Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers.

The circadian clock (CC) is a daily system that regulates the oscillations of physiological processes and can respond to the external environment in order to maintain internal homeostasis. For the functioning of the CC, the clock genes (CG) act in different metabolic pathways through the clock-controlled genes (CCG), providing cellular regulation. The CC's interruption can result in the development of different diseases, such as neurodegenerative and metabolic disorders, as well as cancer. Leukemias correspond to a group of malignancies of the blood and bone marrow that occur when alterations in normal cellular regulatory processes cause the uncontrolled proliferation of hematopoietic stem cells. This review aimed to associate a deregulated CC with the manifestation of leukemia, looking for possible pathways involving CG and their possible role as leukemic biomarkers.

Maternal Chronodisruption Throughout Pregnancy Impairs Glucose Homeostasis and Adipose Tissue Physiology in the Male Rat Offspring.

Compelling evidence in rats support the idea that gestational chronodisruption induces major changes in maternal circadian rhythms and fetal development and that these changes impact adult life at many physiological levels. Using a model of chronic photoperiod shifting throughout gestation (CPS), in which pregnant female rats (Sprague-Dawley strain; n = 16 per group) were exposed to lighting schedule manipulation every 3-4 days reversing the photoperiod completely or light/dark photoperiod (12/12; LD), we explored in the adult rat male offspring body weight gain, glucose homeostasis, adipose tissue content, adipose tissue response to norepinephrine (NE), and adipose tissue proteomic in the basal condition with standard diet (SD) and in response to high-fat diet (HFD). In adult CPS male (100-200 days old; n = 8 per group), we found increasing body weight, under SD and adiposity. Also, we found an increased response to intraperitoneal glucose (IGTT). After 12 weeks of HFD, white adipose tissue depots in CPS offspring were increased further, and higher IGTT and lower intraperitoneal insulin tolerance response were found, despite the lack of changes in food intake. In in vitro experiments, we observed that adipose tissue (WAT and BAT) glycerol response to NE from CPS offspring was decreased, and it was completely abolished by HFD. At the proteomic level, in CPS adipose tissue, 275 proteins displayed differential expression, compared with LD animals fed with a standard diet. Interestingly, CPS offspring and LD fed with HFD showed 20 proteins in common (2 upregulated and 18 downregulated). Based on these common proteins, the IPA analysis found that two functional pathways were significantly altered by CPS: network 1 (AKT/ERK) and network 2 (TNF/IL4; data are available via ProteomeXchange with identifier PXD026315). The present data show that gestational chronodisruption induced deleterious effects in adipose tissue recruitment and function, supporting the idea that adipose tissue function was programmed in utero by gestational chronodisruption, inducing deficient metabolic responses that persist into adulthood.

Sleep quality does not mediate the negative effects of chronodisruption on body composition and metabolic syndrome in healthcare workers in Ecuador.

BACKGROUND AND AIMS: The objective of the present work was to determine to what extent sleep quality may mediate the association between chronodisruption (CD) and metabolic syndrome (MS), and between CD and body composition (BC). METHODOLOGY: Cross-sectional study which included 300 adult health workers, 150 of whom were night shift workers and thereby exposed to CD. Diagnosis of MS was made based on Adult Treatment Panel III criteria. Sleep quality was measured using the Pittsburgh Sleep Quality Index. Body mass index (BMI), fat mass percentage, and visceral fat percentage were measured as indicators of body composition (BC). Data were analyzed using logistic, linear regression and structural equation models. RESULTS: The odds of health workers exposed to CD to suffer MS was 22.13 (IC95 8.68-66.07) when the model was adjusted for age, gender, physical activity and energy consumption. CD was also significantly associated with an increase in fat mass and visceral fat percentages, but not to BMI. Surprisingly, there was not enough evidence supporting the hypothesis that sleep quality contributes to the association between CD and MS or between CD and BC. CONCLUSIONS: Sleep quality does not mediate the negative effects of CD on MS nor on BC.

