Mammalian Rest/Activity Patterns Explained by Physiologically Based Modeling

Circadian rhythms are fundamental to life. In mammals, these rhythms are generated by pacemaker neurons in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN is remarkably consistent in structure and function between species, yet mammalian rest/activity patterns are extremely diverse, including diurnal, nocturnal, and crepuscular behaviors. Two mechanisms have been proposed to account for this diversity: (i) modulation of SCN output by downstream nuclei, and (ii) direct effects of light on activity. These two mechanisms are difficult to disentangle experimentally and their respective roles remain unknown. To address this, we developed a computational model to simulate the two mechanisms and their influence on temporal niche. In our model, SCN output is relayed via the subparaventricular zone (SPZ) to the dorsomedial hypothalamus (DMH), and thence to ventrolateral preoptic nuclei (VLPO) and lateral hypothalamus (LHA). Using this model, we generated rich phenotypes that closely resemble experimental data. Modulation of SCN output at the SPZ was found to generate a full spectrum of diurnal-to-nocturnal phenotypes. Intriguingly, we also uncovered a novel mechanism for crepuscular behavior: if DMH/VLPO and DMH/LHA projections act cooperatively, daily activity is unimodal, but if they act competitively, activity can become bimodal. In addition, we successfully reproduced diurnal/nocturnal switching in the rodent Octodon degu using coordinated inversions in both masking and circadian modulation. Finally, the model correctly predicted the SCN lesion phenotype in squirrel monkeys: loss of circadian rhythmicity and emergence of ∼4-h sleep/wake cycles. In capturing these diverse phenotypes, the model provides a powerful new framework for understanding rest/activity patterns and relating them to underlying physiology. Given the ubiquitous effects of temporal organization on all aspects of animal behavior and physiology, this study sheds light on the physiological changes required to orchestrate adaptation to various temporal niches

Analysis Method and Experimental Conditions Affect Computed Circadian Phase from Melatonin Data

Accurate determination of circadian phase is necessary for research and clinical purposes because of the influence of the master circadian pacemaker on multiple physiologic functions. Melatonin is presently the most accurate marker of the activity of the human circadian pacemaker. Current methods of analyzing the plasma melatonin rhythm can be grouped into three categories: curve-fitting, threshold-based and physiologically-based linear differential equations. To determine which method provides the most accurate assessment of circadian phase, we compared the ability to fit the data and the variability of phase estimates for seventeen different markers of melatonin phase derived from these methodological categories. We used data from three experimental conditions under which circadian rhythms - and therefore calculated melatonin phase - were expected to remain constant or progress uniformly. Melatonin profiles from older subjects and subjects with lower melatonin amplitude were less likely to be fit by all analysis methods. When circadian drift over multiple study days was algebraically removed, there were no significant differences between analysis methods of melatonin onsets (P = 0.57), but there were significant differences between those of melatonin offsets (P<0.0001). For a subset of phase assessment methods, we also examined the effects of data loss on variability of phase estimates by systematically removing data in 2-hour segments. Data loss near onset of melatonin secretion differentially affected phase estimates from the methods, with some methods incorrectly assigning phases too early while other methods assigning phases too late; missing data at other times did not affect analyses of the melatonin profile. We conclude that melatonin data set characteristics, including amplitude and completeness of data collection, differentially affect the results depending on the melatonin analysis method used

Levels and Correlates of Non-Adherence to WHO Recommended Inter-Birth Intervals in Rufiji, Tanzania.

Poorly spaced pregnancies have been documented worldwide to result in adverse maternal and child health outcomes. The World Health Organization (WHO) recommends a minimum inter-birth interval of 33 months between two consecutive live births in order to reduce the risk of adverse maternal and child health outcomes. However, birth spacing practices in many developing countries, including Tanzania, remain scantly addressed. METHODS: Longitudinal data collected in the Rufiji Health and Demographic Surveillance System (HDSS) from January 1999 to December 2010 were analyzed to investigate birth spacing practices among women of childbearing age. The outcome variable, non-adherence to the minimum inter-birth interval, constituted all inter-birth intervals <33 months long. Inter-birth intervals >=33 months long were considered to be adherent to the recommendation. Chi-Square was used as a test of association between non-adherence and each of the explanatory variables. Factors affecting non-adherence were identified using a multilevel logistic model. Data analysis was conducted using STATA (11) statistical software. RESULTS: A total of 15,373 inter-birth intervals were recorded from 8,980 women aged 15--49 years in Rufiji district over the follow-up period of 11 years. The median inter-birth interval was 33.4 months. Of the 15,373 inter-birth intervals, 48.4% were below the WHO recommended minimum length of 33 months between two live births. Non-adherence was associated with younger maternal age, low maternal education, multiple births of the preceding pregnancy, non-health facility delivery of the preceding birth, being an in-migrant resident, multi-parity and being married. CONCLUSION: Generally, one in every two inter-birth intervals among 15--49 year-old women in Rufiji district is poorly spaced, with significant variations by socio-demographic and behavioral characteristics of mothers and newborns. Maternal, newborn and child health services should be improved with a special emphasis on community- and health facility-based optimum birth spacing education in order to enhance health outcomes of mothers and their babies, especially in rural settings

