supplémentaire, que les adolescents sans trouble mental lors des journées sans routine. Dans un quatrième temps, les analyses corrélationnelles entre les données actigraphiques et les scores aux questionnaires auto-rapportés évaluant l’instabilité émotionnelle, l’agressivité et l’impulsivité suggèrent que plus l’adolescent TPL passe du temps éveillé alors qu’il est au lit, plus il déclare présenter des comportements agressifs, surtout physiques, durant le jour. En résumé, cette thèse contribue à la littérature scientifique en explorant pour la première fois le rythme veille-sommeil et son lien avec les manifestations symptomatiques dans le TPL à l’adolescence. Les résultats suggèrent fortement l’importance d’évaluer et de traiter les problèmes du rythme veille-sommeil que présentent ces jeunes lors de la prise en charge. / This dissertation examines sleep-wake patterns and their associations with emotional instability, aggressiveness, and impulsivity in adolescents with Borderline Personality Disorder (BPD). First, a literature review showed in BPD adults similar objective sleep disturbances, as assessed with polysomnography, to those observed in adult depression. Between 1980 and 2010, no study has examined sleep-wake patterns, none has recruited BPD adolescents, and many did not control depression as a confounding factor. Considering these limitations, it became relevant to conduct a study on sleep-wake patterns in euthymic adolescents with BPD. Having a developmental perspective in mind is crucial since adolescence presents many physiological, psychological and social characteristics. Second, a research protocol was set up at the Mood Disorders Clinic. Adolescents with BPD and without current depression were recruited. They wore for nine days or more (period covering two weekends) an actigraph, a non-invasive device assessing ecologically sleep-wake patterns. Because treatment dropout is highly prevalent in BPD adolescents, study feasibility was examined to determine the reasons promoting and those interfering with recruitment and data collection. Reflections on methodological aspects of this study allowed explaining the limits of this type of research protocol. Third, sleep-wake patterns in BPD adolescents (n=18) was characterised. They were compared to youth with Bipolar Disorder (n=6), a mental disorder sharing many common manifestations with BPD, and to adolescents without mental disorder (n=20). Results suggest that BPD adolescents spend more time awake during the rest interval than teenagers from the two other groups. Furthermore, BPD adolescents present higher interdaily variability for rising time and total sleep time than the other adolescents. They wake up an hour later, therefore sleeping one more hour, than adolescents without mental disorder on schedule-free days. Fourth, correlation analyses between actigraphy data and self-report questionnaire scores assessing emotional instability, aggressiveness, and impulsivity suggest that time spent awake during time in bed is associated with more daily physical aggressiveness in BPD adolescents. To summarise, this dissertation adds to the current scientific literature by exploring for the first time sleep-wake patterns and its associations with symptomatic manifestations of BPD in adolescents. From these results, it is highly recommended to assess and treat their sleep-wake disturbances during their therapeutic care.

Thesis (M.S.)--Uniformed Services University of the Health Sciences, 2005. / Running title: Seasonal affective disorder and melanopsin. Typescript (photocopy).