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service

Objective: Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors. Methods: We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms. Results: Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p < 0.001), evening types (PR = 2.58, p < 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p < 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043). Conclusion: It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems.

Chronotype in bipolar disorder: an 18-month prospective study

Objective: Circadian dysregulation plays an important role in the etiology of mood disorders. Evening chronotype is frequent in these patients. However, prospective studies about the influence of chronotype on mood symptoms have reached unclear conclusions in patients with bipolar disorder (BD). The objective of this study was to investigate relationship between chronotype and prognostic factors for BD. Methods: At the baseline, 80 euthymic BD patients answered a demographic questionnaire and clinical scales to evaluate anxiety, functioning and chronotype. Circadian preference was measured using the Morningness-Eveningness Questionnaire, in which lower scores indicate eveningness. Mood episodes and hospitalizations were evaluated monthly for 18 months. Results: Among the BD patients, 14 (17.5%) were definitely morning type, 35 (43.8%), moderately morning, 27 (33.7%) intermediate (neither) and 4 (5%) moderately evening. Eveningness was associated with obesity or overweight (p = 0.03), greater anxiety (p = 0.002) and better functioning (p = 0.01), as well as with mood episodes (p = 0.04), but not with psychiatric hospitalizations (p = 0.82). This group tended toward depressive episodes (p = 0.06), but not (hypo)mania (p = 0.56). Conclusion: This study indicated that evening chronotype predicts a poor prognostic for BD. It reinforces the relevance of treating rhythm disruptions even during euthymia to improve patient quality of life and prevent mood episodes.

Chronotype in bipolar disorder: an 18-month prospective study.

OBJECTIVE: Circadian dysregulation plays an important role in the etiology of mood disorders. Evening chronotype is frequent in these patients. However, prospective studies about the influence of chronotype on mood symptoms have reached unclear conclusions in patients with bipolar disorder (BD). The objective of this study was to investigate relationship between chronotype and prognostic factors for BD. METHODS: At the baseline, 80 euthymic BD patients answered a demographic questionnaire and clinical scales to evaluate anxiety, functioning and chronotype. Circadian preference was measured using the Morningness-Eveningness Questionnaire, in which lower scores indicate eveningness. Mood episodes and hospitalizations were evaluated monthly for 18 months. RESULTS: Among the BD patients, 14 (17.5%) were definitely morning type, 35 (43.8%), moderately morning, 27 (33.7%) intermediate (neither) and 4 (5%) moderately evening. Eveningness was associated with obesity or overweight (p = 0.03), greater anxiety (p = 0.002) and better functioning (p = 0.01), as well as with mood episodes (p = 0.04), but not with psychiatric hospitalizations (p = 0.82). This group tended toward depressive episodes (p = 0.06), but not (hypo)mania (p = 0.56). CONCLUSION: This study indicated that evening chronotype predicts a poor prognostic for BD. It reinforces the relevance of treating rhythm disruptions even during euthymia to improve patient quality of life and prevent mood episodes.

How do stress, sleep quality, and chronotype associate with clinically significant depressive symptoms? A study of young male military recruits in compulsory service.

OBJECTIVE: Although studies have shown an association between poor sleep and chronotype with psychiatric problems in young adults, few have focused on identifying multiple concomitant risk factors. METHODS: We assessed depressive symptoms (Beck Depression Inventory [BDI]), circadian typology (Morningness-Eveningness Questionnaire [MEQ]), sleep quality (Pittsburgh Sleep Quality Index [PSQI]), perceived stress (Perceived Stress Scale [PSS]), social rhythm (Social Rhythm Metrics [SRM]), and salivary cortisol (morning, evening and night, n=37) in 236 men (all 18 years old). Separate analyses were conducted to understand how each PSQI domain was associated with depressive symptoms. RESULTS: Depressive symptoms were more prevalent in individuals with higher perceived stress (prevalence ratio [PR] = 6.429, p < 0.001), evening types (PR = 2.58, p < 0.001) and poor sleepers (PR = 1.808, p = 0.046). Multivariate modeling showed that these three variables were independently associated with depressive symptoms (all p < 0.05). The PSQI items subjective sleep quality and sleep disturbances were significantly more prevalent in individuals with depressive symptoms (PR = 2.210, p = 0.009 and PR = 2.198, p = 0.008). Lower levels of morning cortisol were significantly associated with higher depressive scores (r = -0.335; p = 0.043). CONCLUSION: It is important to evaluate multiple factors related to sleep and chronotype in youth depression studies, since this can provide important tools for comprehending and managing mental health problems.