Death ideation in cancer patients: contributing factors

Advances in cancer research and therapy have improved prognosis and the quality of life of many patients. However, previous epidemiological studies in oncologic patients have shown an increased risk of suicide. Suicidal thoughts, relatively well known in those terminally ill, may be just as important for cancer patients who are survivors or are living with the disease. Nonetheless, there is a relative paucity of data about suicidality in this setting. The authors conducted a prospective observational study to identify death thoughts and to explore the factors associated with suicidal ideation in cancer patients. A sample of 130 patients referred for psychiatric consultation was obtained following informed consent and authorization from the local ethics committee. A semistructured interview assessed sociodemographic data, psychosocial support, and information regarding the cancer process and its treatment. Psychometric instruments were used to evaluate psychopathology, namely the Hospital Anxiety and Depression Scale, the Beck Hopelessness Scale, and the Beck Scale for Suicide Ideation. Psychiatric diagnoses were obtained through the application of the Mini International Neuropsychiatric Interview. Death ideation was identified in 34.6% of patients, yet only 10% had active suicidal thoughts. Risk of suicide was associated with female gender, a psychiatric diagnosis (major depressive disorder, panic disorder, or dysthymia), difficult interpersonal relationships, associated pain, high hopelessness, and depressive and anxiety symptoms. Although suicidal thoughts are frequent in cancer patients at different stages of disease, most are transitory. Risk factors for suicidal ideation have been identified, such as depression, hopelessness, uncontrolled pain, and difficult interpersonal relationships. Further assessment is necessary to identify those at higher risk of attempting suicide, and underlying psychiatric disorders should be vigorously treated

The Mediating Role of Rumination in the Relation Between Quality of Attachment Relations and Depressive Symptoms in Non-Clinical Adolescents

This study examined associations between indices of the quality of attachment relationships of adolescents with parents and peers, rumination, and symptoms of depression. More specifically, a mediation model was investigated in which rumination was hypothesized to mediate the relation between quality of attachment relations and symptoms of depression. A total of 455 high school students completed a battery of questionnaires, including quality of attachment relations, rumination, and depression. Results showed that most indices of quality of attachment relations were significantly associated with rumination and symptoms of depression. When examining the relative contribution of these variables in explaining variance in depression symptoms, trust in parents, communication with peers, and alienation from peers accounted for a significant portion of the variance in depression scores. Finally, the relation between communication with peers and depressive symptoms was fully mediated by rumination, whereas partial mediation was found for the relations between parental trust and depressive symptoms, and between alienation from peers and depressive symptoms. Implications of the findings may be that the treatment of depression in adolescence should consist of both cognitive interventions aimed at targeting ruminative thinking as well as a focus on interpersonal relationships of the adolescent with parents and peers

Harmonics of Circadian Gene Transcription in Mammals

The circadian clock is a molecular and cellular oscillator found in most mammalian tissues that regulates rhythmic physiology and behavior. Numerous investigations have addressed the contribution of circadian rhythmicity to cellular, organ, and organismal physiology. We recently developed a method to look at transcriptional oscillations with unprecedented precision and accuracy using high-density time sampling. Here, we report a comparison of oscillating transcription from mouse liver, NIH3T3, and U2OS cells. Several surprising observations resulted from this study, including a 100-fold difference in the number of cycling transcripts in autonomous cellular models of the oscillator versus tissues harvested from intact mice. Strikingly, we found two clusters of genes that cycle at the second and third harmonic of circadian rhythmicity in liver, but not cultured cells. Validation experiments show that 12-hour oscillatory transcripts occur in several other peripheral tissues as well including heart, kidney, and lungs. These harmonics are lost ex vivo, as well as under restricted feeding conditions. Taken in sum, these studies illustrate the importance of time sampling with respect to multiple testing, suggest caution in use of autonomous cellular models to study clock output, and demonstrate the existence of harmonics of circadian gene expression in the mouse

Familial influences on the clinical characteristics of major depression: a twin study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66157/1/j.1600-0447.1992.tb03283.x.pd

Depression in Primary care: Interpersonal Counseling vs Selective serotonin reuptake inhibitors. The DEPICS Study. A multicenter randomized controlled trial. Rationale and design

<p>Abstract</p> <p>Background</p> <p>Depression is a frequently observed and disabling condition in primary care, mainly treated by Primary Care Physicians with antidepressant drugs. Psychological interventions are recommended as first-line treatment by the most authoritative international guidelines but few evidences are available on their efficacy and effectiveness for mild depression.</p> <p>Methods/Design</p> <p>This multi-center randomized controlled trial was conducted in 9 Italian centres with the aim to compare the efficacy of Inter-Personal Counseling, a brief structured psychological intervention, to that of Selective Serotonin Reuptake Inhibitors. Patients with depressive symptoms referred by Primary Care Physicians to psychiatric consultation-liaison services were eligible for the study if they met the DSM-IV criteria for major depression, had a score ≥13 on the 21-item Hamilton Depression Rating Scale, and were at their first or second depressive episode. The primary outcome was remission of depressive symptoms at 2-months, defined as a HDRS score ≤ 7. Secondary outcome measures were improvement in global functioning and recurrence of depressive symptoms at 12-months. Patients who did not respond to Inter-Personal Counseling or Selective Serotonin Reuptake Inhibitors at 2-months received augmentation with the other treatment.</p> <p>Discussion</p> <p>This trial addresses some of the shortcomings of existing trials targeting major depression in primary care by evaluating the comparative efficacy of a brief psychological intervention that could be easily disseminated, by including a sample of patients with mild/moderate depression and by using different outcome measures.</p> <p>Trial registration</p> <p>Australian New Zealand Clinical Trials Registry ACTRN12608000479303</p