Dysregulation of Circadian Rhythms in Autism Spectrum Disorders.

BACKGROUND: The alterations in neurological and neuroendocrine functions observed in the autism spectrum disorder (ASD) involves environmentally dependent dysregulation of neurodevelopment, in interaction with multiple coding gene defects. Disturbed sleep-wake patterns, as well as abnormal melatonin and glucocorticoid secretion, show the relevance of an underlying impairment of the circadian timing system to the behavioral phenotype of ASD. Thus, understanding the mechanisms involved in the circadian dysregulation in ASD could help to identify early biomarkers to improve the diagnosis and therapeutics as well as providing a significant impact on the lifelong prognosis. OBJECTIVE: In this review, we discuss the organization of the circadian timing system and explore the connection between neuroanatomic, molecular, and neuroendocrine responses of ASD and its clinical manifestations. Here we propose interconnections between circadian dysregulation, inflammatory baseline and behavioral changes in ASD. Taking into account, the high relevancy of melatonin in orchestrating both circadian timing and the maintenance of physiological immune quiescence, we raise the hypothesis that melatonin or analogs should be considered as a pharmacological approach to suppress inflammation and circadian misalignment in ASD patients. STRATEGY: This review provides a comprehensive update on the state-of-art of studies related to inflammatory states and ASD with a special focus on the relationship with melatonin and clock genes. The hypothesis raised above was analyzed according to the published data. CONCLUSION: Current evidence supports the existence of associations between ASD to circadian dysregulation, behavior problems, increased inflammatory levels of cytokines, sleep disorders, as well as reduced circadian neuroendocrine responses. Indeed, major effects may be related to a low melatonin rhythm. We propose that maintaining the proper rhythm of the circadian timing system may be helpful to improve the health and to cope with several behavioral changes observed in ASD subjects.

Monitoring whole blood, plasma and serum variables of Nile tilapia during 24 hours, after capture stress / Monitoramento das variáveis do sangue total, plasma e soro de Tilápia-do-Nilo, durante 24 horas, após estresse de captura

Stress is know as responsible for the decrease in immunity and reduced survival, growth, and reproductive capacity of animals. Besides, organisms respond to certain biological rhythms, such as circadian, to which animals naturally adjust. This study aimed to monitor the plasma (lactate and total protein), serum (cortisol and cholesterol) and whole blood (glucose) variables in tilapia in a 24 h cycle. A set of 49 aquariums with 5 individuals each were used. All of them, at the beginning of the experiment, were subjected to the same stress of capture and handling. The animals from the first aquaria were sampled after 15 min of stress. Blood samples from animals of the remaining aquarium were sequentially drawn at 30-min intervals. Radar charts were used to visualize the hourly change in the measured variables. Significant differences of each analysis between the measured variables by aquarium and the phases of the circadian cycle (light-dark) and morning-afternoon-night-dawn intervals, were evaluated using the Mann-Whitney and Kruskal-Wallis tests, respectively. A positive relationship between cortisol and glucose levels was found. Most analysis, except cholesterol and lactate did not show any significant difference between light and dark periods, and the intensity and frequency of peaks observed were not deleterious to individuals.

O estresse é conhecidamente responsável pela diminuição da imunidade e redução da sobrevivência, crescimento e capacidade reprodutiva dos animais. Além disso, os organismos respondem a certos ritmos biológicos, como o circadiano, aos quais se ajustam naturalmente. Este estudo teve como objetivo monitorar as variáveis plasmática (lactato e proteína total), soro (cortisol e colesterol) e sangue total (glicose) na tilápia em um período de 24 h. Quarenta e nove aquários com 5 indivíduos cada foram utilizados. Todos eles, no início do experimento, foram submetidos ao mesmo estresse de captura e manuseio. Os animais do primeiro aquários foram amostrados após 15 min do estresse. Os demais As amostras de sangue de indivíduos de cada aquário foram sequencialmente em intervalos de 30 min. Somente os indivíduos do primeiro aquário foram analisados após 15 minutos de estresse. Os gráficos de radar foram usadas para visualizar a variação horária nas variáveis medidas. Diferenças estatisticamente significativas entre a média dos indivíduos de cada aquário, para as fases do ciclo circadiano (luz-escuro) e os intervalos manhã-tarde-noite-madrugada foram respectivamente avaliadas utilizando os testes Mann-Whitney e Kruskal-Wallis. Observou-se relação positiva entre os níveis de cortisol e glicose. As análises, com exceção de colesterol e lactato, não mostraram diferença significativa entre períodos de luz e sombras, e a intensidade e a freqüência dos picos observados não foram prejudiciais aos indivíduos.

Monitoring whole blood, plasma and serum variables of Nile tilapia during 24 hours, after capture stress / Monitoramento das variáveis do sangue total, plasma e soro de Tilápia-do-Nilo, durante 24 horas, após estresse de captura

Stress is know as responsible for the decrease in immunity and reduced survival, growth, and reproductive capacity of animals. Besides, organisms respond to certain biological rhythms, such as circadian, to which animals naturally adjust. This study aimed to monitor the plasma (lactate and total protein), serum (cortisol and cholesterol) and whole blood (glucose) variables in tilapia in a 24 h cycle. A set of 49 aquariums with 5 individuals each were used. All of them, at the beginning of the experiment, were subjected to the same stress of capture and handling. The animals from the first aquaria were sampled after 15 min of stress. Blood samples from animals of the remaining aquarium were sequentially drawn at 30-min intervals. Radar charts were used to visualize the hourly change in the measured variables. Significant differences of each analysis between the measured variables by aquarium and the phases of the circadian cycle (light-dark) and morning-afternoon-night-dawn intervals, were evaluated using the Mann-Whitney and Kruskal-Wallis tests, respectively. A positive relationship between cortisol and glucose levels was found. Most analysis, except cholesterol and lactate did not show any significant difference between light and dark periods, and the intensity and frequency of peaks observed were not deleterious to individuals.(AU)

O estresse é conhecidamente responsável pela diminuição da imunidade e redução da sobrevivência, crescimento e capacidade reprodutiva dos animais. Além disso, os organismos respondem a certos ritmos biológicos, como o circadiano, aos quais se ajustam naturalmente. Este estudo teve como objetivo monitorar as variáveis plasmática (lactato e proteína total), soro (cortisol e colesterol) e sangue total (glicose) na tilápia em um período de 24 h. Quarenta e nove aquários com 5 indivíduos cada foram utilizados. Todos eles, no início do experimento, foram submetidos ao mesmo estresse de captura e manuseio. Os animais do primeiro aquários foram amostrados após 15 min do estresse. Os demais As amostras de sangue de indivíduos de cada aquário foram sequencialmente em intervalos de 30 min. Somente os indivíduos do primeiro aquário foram analisados após 15 minutos de estresse. Os gráficos de radar foram usadas para visualizar a variação horária nas variáveis medidas. Diferenças estatisticamente significativas entre a média dos indivíduos de cada aquário, para as fases do ciclo circadiano (luz-escuro) e os intervalos manhã-tarde-noite-madrugada foram respectivamente avaliadas utilizando os testes Mann-Whitney e Kruskal-Wallis. Observou-se relação positiva entre os níveis de cortisol e glicose. As análises, com exceção de colesterol e lactato, não mostraram diferença significativa entre períodos de luz e sombras, e a intensidade e a freqüência dos picos observados não foram prejudiciais aos indivíduos.(AU)

The Period 2 Enhancer Nobiletin as Novel Therapy in Murine Models of Circadian Disruption Resembling Delirium.

OBJECTIVES: Delirium occurs in approximately 30% of critically ill patients, and the risk of dying during admission doubles in those patients. Molecular mechanisms causing delirium are largely unknown. However, critical illness and the ICU environment consistently disrupt circadian rhythms, and circadian disruptions are strongly associated with delirium. Exposure to benzodiazepines and constant light are suspected risk factors for the development of delirium. Thus, we tested the functional role of the circadian rhythm protein Period 2 (PER2) in different mouse models resembling delirium. DESIGN: Animal study. SETTING: University experimental laboratory. SUBJECTS: Wildtype, Per2 mice. INTERVENTIONS: Midazolam, lipopolysaccharide (lipopolysaccharide), constant light, nobiletin, or sham-treated animals. MEASUREMENTS AND MAIN RESULTS: Midazolam significantly reduced the expression of PER2 in the suprachiasmatic nucleus and the hippocampus of wild-type mice. Behavioral tests following midazolam exposure revealed a robust phenotype including executive dysfunction and memory impairment suggestive of delirium. These findings indicated a critical role of hippocampal expressed PER2. Similar results were obtained in mice exposed to lipopolysaccharide or constant light. Subsequent studies in Per2 mice confirmed a functional role of PER2 in a midazolam-induced delirium-like phenotype. Using the small molecule nobiletin to enhance PER2 function, the cognitive deficits induced by midazolam or constant light were attenuated in wild-type mice. CONCLUSIONS: These experiments identify a novel role for PER2 during a midazolam- or constant light-induced delirium-like state, highlight the importance of hippocampal PER2 expression for cognitive function, and suggest the PER2 enhancer nobiletin as potential therapy in delirium-like conditions associated with circadian disruption.

Genetic polymorphisms associated with circadian rhythm dysregulation provide new perspectives on bipolar disorder.

OBJECTIVES: The objective of this study was to present a broad view of how genetic polymorphisms in genes that control the rhythmicity and function of circadian rhythm may influence the etiology, pathophysiology and treatment of bipolar disorder (BD). METHODS: A bibliographic search was performed to identify and select papers reporting studies on variations in circadian genes and BD. A search of Medline, Google Scholar, Scopus, and Web of Science was carried out to review the literature. RESULTS: Several studies provide evidence of contributions of variations in circadian genes to disease etiology, pathophysiological variations and lithium drug response. Dysfunction of the sleep-wake cycle, an important brain function regulator, is indicated as the primary means by which circadian gene variations act in mood disorders. CONCLUSIONS: Investigations of the effects of circadian genes have suggested that the chronotype offers hope for guiding and improving management of patients with BD. However, BD is a disease of a complex nature and presents multiple endophenotypes determined by different associations between genetics and the environment. Thus, new genomic studies to delimit variations that may help improve the clinical condition of these patients are extremely important.

White Adipose Tissue and Circadian Rhythm Dysfunctions in Obesity: Pathogenesis and Available Therapies.

A combined neuroendocrine, metabolic, and chronobiological view can help to better understand the multiple and complex mechanisms involved in obesity development and maintenance, as well as to provide new effective approaches for its control and treatment. Indeed, we have currently updated data on the whole adipogenic process involved in white adipose tissue (WAT) mass expansion, namely due to a mechanism whereby WAT cells become hypertrophic, thus inducing a serious local (WAT) inflammatory condition that in turn, will impair not only the cross-talk between the hypothalamus and the WAT, but also favoring the development of deep and widespread neuroendocrine-metabolic dysfunction. Moreover, we also have revisited the circadian clock genes involved in dysfunctional WAT mass expansion and the mechanisms that may lead to obesity development, including early metabolic dysfunctions, enhanced oxidative stress and distorted energy homeostasis. The epigenetic changes of clock genes driving metabolic disease and obesity development have also been included in this review. Finally, we have also underlined the relevance of metabolic homeostasis regulation by central and peripheral organ clocks, sleep disturbances, nutrients, and feeding time, as key factors in obesity development as well as both, classical and chronotherapeutic approaches for its prevention and treatment.

The ticking clock of Cayo Santiago macaques and its implications for understanding human circadian rhythm disorders.

The circadian clock disorders in humans remain poorly understood. However, their impact on the development and progression of major human conditions, from cancer to insomnia, metabolic or mental illness becomes increasingly apparent. Addressing human circadian disorders in animal models is, in part, complicated by inverse temporal relationship between the core clock and specific physiological or behavioral processes in diurnal and nocturnal animals. Major advantages of a macaque model for translational circadian research, as a diurnal vertebrate phylogenetically close to humans, are further emphasized by the discovery of the first familial circadian disorder in non-human primates among the rhesus monkeys originating from Cayo Santiago. The remarkable similarity of their pathological phenotypes to human Delayed Sleep Phase Disorder (DSPD), high penetrance of the disorder within one branch of the colony and the large number of animals available provide outstanding opportunities for studying the mechanisms of circadian disorders, their impact on other pathological conditions, and for the development of novel and effective treatment strategies.

Avaliação do reparo ósseo na interface osso/implante em ratos pinealectomizados: análise histológica, imunoistoquimica, histométrica, biomecânica e por microct / Bone repair evaluation in bone/implant interface in pinealectomized rats: histological, immunohistochemistry, histometric, biomechanics and microCT analysis

O presente estudo teve como objetivo investigar a interface osso / implante em ratos pinealectomizados tratados com melatonina. Métodos: 30 ratos, machos, adultos foram divididos em 3 grupos: controle (CO), pinealectomizados (PnX) e pinealectomizado com melatonina (PNXm). Após 30 dias da Pinealectomia, um implante foi instalado em cada tíbia e a eutanásia foi realizada aos 42 dias. As amostras foram submetidas a histomorfométrica (ELCOI e AON), biomecânica (de torque reverso), microtomografia e análise imunoistoquímica. Os dados quantitativos foram submetidos à análise estatística (P <0,05). Para os resultados histométricos, valores ELCOI para PNX foram menores quando comparados com PNXm (P = 0,0393), enquanto AON não mostrou diferença entre os grupos (P = 0,761). Os valores de torque reverso não mostraram diferença entre os grupos PNX e PNXm (P = 0,5000), e as interações CO vs PNXm, e CO vs PNX mostraram diferença significativa (P <0,05). Os parâmetros volumétricas BV/TV (P = 0,933); Tr.N (P = 0,933); Tb.Th (P = 0,933), Tb.Sp (P = 0,200) não apresentaram diferença estatística. A imunomarcação para OPG, RANKL, TRAP e osteocalcina mostrou similaridade entre os grupos, apesar da PNXm parece assemelhar-se às condições fisiológicas (CO). Portanto, a melatonina melhorou a remodelação óssea na região peri-implante em ratos pinealectomizados

This study aimed to investigate the interface bone/implant in pinealectomized rats treated with melatonin. 30 rats, male, adults were divided into 3 groups: control (CO), pinealectomized (PNX) and pinealectomized with melatonin (PNXm). After 30 days of the pinealectomy, one implant was installed on each tibia and euthanasia was performed at 42 days. The samples were submitted to histometric (BIC and NB), biomechanical (reverse torque), microtomography and immunohistochemical analysis. The quantitative data were subjected to statistical analysis (P<0.05). For the histometric results, BIC values to PNX were lower when compared to PNXm (P=0.0393), whereas NB did not showed difference among the groups (P=0.761). Reverse torque did not show difference between the groups PNX and PNXm (P=0,5000), and the interactions CO vs PNXm, and CO vs PNX showed significantly difference (P<0.05). The volumetric parameters BV/TV (P=0.933); Tr.N (P=0.933); Tb.Th (P=0.933), Tb.Sp (P=0.200) did not present statistical difference. The immunolabeling for OPG, RANKL, TRAP and osteocalcin showed similarity among the groups, despite the PNXm it seems to resemble to physiological conditions (CO). Therefore, melatonin improved the bone turnover in peri-implant region in pinealectomized rats

Avaliação do reparo ósseo na interface osso/implante em ratos pinealectomizados: análise histológica, imunoistoquimica, histométrica, biomecânica e por microct / Bone repair evaluation in bone/implant interface in pinealectomized rats: histological, immunohistochemistry, histometric, biomechanics and microCT analysis

O presente estudo teve como objetivo investigar a interface osso / implante em ratos pinealectomizados tratados com melatonina. Métodos: 30 ratos, machos, adultos foram divididos em 3 grupos: controle (CO), pinealectomizados (PnX) e pinealectomizado com melatonina (PNXm). Após 30 dias da Pinealectomia, um implante foi instalado em cada tíbia e a eutanásia foi realizada aos 42 dias. As amostras foram submetidas a histomorfométrica (ELCOI e AON), biomecânica (de torque reverso), microtomografia e análise imunoistoquímica. Os dados quantitativos foram submetidos à análise estatística (P <0,05). Para os resultados histométricos, valores ELCOI para PNX foram menores quando comparados com PNXm (P = 0,0393), enquanto AON não mostrou diferença entre os grupos (P = 0,761). Os valores de torque reverso não mostraram diferença entre os grupos PNX e PNXm (P = 0,5000), e as interações CO vs PNXm, e CO vs PNX mostraram diferença significativa (P <0,05). Os parâmetros volumétricas BV/TV (P = 0,933); Tr.N (P = 0,933); Tb.Th (P = 0,933), Tb.Sp (P = 0,200) não apresentaram diferença estatística. A imunomarcação para OPG, RANKL, TRAP e osteocalcina mostrou similaridade entre os grupos, apesar da PNXm parece assemelhar-se às condições fisiológicas (CO). Portanto, a melatonina melhorou a remodelação óssea na região peri-implante em ratos pinealectomizados.

This study aimed to investigate the interface bone/implant in pinealectomized rats treated with melatonin. 30 rats, male, adults were divided into 3 groups: control (CO), pinealectomized (PNX) and pinealectomized with melatonin (PNXm). After 30 days of the pinealectomy, one implant was installed on each tibia and euthanasia was performed at 42 days. The samples were submitted to histometric (BIC and NB), biomechanical (reverse torque), microtomography and immunohistochemical analysis. The quantitative data were subjected to statistical analysis (P<0.05). For the histometric results, BIC values to PNX were lower when compared to PNXm (P=0.0393), whereas NB did not showed difference among the groups (P=0.761). Reverse torque did not show difference between the groups PNX and PNXm (P=0,5000), and the interactions CO vs PNXm, and CO vs PNX showed significantly difference (P<0.05). The volumetric parameters BV/TV (P=0.933); Tr.N (P=0.933); Tb.Th (P=0.933), Tb.Sp (P=0.200) did not present statistical difference. The immunolabeling for OPG, RANKL, TRAP and osteocalcin showed similarity among the groups, despite the PNXm it seems to resemble to physiological conditions (CO). Therefore, melatonin improved the bone turnover in peri-implant region in pinealectomized rats.

Differences in sleep disturbances among offspring of parents with and without bipolar disorder: association with conversion to bipolar disorder.

OBJECTIVES: Disruptions in sleep and dysregulation in circadian functioning may represent core abnormalities in the pathophysiology of bipolar disorder (BP). However, it is not clear whether these dysfunctions are state or trait markers of BP. This report compared sleep and circadian phenotypes among three groups: offspring of parents with BP diagnosed with BP at intake (BP/OB; n = 47), offspring of parents with BP without BP at intake (non-BP/OB; n = 386), and offspring of matched control parents who did not have BP (controls; n = 301). We also examined the association of baseline sleep parameters with subsequent development of BP among the non-BP/OB group. METHODS: Pittsburgh Bipolar Offspring Study youth (ages 6-18 years) and their parents completed assessments every two years pertaining to the child's sleep and circadian phenotypes and current psychopathology. Mixed-effects models examined differences in baseline sleep and circadian variables among the three groups. RESULTS: BP/OB offspring who were in a mood episode differed significantly on sleep parameters from the non-BP/OB and the offspring of controls, such as having inadequate sleep. Mixed logistic regression procedures showed that baseline sleep and circadian variables, such as frequent waking during the night, significantly predicted the development of BP among non-BP/OB over longitudinal follow-up. CONCLUSIONS: While lifetime diagnostic status accounted for differences among the groups in sleep and circadian disturbances, psychopathology explained the differences even further. Additionally, sleep disturbance may be a prognostic indicator of the development of BP in high-risk youth. Future studies are required to further disentangle whether sleep and circadian disruption are state or trait features of BP.

Differential susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes

Objective:Circadian disturbances common to modern lifestyles have been associated with mood disorders. Animal models that mimic such rhythm disturbances are useful in translational research to explore factors contributing to depressive disorders. This study aimed to verify the susceptibility of BALB/c, C57BL/6N, and CF1 mice to photoperiod changes.Methods:Thermochron iButtons implanted in the mouse abdomen were used to characterize temperature rhythms. Mice were maintained under a 12:12 h light-dark (LD) cycle for 15 days, followed by a 10:10 h LD cycle for 10 days. Cosinor analysis, Rayleigh z test, periodograms, and Fourier analysis were used to analyze rhythm parameters. Paired Student's t test was used to compare temperature amplitude, period, and power of the first harmonic between normal and shortened cycles.Results:The shortened LD cycle significantly changed temperature acrophases and rhythm amplitude in all mouse strains, but only BALB/c showed altered period.Conclusion:These findings suggest that BALB/c, the preferred strain for stress-induced models of depression, should also be favored for exploring the relationship between circadian rhythms and mood. Temperature rhythm proved to be a useful parameter for characterizing rhythm disruption in mice. Although disruption of temperature rhythm has been successfully documented in untethered mice, an evaluation of desynchronization of other rhythms is warranted.

Biological rhythms in bipolar and depressive disorders: A community study with drug-naïve young adults.

AIM: To assess biological rhythm disruptions among drug-naïve young adults with bipolar disorder (BD), major depressive disorder (MDD), and community controls. METHODS: This was a cross-sectional study nested in a population-based study. BD and MDD were diagnosed using the Structured Clinical Interview for DSM-IV. Biological rhythm disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). RESULTS: Two hundred seventeen subjects were assessed (49 BD, 74 MDD, and 94 community controls). Biological rhythm disruption was higher in subjects with BD (40.32±9.92; p<0.001) and MDD (36.23±8.71; p<0.001) than community controls (27.67±6.88). Subjects with BD had a higher BRIAN total score (p=0.028) and higher disruption in sleep/social domains (p=0.018) as compared to MDD. In addition, the BRIAN scores were higher in current MDD, euthymic BD, and BD in current episode group, as compared to community controls. LIMITATION: Cross-sectional design. Absence of assessment of biomarkers of biological rhythms. CONCLUSION: Bipolar disorder and major depressive disorder are associated with disruption in biological rhythm. In addition, disruption in sleep/social rhythms is higher in subjects with BD when compared to subjects with MDD. We also verified biological rhythm disruption in subjects with BD during euthymic status, but not in remitted MDD. Regulation of biological rhythm may be a means to identify patients with mood disorders and potentially differentiate MDD from BD.